Maternal inflammation during pregnancy and offspring brain development: the role of mitochondria

  • Lauren E. Gyllenhammer
    Affiliations
    Development, Health and Disease Research Program, University of California, School of Medicine, Irvine, CA, USA

    Department of Pediatrics, University of California, School of Medicine, Irvine, CA, USA
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  • Jerod M. Rasmussen
    Affiliations
    Development, Health and Disease Research Program, University of California, School of Medicine, Irvine, CA, USA

    Department of Pediatrics, University of California, School of Medicine, Irvine, CA, USA
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  • Nina Bertele
    Affiliations
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Medical Psychology
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  • Amy Halbing
    Affiliations
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Medical Psychology

    Charité – Universitätsmedizin Berlin, Einstein Center for Neurosciences Berlin, 10117, Berlin, Germany. corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Medical Psychology
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  • Sonja Entringer
    Affiliations
    Development, Health and Disease Research Program, University of California, School of Medicine, Irvine, CA, USA

    Department of Pediatrics, University of California, School of Medicine, Irvine, CA, USA

    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Medical Psychology
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  • Pathik D. Wadhwa
    Affiliations
    Development, Health and Disease Research Program, University of California, School of Medicine, Irvine, CA, USA

    Department of Pediatrics, University of California, School of Medicine, Irvine, CA, USA

    Department of Psychiatry and Human Behavior, University of California, School of Medicine, Irvine, CA, USA

    Department of Obstetrics and Gynecology, University of California, School of Medicine, Irvine, CA, USA

    Department of Epidemiology, University of California, School of Medicine, Irvine, CA, USA
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  • Claudia Buss
    Correspondence
    Corresponding Author: Claudia Buss Luisenstrasse 57 10117 Berlin, Germany +49 30 450 529 224,
    Affiliations
    Development, Health and Disease Research Program, University of California, School of Medicine, Irvine, CA, USA

    Department of Pediatrics, University of California, School of Medicine, Irvine, CA, USA

    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Medical Psychology
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Open AccessPublished:November 17, 2021DOI:https://doi.org/10.1016/j.bpsc.2021.11.003

      Abstract

      The association between maternal immune activation (MIA) during pregnancy and risk for offspring neuropsychiatric disorders has been increasingly recognized over the past several years. Among the mechanistic pathways that have been described through which maternal inflammation during pregnancy may affect fetal brain development, the role of mitochondria has received little attention. In the current review the role of mitochondria as a potential mediator of the association between MIA during pregnancy and offspring brain development and risk for psychiatric disorders will be proposed. As a basis for this postulation convergent evidence is presented supporting the obligatory role of mitochondria in brain development, the role of mitochondria as mediators and initiators of inflammatory processes, and evidence of mitochondrial dysfunction in pre-clinical MIA exposure models and human neurodevelopmental disorders. Elucidating the role of mitochondria as a potential mediator of MIA-induced alterations in brain development and neurodevelopmental disease risk may not only provide new insight into the pathophysiology of mental health disorders that have their origins in exposure to infection/immune activation during pregnancy but may also offer new therapeutic targets.

      Key words

      1. Introduction: MIA, mitochondria and brain development

      Maternal immune activation (MIA) during pregnancy constitutes a well-established risk factor for offspring neuropsychiatric disorders. A convergent body of epidemiological, preclinical, and prospective observational research supports the embryonic/fetal period of brain development as being particularly susceptible to disorganizing influences. Inflammatory mediators play a key role for both healthy as well as abnormal brain development during the intrauterine period of life, at which time the developing embryo/fetus responds to ‘suboptimal’ conditions by producing structural and functional changes in cells, tissues and systems that modulate susceptibility for many complex common disorders (i.e., the concept of fetal, or developmental, programming of health and disease risk). Several mechanistic pathways have been described through which maternal inflammation during pregnancy may affect fetal brain development either via direct mechanisms of action like pro-inflammatory cytokine-induced intracellular signaling pathways (
      • Jonakait G.M.
      The effects of maternal inflammation on neuronal development: possible mechanisms.
      ) or indirectly via effects such as priming microglial functioning (
      • Knuesel I.
      • Chicha L.
      • Britschgi M.
      • Schobel S.A.
      • Bodmer M.
      • Hellings J.A.
      • et al.
      Maternal immune activation and abnormal brain development across CNS disorders.
      ). Mitochondria, which are sensitive to immune alterations, are fundamentally important to many of these processes and others, and thus may mediate some of the inflammatory-related influences on brain development. Furthermore, there is a large body of clinical epidemiological studies that demonstrate the presence of mitochondrial dysfunction in the context of neurodevelopmental disorders, for which maternal infection/immune activation during pregnancy is an established risk factor (see section 3.3 for more details). However, the specific importance of mitochondria in the association between MIA during pregnancy and offspring neurodevelopment has received little attention to date. In this review, we first discuss plasticity of the developing brain and the mitochondrial biology system during fetal life and describe the specific role mitochondria play in all aspects of brain development. We then review literature in support of maternal inflammation during pregnancy altering mitochondrial biology and of mitochondrial biology acting as a potential mediator of the association between MIA during pregnancy and altered offspring brain development and risk for psychiatric disorders. While the evidence in the current review for supporting mitochondrial dysfunction as a mediator of the association between MIA and offspring risk for neurodevelopmental disorders stems from preclinical models inducing MIA by acute infections, we note that mitochondrial dysfunction likely also plays an important role in the association between offspring neurodevelopmental disorders and chronic maternal inflammation during pregnancy, which is common in the context of highly prevalent maternal conditions/circumstance like obesity, stress, as well as exposure to environmental toxins (
      • Bilbo S.D.
      • Block C.L.
      • Bolton J.L.
      • Hanamsagar R.
      • Tran P.K.
      Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders.
      ).We conclude by articulating current knowledge gaps and future research directions.

      2. The developing brain: role of mitochondria

      Before we discuss how MIA may affect brain development via mitochondrial function (in section 3), in this section we first provide a basic overview of fundamental brain developmental processes and of key aspects of mitochondrial structure and function and then describe the role of mitochondrial function in brain development.

      2.1 Overview of human brain development

      Comprehensive in-depth descriptions of embryonic and fetal brain development have been provided elsewhere (
      • Stiles J.
      • Jernigan T.L.
      The basics of brain development.
      ,
      • Silbereis J.C.
      • Pochareddy S.
      • Zhu Y.
      • Li M.
      • Sestan N.
      The Cellular and Molecular Landscapes of the Developing Human Central Nervous System.
      )(ref (
      • Meng H.
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      • Feng L.
      • Teng G.
      • et al.
      Development of the subcortical brain structures in the second trimester: assessment with 7.0-T MRI.
      ) for subcortical development) and are beyond the scope of the current paper, but an overview of the temporal sequence of critical developmental steps is provided here and discussed further in section 2.3. Developmental neurogenesis is the critical process by which neural stem cells (NSCs) differentiate into the distinct cell types that constitute a functioning neural circuitry. This process starts with NSCs in the neural tube expanding their pool via symmetrical division. NSC division then becomes asymmetric, allowing for the generation of a copy of the original NSC and a neural progenitor cell (NPC), that will primarily differentiate into a neuron, or into a glia cell (astrocyte, microglia, or oligodendrocyte) (
      • McConnell S.K.
      Constructing the cerebral cortex: neurogenesis and fate determination.
      ,
      • Paridaen J.T.
      • Huttner W.B.
      Neurogenesis during development of the vertebrate central nervous system.
      ,
      • Rao M.S.
      • Mayer-Proschel M.
      Glial-restricted precursors are derived from multipotent neuroepithelial stem cells.
      ). While NSCs continue to divide within the ventricular zone, NPCs begin a process of migration in the formation of the cortex (
      • Stiles J.
      • Jernigan T.L.
      The basics of brain development.
      ). The first cells arriving in the cortical plate will form layer VI while later-born cells form progressively more superficial layers (
      • Kriegstein A.R.
      • Noctor S.C.
      Patterns of neuronal migration in the embryonic cortex.
      ,

      ten Donkelaar HJ, Yamada S, Shiota K, and van der Vliet T (2014): Overview of the Development of the Human Brain and Spinal Cord, in Clinical Neuroembryology: Development and Developmental Disorders of the Human Central Nervous System. Springer Berlin Heidelberg: Berlin, Heidelberg. pp 1-52.

      ). After migrating to their final destination, neurons begin to form synaptic connections within the developing brain with rapid acceleration in the third trimester (
      • Bourgeois J.P.
      Synaptogenesis, heterochrony and epigenesis in the mammalian neocortex.
      ). Around mid-gestation, gliogenesis and the process of myelination begins, allowing for more efficient cell-to-cell communication (
      • Abraham H.
      • Vincze A.
      • Jewgenow I.
      • Veszpremi B.
      • Kravjak A.
      • Gomori E.
      • et al.
      Myelination in the human hippocampal formation from midgestation to adulthood.
      ). Ex-utero synaptogenesis, myelination, and pruning are dominant developmental processes in early postnatal life and perpetuate until at least early adulthood (
      • Stiles J.
      • Jernigan T.L.
      The basics of brain development.
      ).

      2.2 Overview of the mitochondrial biology system

      Mitochondria are multifunctional double-membrane organelles that regulate several fundamental cellular processes, including the production of over 90% of cellular energy. Through oxidative phosphorylation (OXPHOS), mitochondria oxidize the food we eat, with the air we breathe, to generate cellular energy in the form of ATP (adenosine triphosphate). Through OXPHOS, mitochondria shuttle electrons through the four respiratory complexes (Complex I-IV) of the electron transport chain to generate a proton gradient across the inner mitochondrial membrane (mitochondrial membrane potential (MMP)) that powers the production of ATP. Measurement of any of these collective steps, is referred to as mitochondrial bioenergetic function. Early embryonic and fetal development, especially of the brain, is an energy demanding process (
      • Kuzawa C.W.
      • Chugani H.T.
      • Grossman L.I.
      • Lipovich L.
      • Muzik O.
      • Hof P.R.
      • et al.
      Metabolic costs and evolutionary implications of human brain development.
      ), and thus, mitochondrial health and the capacity to meet the bioenergetic demands of the cell, place mitochondria central to this process of early development.
      Beyond this essential and well-established bioenergetic function, mitochondria are increasingly viewed as active regulators of signal transduction in numerous pathways (
      • Chandel N.S.
      Mitochondria as signaling organelles.
      ), serving an important role in cellular signaling, regulating cell proliferation, differentiation and apoptosis, primarily through the modulation of Ca2+ homeostasis, metabolite availability, cellular redox, and production of reactive oxygen species (ROS) (
      • Kasahara A.
      • Scorrano L.
      Mitochondria: from cell death executioners to regulators of cell differentiation.
      ,
      • D'Autreaux B.
      • Toledano M.B.
      ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis.
      ,
      • Aon M.A.
      • Cortassa S.
      • Juhaszova M.
      • Sollott S.J.
      Mitochondrial health, the epigenome and healthspan.
      ). While ROS at low levels is now considered a standard signaling molecule (
      • D'Autreaux B.
      • Toledano M.B.
      ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis.
      ,
      • Pourova J.
      • Kottova M.
      • Voprsalova M.
      • Pour M.
      Reactive oxygen and nitrogen species in normal physiological processes.
      ), when mitochondrial function is impaired, damaging elevations of ROS levels can occur (
      • Pitkanen S.
      • Robinson B.H.
      Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase.
      ), which places mitochondria at the center of cellular production and regulation of oxidative stress (
      • Hill B.G.
      • Benavides G.A.
      • Lancaster Jr., J.R.
      • Ballinger S.
      • Dell'Italia L.
      • Jianhua Z.
      • et al.
      Integration of cellular bioenergetics with mitochondrial quality control and autophagy.
      ,
      • Shokolenko I.
      • Venediktova N.
      • Bochkareva A.
      • Wilson G.L.
      • Alexeyev M.F.
      Oxidative stress induces degradation of mitochondrial DNA.
      ). Importantly, there is increasing understanding that these layered aspects of mitochondrial function and signaling regulate cell specification in early development, such that mitochondrial activity is a necessary requirement for differentiation in embryonic and neuronal stem cells (as will be discussed below) (
      • Mandal S.
      • Lindgren A.G.
      • Srivastava A.S.
      • Clark A.T.
      • Banerjee U.
      Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells.
      ,
      • Pereira S.L.
      • Graos M.
      • Rodrigues A.S.
      • Anjo S.I.
      • Carvalho R.A.
      • Oliveira P.J.
      • et al.
      Inhibition of mitochondrial complex III blocks neuronal differentiation and maintains embryonic stem cell pluripotency.
      ). Furthermore, mitochondria serve as a site of production for various metabolic substrates (
      • Papadopoulos V.
      • Miller W.L.
      Role of mitochondria in steroidogenesis.
      ,
      • Cheng Z.
      • Ristow M.
      Mitochondria and metabolic homeostasis.
      ,
      • Ahn C.S.
      • Metallo C.M.
      Mitochondria as biosynthetic factories for cancer proliferation.
      ) essential for rapid cellular proliferation during embryonic and fetal development.
      These many and multi-faceted aspects of mitochondrial function are closely tied to the dynamic form and structure of mitochondria, and to the spatial interaction of these organelles with each other and with other intracellular structures. The approximately 102 -103 mitochondria per cell form dynamic branched networks, and when two or more mitochondrion combine, this is known as fusion, whereas their separation is known as fission (
      • Frederick R.L.
      • Shaw J.M.
      Moving mitochondria: establishing distribution of an essential organelle.
      ,
      • Boldogh I.R.
      • Pon L.A.
      Mitochondria on the move.
      ). These opposing processes (i.e., fission/fusion dynamics) are carefully balanced, serving an important regulatory role in bioenergetic function (
      • Westermann B.
      Bioenergetic role of mitochondrial fusion and fission.
      ). Furthermore, mitochondrial fission can be used to isolate poorly functioning or damaged mitochondrial components for destruction (mitophagy), and this mitophagy is carefully balanced by the generation of new mitochondria (mitochondrial biogenesis) (
      • Hux V.J.
      • Roberts J.M.
      • Okun M.L.
      Allostatic load in early pregnancy is associated with poor sleep quality.
      ). Mitochondria maintain normal functions through such mitochondrial quality control measures (i.e., mitophagy/biogenesis), and this controlled regulation of mitochondrial content (or cellular density) is necessary to maintain mitochondrial health and to meet the energy demands of the cell. Appropriate mitochondrial density is not only critical at the cellular level, but the spatial distribution and subcellular density of mitochondria within the cell is critical too. The multiple mitochondria per cell are not evenly distributed and are recruited, for example, to energy or calcium demanding subcellular compartments, such as the presynaptic terminal in neurons (
      • Billups B.
      • Forsythe I.D.
      Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses.
      ). Perturbations in mitochondrial movement and recruitment to specific sites of the cell can lead to subcellular ATP depletion and interfere with the mitochondrial Ca2+ signaling particularly important for neuronal development (discussed further below).
      Mitochondria are maternally inherited bacterial endosymbionts, that accordingly, contain their own genome (i.e., mtDNA) that is unique from nuclear DNA (
      • Lane N.
      Serial endosymbiosis or singular event at the origin of eukaryotes?.
      ). The health (i.e., quantity and quality) of mtDNA is critical to success in the earliest stages of development, as levels of mtDNA and ATP production are tied to rates of fertilization and implantation (
      • Van Blerkom J.
      • Davis P.W.
      • Lee J.
      ATP content of human oocytes and developmental potential and outcome after in-vitro fertilization and embryo transfer.
      ,
      • Santos T.A.
      • El Shourbagy S.
      • St John J.C.
      Mitochondrial content reflects oocyte variability and fertilization outcome.
      ), as well as placental and fetal growth (
      • Wakefield S.L.
      • Lane M.
      • Mitchell M.
      Impaired mitochondrial function in the preimplantation embryo perturbs fetal and placental development in the mouse.
      ). mtDNA does not contain histones or telomeres and is located in close proximity to the OXPHOS machinery that produce ROS. As a result mtDNA is more susceptible than nuclear DNA to damage (
      • Yakes F.M.
      • Van Houten B.
      Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress.
      ,
      • Furda A.
      • Santos J.H.
      • Meyer J.N.
      • Van Houten B.
      Quantitative PCR-based measurement of nuclear and mitochondrial DNA damage and repair in mammalian cells.
      ,
      • Van Houten B.
      • Woshner V.
      • Santos J.H.
      Role of mitochondrial DNA in toxic responses to oxidative stress.
      ), and demonstrates a higher intrinsic mutation rate (
      • Sato A.
      • Endo H.
      • Umetsu K.
      • Sone H.
      • Yanagisawa Y.
      • Saigusa A.
      • et al.
      Polymorphism, heteroplasmy, mitochondrial fusion and diabetes.
      ). Notably, the mtDNA in oxygen demanding tissues, such as the brain, demonstrate even higher levels of mtDNA damage, of which the immature/developing brain is particularly susceptible, due to its poorly developed scavenging systems and high availability of iron for the catalytic formation of free radicals (
      • Blomgren K.
      • Hagberg H.
      Free radicals, mitochondria, and hypoxia-ischemia in the developing brain.
      ). The accumulation of mtDNA defects impairs mitochondrial bioenergetic function, and such changes are generally stable and amplified over time (
      • Picard M.
      • Vincent A.E.
      • Turnbull D.M.
      Expanding Our Understanding of mtDNA Deletions.
      ). Thus, prenatal exposures that impact mtDNA quality (e.g., deletion and mutation) provides a plausible mechanism by which phenotypes of mitochondrial dysfunction may persist over time and confer long term effects on health and disease risk.
      We have recently reviewed the evidence to support the developmental plasticity of mitochondrial biology (
      • Gyllenhammer L.E.
      • Entringer S.
      • Buss C.
      • Wadhwa P.D.
      Developmental programming of mitochondrial biology: a conceptual framework and review.
      ), and herein argue that because mitochondria play a fundamental role in all aspects of cellular function in early development, any perturbation to the system, for example, in the context of MIA, will have long-term downstream effects. Thus, in addition to MIA-induced alterations in mitochondrial function during critical processes of brain development having long lasting consequences on its integrity (as reviewed below) programmed alterations in mitochondrial function by prenatal environmental conditions, like inflammation, have the potential to affect functioning of the brain and disease susceptibility across the lifespan (Figure 1).
      Figure thumbnail gr1
      Figure 1Conceptual Figure Legend: Note. ROS=Reactive Oxygen Species, mtDNA=mitochondrial DNA. Maternal immune activation (MIA) can alter aspects of offspring mitochondrial structure and function including mitochondrial biogenesis/mitophagy, oxidative stress/ROS production, bioenergetic function, fission/fusion dynamics, and mtDNA quality. Mitochondrial biogenesis and mitophagy refer to the coordinated control of mitochondrial content, either through the generation of new mitochondria (mitochondrial biogenesis) or the controlled destruction/regulated turnover of mitochondria (mitophagy). Mitochondrial oxidative stress/ROS production refer to an imbalance between free radical production (mitochondrial derived) and antioxidant control of these species, which may result in damaged proteins, lipids, DNA, etc. Bioenergetic function refers to mitochondrial capacity to meet the energetic needs (e.g., ATP) of the cell or subcellular compartment. Mitochondria organelles form a dynamic reticulated network, and the subsections of this network can separate from and fuse with each other, referred to as fission/fusion dynamics. Specifically, fusion involves the tethering of two adjacent mitochondria followed by merging, of the inner and outer mitochondrial membranes, whereas fission is the opposing process of fragmentation of a mitochondrial network into two or more mitochondria. Finally, mtDNA quality refers to the level and phenotypic impact (burden) of mtDNA mutations and deletions within an individual mitochondrion or across mitochondria in a cell or tissue. As all of these aspects of mitochondrial function are crucially involved in neurodevelopmental processes, these MIA-induced alterations can affect neurodevelopment at different stages. Moreover, alterations in mitochondrial structure/function due to MIA may be programmed and, hence, can persist over the life span. Thus, in addition to the effects of MIA-induced alterations in mitochondrial function on the developing brain, these mitochondrial alterations may continue to exert long-term effects on the brain (and other systems) over the lifespan of the individual. Adapted from Nutton et al. 2011, created with BioRender.com.

      2.3 Obligatory role for mitochondrial function in brain development

      2.3.1 In neurogenesis

      Stem cells possess the dual capacity to either self-renew or commit to a specific cell type via differentiation and proliferation. Increasingly, mitochondrial bioenergetic function and fission/fusion dynamics are being recognized as essential regulators of each of these processes. With respect to stem cell renewal capacity, the crucial role of fission/fusion dynamics has been demonstrated via manipulation of fission (mitofusin-1 & -2 (MFN1/2)) and fusion proteins (dynamin-related protein 1(DRP1)) in uncommitted mouse cells (
      • Khacho M.
      • Clark A.
      • Svoboda D.S.
      • Azzi J.
      • MacLaurin J.G.
      • Meghaizel C.
      • et al.
      Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program.
      ). Specifically, loss of MFN1/2 resulted in a drastic inability to form neurospheres, while DRP1 increased neurosphere yield (
      • Khacho M.
      • Clark A.
      • Svoboda D.S.
      • Azzi J.
      • MacLaurin J.G.
      • Meghaizel C.
      • et al.
      Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program.
      ). Furthermore, loss of the fusion protein (optic atrophy 1 (OPA1)) resulted in decreased primary and secondary neurospheres (
      • Khacho M.
      • Clark A.
      • Svoboda D.S.
      • Azzi J.
      • MacLaurin J.G.
      • Meghaizel C.
      • et al.
      Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program.
      ).
      Both mitochondrial biogenesis and bioenergetics regulate fate decisions of NPCs to either proliferation or differentiation. Differentiated NSCs are characterized by low mitochondrial and mtDNA content, and the switch from glycolytic metabolism to mitochondrial OXPHOS, controls the shift from NSC proliferation to NSC differentiation into NPCs and subsequent cell types(45-48). Preclinical murine studies demonstrate that mitochondrial bioenergetics are necessary for NPC differentiation and proliferation. Specifically, a one-day treatment of rotenone, a mitochondrial Complex I inhibitor, on cell cultures derived from mouse pups (postnatal day 5) can reduce NPC proliferation and differentiation, while a long-term rotenone treatment fully inhibits NPC proliferation and differentiation (
      • Park K.-Y.
      • Kim Man S.
      Inhibition of Proliferation and Neurogenesis of Mouse Subventricular Zone Neural Stem Cells by a Mitochondrial Inhibitor Rotenone.
      ,
      • Park K.-Y.
      • Kim Man S.
      Effects of Transient Treatment with Rotenone, a Mitochondrial Inhibitor, on Mouse Subventricular Zone Neural Stem Cells.
      ). Moreover, genetically induced mitochondrial dysfunction (i.e., by ablating mitochondrial Complex II gene), leads to impaired differentiation of glia-like central NSCs into neurons and oligodendrocytes (but not into astrocytes), leading to brain atrophy and early death (
      • Diaz-Castro B.
      • Pardal R.
      • Garcia-Flores P.
      • Sobrino V.
      • Duran R.
      • Piruat J.I.
      • et al.
      Resistance of glia-like central and peripheral neural stem cells to genetically induced mitochondrial dysfunction--differential effects on neurogenesis.
      ).
      Besides the described metabolic changes in the scope of neurogenesis, mitochondria also change their morphology and dynamics depending on the state of the developing cell(52, 53). While the mitochondrion appears rather simple in mouse NSCs (i.e., round containing little cristae), during differentiation, it becomes a complex tubular network of elongated cristae-rich mitochondria with a dense matrix (
      • Bukowiecki R.
      • Adjaye J.
      • Prigione A.
      Mitochondrial function in pluripotent stem cells and cellular reprogramming.
      ,
      • Folmes C.D.
      • Nelson T.J.
      • Martinez-Fernandez A.
      • Arrell D.K.
      • Lindor J.Z.
      • Dzeja P.P.
      • et al.
      Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming.
      ,
      • Mils V.
      • Bosch S.
      • Roy J.
      • Bel-Vialar S.
      • Belenguer P.
      • Pituello F.
      • et al.
      Mitochondrial reshaping accompanies neural differentiation in the developing spinal cord.
      ,
      • Prieto J.
      • Leon M.
      • Ponsoda X.
      • Garcia-Garcia F.
      • Bort R.
      • Serna E.
      • et al.
      Dysfunctional mitochondrial fission impairs cell reprogramming.
      ,
      • Prieto J.
      • Leon M.
      • Ponsoda X.
      • Sendra R.
      • Bort R.
      • Ferrer-Lorente R.
      • et al.
      Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming.
      ). Empirical studies in this context point to the pivotal role of the mitochondrial fission protein DRP1 in mitochondrial dynamics during neurogenesis. More specifically, while a knock-down of DRP1 was found to lead to an impairment of mitochondrial fission promoting NSC differentiation in human pluripotent stem cells, an overexpression of active DRP1 mutant was found to enhance pluripotency (
      • Son G.
      • Han J.
      Roles of mitochondria in neuronal development.
      ,
      • Hoque A.
      • Sivakumaran P.
      • Bond S.T.
      • Ling N.X.Y.
      • Kong A.M.
      • Scott J.W.
      • et al.
      Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells.
      ).
      Neuronal migration, a highly energetic process, is also critically dependent on mitochondrial dynamics and bioenergetics. For example, the genetic disruption of OXPHOS in mice, lacking ANT1 (adenine nucleotide transferase 1), a protein encoding an inner mitochondrial membrane protein that transports ADP (adenosine diphosphate) into mitochondria and ATP from mitochondria to the cytosol, has been related to alterations of interneuron migration. These data suggest that interneuron polarity during migration is particularly sensitive to disruptions in mitochondrial bioenergetics, and that OXPHOS is required for normal migration of interneurons from the basal forebrain to the neocortex (
      • Lin-Hendel E.G.
      • McManus M.J.
      • Wallace D.C.
      • Anderson S.A.
      • Golden J.A.
      Differential Mitochondrial Requirements for Radially and Non-radially Migrating Cortical Neurons: Implications for Mitochondrial Disorders.
      ). Other mouse models show that, under basal conditions, autophagy levels are correlated with the bioenergetic requirements of cells and that decreases in ATP/ADP levels – due to abnormalities in OXPHOS – during the migratory phase lead to the entry of cells into the stationary phase and to the induction of autophagy (
      • Bressan C.
      • Pecora A.
      • Gagnon D.
      • Snapyan M.
      • Labrecque S.
      • De Koninck P.
      • et al.
      The dynamic interplay between ATP/ADP levels and autophagy sustain neuronal migration in vivo.
      ). Hence, these findings point to the critical contribution of the integrity of OXPHOS to the dynamic regulation of the pace and periodicity of neuronal migration.

      2.3.2 In glial cell development

      In the process of gliogenesis, NSCs differentiate into non-neuronal glial cell-types including astrocytes, oligodendrocytes, and microglia. With respect to astrocytes during development, mitochondria play a role in regulating astrocyte maturation and subsequent synapse formation (
      • Zehnder T.
      • Petrelli F.
      • Romanos J.
      • De Oliveira Figueiredo E.C.
      • Lewis Jr., T.L.
      • Deglon N.
      • et al.
      Mitochondrial biogenesis in developing astrocytes regulates astrocyte maturation and synapse formation.
      ). Specifically, recent evidence has demonstrated that conditional deletion of the metabolic regulator PGC-1α (peroxisome proliferator-activated receptor gamma co-activator 1α) controls the mitochondrial biogenesis in developing astrocytes, and compromises the proliferation and maturation of astrocytes with a subsequent effect on the number and function of excitatory synapses in mice (
      • Zehnder T.
      • Petrelli F.
      • Romanos J.
      • De Oliveira Figueiredo E.C.
      • Lewis Jr., T.L.
      • Deglon N.
      • et al.
      Mitochondrial biogenesis in developing astrocytes regulates astrocyte maturation and synapse formation.
      ).
      The importance of mitochondrial functioning in the context of oligodendrocyte development is evident from studies using developing human oligodendroglial cells differentially exposed to rotenone, inhibiting bioenergetic function (
      • Schoenfeld R.
      • Wong A.
      • Silva J.
      • Li M.
      • Itoh A.
      • Horiuchi M.
      • et al.
      Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation.
      ). Specifically, in vitro, differentiated oligodendroglial cells have been observed to be uniquely sensitive (e.g., viability and ATP synthesis) to rotenone exposure relative to undifferentiated cells (
      • Schoenfeld R.
      • Wong A.
      • Silva J.
      • Li M.
      • Itoh A.
      • Horiuchi M.
      • et al.
      Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation.
      ), thus demonstrating the fundamental importance of mitochondrial function in oligodendrocyte development. Because oligodendrocytes are the myelinating cells of the central nervous system, their health is of consequence to myelination in humans both perinatally (
      • Tolcos M.
      • Petratos S.
      • Hirst J.J.
      • Wong F.
      • Spencer S.J.
      • Azhan A.
      • et al.
      Blocked, delayed, or obstructed: What causes poor white matter development in intrauterine growth restricted infants?.
      ) and well into at least late childhood (
      • Baumann N.
      • Pham-Dinh D.
      Biology of oligodendrocyte and myelin in the mammalian central nervous system.
      ,
      • Miller D.J.
      • Duka T.
      • Stimpson C.D.
      • Schapiro S.J.
      • Baze W.B.
      • McArthur M.J.
      • et al.
      Prolonged myelination in human neocortical evolution.
      ) with long-term effects for efficiency of neural signal transduction.
      Yolk-sac derived microglia enter the developing brain primarily before the formation of the blood-brain barrier. After migration into the brain in this early gestational period, they are believed to self-sustain through adulthood where they form the basis of the immune response in the central nervous system (
      • Tan Y.L.
      • Yuan Y.
      • Tian L.
      Microglial regional heterogeneity and its role in the brain.
      ). While the specific role for mitochondria in the proliferation and migration of microglial cells is not yet entirely clear, xenographic transfer of hamster mitochondria into embryonic ischemic cortical rat neurons has been shown to transiently increase the proliferation of microglia (
      • Huang P.J.
      • Kuo C.C.
      • Lee H.C.
      • Shen C.I.
      • Cheng F.C.
      • Wu S.F.
      • et al.
      Transferring Xenogenic Mitochondria Provides Neural Protection Against Ischemic Stress in Ischemic Rat Brains.
      ).

      2.3.3 In the development of the blood-brain barrier (BBB)

      The BBB is a semipermeable border composed of endothelial cells restricting solutes from entry into the extracellular space surrounding the central nervous system. The integrity of the BBB can be indirectly tied to mitochondria as microglia and astrocytes (discussed above) underlie its formation (
      • Saili K.S.
      • Zurlinden T.J.
      • Schwab A.J.
      • Silvin A.
      • Baker N.C.
      • Hunter 3rd, E.S.
      • et al.
      Blood-brain barrier development: Systems modeling and predictive toxicology.
      ). Further evidence supports the direct relevance of mitochondria to the BBB. Specifically in preclinical models, endothelial cells found within the BBB are enriched for mitochondria, containing twice the mitochondrial content relative to endothelial cells in other tissues (
      • Oldendorf W.H.
      • Cornford M.E.
      • Brown W.J.
      The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat.
      ), and recent experimental evidence in mature rodents supports a causal role of impaired mitochondrial function in the degradation of the BBB integrity (
      • Doll D.N.
      • Hu H.
      • Sun J.
      • Lewis S.E.
      • Simpkins J.W.
      • Ren X.
      Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier.
      ).

      2.3.4 In axonal development

      The development of axonal projections that originate in the cell body and extend to target neurons is essential to the formation of circuits underlying human behavior (
      • Ye X.
      • Qiu Y.
      • Gao Y.
      • Wan D.
      • Zhu H.
      A Subtle Network Mediating Axon Guidance: Intrinsic Dynamic Structure of Growth Cone, Attractive and Repulsive Molecular Cues, and the Intermediate Role of Signaling Pathways.
      ). Axonal growth is a highly energetic and mitochondrial-dependent process as evidenced by the spatiotemporal distribution of mitochondria during extension. For example, in actively growing chick and rodent axons, there is a marked increase in subcellular mitochondrial density in the far distal regions adjacent to the growth cone (
      • Morris R.L.
      • Hollenbeck P.J.
      The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth.
      ), with additional clusters found in branch points (
      • Dedov V.N.
      • Armati P.J.
      • Roufogalis B.D.
      Three-dimensional organisation of mitochondrial clusters in regenerating dorsal root ganglion (DRG) neurons from neonatal rats: evidence for mobile mitochondrial pools.
      ). Further, when axonal reorganization occurs (e.g., in the case of physical restriction or destruction) via depolymerization of the actin filaments, mitochondrial distribution changes in response by favoring more proximally growing axons that represent better candidates for eventual connection to target neurons. This energetic prioritization has been further demonstrated via alternating branch growth in rat hippocampal neurons where mitochondrial transport into newly formed axons occurs after the nascent axon has elongated past the length of other minor processes extending out from the cell body (
      • Ruthel G.
      • Hollenbeck P.J.
      Response of mitochondrial traffic to axon determination and differential branch growth.
      ).
      In addition to singular neuron to neuron connections, the functional mapping between neuronal networks is further facilitated by axonal branching, where collateral branches extend out from the singular axon to form a dense network of terminal arbors (
      • Kalil K.
      • Dent E.W.
      Branch management: mechanisms of axon branching in the developing vertebrate CNS.
      ) with multiple endpoint targets. Several recent studies have highlighted the critical role mitochondria play in the branching process. For example, branching sites are largely dependent on the density, positioning, and functioning of stalled mitochondria (i.e., those exhibiting neither anterograde or retrograde transport) along the axon. Specifically, it has been demonstrated that the mitochondria-associated microtubule binding protein syntaphilin is necessary for axonal branching in mouse models, suggesting a direct link between mitochondria immobilization, mitochondrial spatiotemporal density and branch formation (
      • Courchet J.
      • Lewis Jr., T.L.
      • Lee S.
      • Courchet V.
      • Liou D.Y.
      • Aizawa S.
      • et al.
      Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture.
      ). Collectively, this then supports the fundamental importance of mitochondria in providing sufficient ATP for axonal growth, and further, because redistribution of resources is only necessary in the case of limitation, it suggests that axonal extension and branching may be a rate limited process susceptible to mitochondrial dysfunction. For a more complete review of the role of mitochondria in axonal development, please see Smith et al. (
      • Smith G.M.
      • Gallo G.
      The role of mitochondria in axon development and regeneration.
      ).

      2.3.5 In synaptogenesis

      Following the processes of neural proliferation, differentiation, migration, and finally axonal formation, synapses are assembled for establishing interneuronal communication (synaptogenesis) (
      • Tau G.Z.
      • Peterson B.S.
      Normal development of brain circuits.
      ). It stands to reason, then, that because processes upstream of synapse formation are mitochondria dependent (see above sections), synaptogenesis is indirectly mitochondria-dependent. In addition to this indirect role, there is evidence of a specific direct role for mitochondria in the formation of synaptic connections. In one study of embryonic (day18) rodent hippocampal neurons manipulated using dynamin-like GTPases (DRP1 and OPA1) to reduce dendritic mitochondria content, Li et al. (2004) conclude that mitochondria are an essential and limiting factor for synaptogenesis based on observed correlations between the intra-neuronal spatial distribution of mitochondria and synapse plasticity (
      • Li Z.
      • Okamoto K.
      • Hayashi Y.
      • Sheng M.
      The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses.
      ). Furthermore, Stavsky et al. (2021) observed that when deleting NCLX (the mitochondrial sodium calcium lithium exchanger (
      • Boyman L.
      • Williams G.S.
      • Khananshvili D.
      • Sekler I.
      • Lederer W.J.
      NCLX: the mitochondrial sodium calcium exchanger.
      )) in mice and culturing hippocampal neurons from newborn pups (postnatal day 0-2), neuronal mitochondria demonstrated basal calcium overload, membrane depolarization, and reduced calcium influx and efflux (
      • Stavsky A.
      • Stoler O.
      • Kostic M.
      • Katoshevsky T.
      • Assali E.A.
      • Savic I.
      • et al.
      Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation.
      ). In addition, the authors observed reduced calcium transients in the presynaptic terminals that led to a lower probability of neurotransmitter release and weaker synaptic transmission (
      • Stavsky A.
      • Stoler O.
      • Kostic M.
      • Katoshevsky T.
      • Assali E.A.
      • Savic I.
      • et al.
      Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation.
      ). Finally, a model of growth retardation involving placental mass reduction has been shown to decrease the density of synapses and increase subcellular mitochondrial density in the visual cortex of offspring fetal sheep (gestation day 140) (
      • Bisignano M.
      • Rees S.
      The effects of intrauterine growth retardation on synaptogenesis and mitochondrial formation in the cerebral and cerebellar cortices of fetal sheep.
      ). The authors posit that the observed increase in mitochondrial density (e.g., increased aerobic efficiency) is a compensation mechanism to counteract reductions in synaptogenesis (
      • Bisignano M.
      • Rees S.
      The effects of intrauterine growth retardation on synaptogenesis and mitochondrial formation in the cerebral and cerebellar cortices of fetal sheep.
      ), thus suggesting a rate limited role of mitochondria in the formation of synapses.

      3. Inflammation and mitochondrial function: focus on the intrauterine period

      As reviewed above, virtually all aspects of brain development are ultimately mitochondria-dependent. To support the premise that mitochondria mediate aspects of MIA-induced effects on the developing brain, the following section provides evidence of altered offspring mitochondrial structure and function in the context of MIA.

      3.1 Immune mediators and mitochondrial function

      A growing body of research suggests that mitochondria act as central hubs in the regulation of innate immunity and inflammatory responses (
      • Mohanty A.
      • Tiwari-Pandey R.
      • Pandey N.R.
      Mitochondria: the indispensable players in innate immunity and guardians of the inflammatory response.
      ), and are thus acutely sensitive to inflammatory processes. For example, in vitro exposure to inflammatory molecules has been linked to overall cellular reductions in mitochondrial bioenergetics (
      • Nair S.
      • Sobotka K.S.
      • Joshi P.
      • Gressens P.
      • Fleiss B.
      • Thornton C.
      • et al.
      Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo.
      ,
      • Voloboueva L.A.
      • Emery J.F.
      • Sun X.
      • Giffard R.G.
      Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin.
      ,
      • Park J.
      • Min J.S.
      • Kim B.
      • Chae U.B.
      • Yun J.W.
      • Choi M.S.
      • et al.
      Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways.
      ,
      • Zell R.
      • Geck P.
      • Werdan K.
      • Boekstegers P.
      TNF-alpha and IL-1 alpha inhibit both pyruvate dehydrogenase activity and mitochondrial function in cardiomyocytes: evidence for primary impairment of mitochondrial function.
      ,
      • Doll D.N.
      • Rellick S.L.
      • Barr T.L.
      • Ren X.
      • Simpkins J.W.
      Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity.
      ,
      • Haileselassie B.
      • Joshi A.U.
      • Minhas P.S.
      • Mukherjee R.
      • Andreasson K.I.
      • Mochly-Rosen D.
      Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy.
      ), increased intracellular ROS (
      • Park J.
      • Min J.S.
      • Kim B.
      • Chae U.B.
      • Yun J.W.
      • Choi M.S.
      • et al.
      Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways.
      ,
      • Chen X.H.
      • Zhao Y.P.
      • Xue M.
      • Ji C.B.
      • Gao C.L.
      • Zhu J.G.
      • et al.
      TNF-alpha induces mitochondrial dysfunction in 3T3-L1 adipocytes.
      ,
      • Ji C.
      • Chen X.
      • Gao C.
      • Jiao L.
      • Wang J.
      • Xu G.
      • et al.
      IL-6 induces lipolysis and mitochondrial dysfunction, but does not affect insulin-mediated glucose transport in 3T3-L1 adipocytes.
      ), increased mitochondrial fragmentation/fission (
      • Gao F.
      • Reynolds M.B.
      • Passalacqua K.D.
      • Sexton J.Z.
      • Abuaita B.H.
      • O'Riordan M.X.D.
      The Mitochondrial Fission Regulator DRP1 Controls Post-Transcriptional Regulation of TNF-alpha.
      ,
      • Yu W.
      • Wang X.
      • Zhao J.
      • Liu R.
      • Liu J.
      • Wang Z.
      • et al.
      Stat2-Drp1 mediated mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages.
      ), and decreases in mtDNA content (
      • Suematsu N.
      • Tsutsui H.
      • Wen J.
      • Kang D.
      • Ikeuchi M.
      • Ide T.
      • et al.
      Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes.
      ,
      • Vadrot N.
      • Ghanem S.
      • Braut F.
      • Gavrilescu L.
      • Pilard N.
      • Mansouri A.
      • et al.
      Mitochondrial DNA maintenance is regulated in human hepatoma cells by glycogen synthase kinase 3beta and p53 in response to tumor necrosis factor alpha.
      ). These inflammation-induced changes in mitochondria have been observed in vitro in neural and glial cells (
      • Nair S.
      • Sobotka K.S.
      • Joshi P.
      • Gressens P.
      • Fleiss B.
      • Thornton C.
      • et al.
      Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo.
      ,
      • Voloboueva L.A.
      • Emery J.F.
      • Sun X.
      • Giffard R.G.
      Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin.
      ,
      • Park J.
      • Min J.S.
      • Kim B.
      • Chae U.B.
      • Yun J.W.
      • Choi M.S.
      • et al.
      Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways.
      ,
      • Doll D.N.
      • Rellick S.L.
      • Barr T.L.
      • Ren X.
      • Simpkins J.W.
      Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity.
      ,
      • Haileselassie B.
      • Joshi A.U.
      • Minhas P.S.
      • Mukherjee R.
      • Andreasson K.I.
      • Mochly-Rosen D.
      Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy.
      ,
      • Katoh M.
      • Wu B.
      • Nguyen H.B.
      • Thai T.Q.
      • Yamasaki R.
      • Lu H.
      • et al.
      Polymorphic regulation of mitochondrial fission and fusion modifies phenotypes of microglia in neuroinflammation.
      ), and through in vivo injection of the endotoxin lipopolysaccahride directly into the brain compartment (
      • Hunter R.L.
      • Dragicevic N.
      • Seifert K.
      • Choi D.Y.
      • Liu M.
      • Kim H.C.
      • et al.
      Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system.
      ). In addition, immune cell activation and quiescence is coupled with mitochondrial function and content (
      • Pearce E.L.
      • Poffenberger M.C.
      • Chang C.H.
      • Jones R.G.
      Fueling immunity: insights into metabolism and lymphocyte function.
      ,
      • Pearce E.L.
      • Pearce E.J.
      Metabolic pathways in immune cell activation and quiescence.
      ), and lipopolysaccahride administration has been shown to repurpose lymphocyte mitochondria from ATP synthesis to ROS production (
      • Mills E.L.
      • Kelly B.
      • Logan A.
      • Costa A.S.H.
      • Varma M.
      • Bryant C.E.
      • et al.
      Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages.
      ), further potentiating a pro-inflammatory state. Importantly, this process has specifically been demonstrated in microglia, with mitochondrial structure (fission/fusion dynamics) thought to play a central role in the process (
      • Nair S.
      • Sobotka K.S.
      • Joshi P.
      • Gressens P.
      • Fleiss B.
      • Thornton C.
      • et al.
      Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo.
      ,
      • Voloboueva L.A.
      • Emery J.F.
      • Sun X.
      • Giffard R.G.
      Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin.
      ). Moreover, perhaps due to mitochondria’s bacterial origins, molecules originating from mitochondria itself (i.e., ATP, mtDNA, mROS) act as danger-associated molecular patterns in the intra- and extra-cellular environment, responsible for the activation of Nodlike receptor family, pyrin domain containing 3 (NLRP3) inflammasome and subsequent amplification of inflammatory responses (
      • Jo E.K.
      • Kim J.K.
      • Shin D.M.
      • Sasakawa C.
      Molecular mechanisms regulating NLRP3 inflammasome activation.
      ,
      • Shimada K.
      • Crother T.R.
      • Karlin J.
      • Dagvadorj J.
      • Chiba N.
      • Chen S.
      • et al.
      Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis.
      ,
      • Zhang Q.
      • Raoof M.
      • Chen Y.
      • Sumi Y.
      • Sursal T.
      • Junger W.
      • et al.
      Circulating mitochondrial DAMPs cause inflammatory responses to injury.
      ,
      • Collins L.V.
      • Hajizadeh S.
      • Holme E.
      • Jonsson I.M.
      • Tarkowski A.
      Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses.
      ). Thus, mitochondrial function is not only sensitive to inflammatory stimuli, but the release of mitochondrial molecules in response to inflammation or cellular stress can directly induce neuroinflammation, akin to a positive feedback loop. In this context, mitochondria are not only a potential target and mediator of MIA-dependent effects on the developing brain, but may participate in a self-reinforcing cellular stress response cycle, such as is discussed in the cellular danger response model (
      • Naviaux R.K.
      Antipurinergic therapy for autism-An in-depth review.
      ). This interrelationship between mitochondria and inflammation is evident across the lifespan, but is particularly consequential during the sensitive window of embryological/fetal brain development.

      3.2 Mitochondrial dysfunction as a mediator of preclinical MIA-related effects on the developing brain

      Mitochondria are developmentally plastic (
      • Gyllenhammer L.E.
      • Entringer S.
      • Buss C.
      • Wadhwa P.D.
      Developmental programming of mitochondrial biology: a conceptual framework and review.
      ), their structure and function are altered by inflammatory stimuli (reviewed above), and we propose herein that they are a likely mediator underlying the impact of MIA exposure on offspring neurodevelopmental. We conducted a review of empirical studies in which MIA was induced during pregnancy and mitochondria-relevant measures were obtained in either neuronal or glial cells/tissue of the offspring. Our review identified 12 published preclinical (primarily murine) studies (Table 1) (
      • Zhu Y.
      • Carvey P.M.
      • Ling Z.
      Altered glutathione homeostasis in animals prenatally exposed to lipopolysaccharide.
      ,
      • Swanepoel T.
      • Moller M.
      • Harvey B.H.
      N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges.
      ,
      • Naviaux R.K.
      • Zolkipli Z.
      • Wang L.
      • Nakayama T.
      • Naviaux J.C.
      • Le T.P.
      • et al.
      Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
      ,
      • Doehner J.
      • Genoud C.
      • Imhof C.
      • Krstic D.
      • Knuesel I.
      Extrusion of misfolded and aggregated proteins--a protective strategy of aging neurons?.
      ,
      • Anderson A.
      • Genaro-Mattos T.C.
      • Allen L.B.
      • Koczok K.
      • Korade Z.
      • Mirnics K.
      Interaction of maternal immune activation and genetic interneuronal inhibition.
      ,
      • Gyorffy B.A.
      • Gulyassy P.
      • Gellen B.
      • Volgyi K.
      • Madarasi D.
      • Kis V.
      • et al.
      Widespread alterations in the synaptic proteome of the adolescent cerebral cortex following prenatal immune activation in rats.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Zawadzka A.
      • Frontczak-Baniewicz M.
      • Gewartowska M.
      • Dominiak A.
      • et al.
      The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Jesko H.
      • Czapski G.A.
      • Wilkaniec A.
      • Zawadzka A.
      • et al.
      Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.
      ,
      • Farrelly L.
      • Focking M.
      • Piontkewitz Y.
      • Dicker P.
      • English J.
      • Wynne K.
      • et al.
      Maternal immune activation induces changes in myelin and metabolic proteins, some of which can be prevented with risperidone in adolescence.
      ,
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      ,
      • Al-Amin M.M.
      • Alam T.
      • Hasan S.M.
      • Hasan A.T.
      • Quddus A.H.
      Prenatal maternal lipopolysaccharide administration leads to age- and region-specific oxidative stress in the early developmental stage in offspring.
      ,
      • Briscoe T.
      • Duncan J.
      • Cock M.
      • Choo J.
      • Rice G.
      • Harding R.
      • et al.
      Activation of NF-kappaB transcription factor in the preterm ovine brain and placenta after acute LPS exposure.
      ) providing evidence for MIA-induced changes in offspring brain mitochondrial structure/morphology (
      • Doehner J.
      • Genoud C.
      • Imhof C.
      • Krstic D.
      • Knuesel I.
      Extrusion of misfolded and aggregated proteins--a protective strategy of aging neurons?.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Zawadzka A.
      • Frontczak-Baniewicz M.
      • Gewartowska M.
      • Dominiak A.
      • et al.
      The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Jesko H.
      • Czapski G.A.
      • Wilkaniec A.
      • Zawadzka A.
      • et al.
      Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.
      ), mitochondrial content/density (
      • Doehner J.
      • Genoud C.
      • Imhof C.
      • Krstic D.
      • Knuesel I.
      Extrusion of misfolded and aggregated proteins--a protective strategy of aging neurons?.
      ), indirect (
      • Anderson A.
      • Genaro-Mattos T.C.
      • Allen L.B.
      • Koczok K.
      • Korade Z.
      • Mirnics K.
      Interaction of maternal immune activation and genetic interneuronal inhibition.
      ,
      • Gyorffy B.A.
      • Gulyassy P.
      • Gellen B.
      • Volgyi K.
      • Madarasi D.
      • Kis V.
      • et al.
      Widespread alterations in the synaptic proteome of the adolescent cerebral cortex following prenatal immune activation in rats.
      ,
      • Farrelly L.
      • Focking M.
      • Piontkewitz Y.
      • Dicker P.
      • English J.
      • Wynne K.
      • et al.
      Maternal immune activation induces changes in myelin and metabolic proteins, some of which can be prevented with risperidone in adolescence.
      ) and direct measures of mitochondrial bioenergetic function (electron transport chain enzymatic activity (
      • Naviaux R.K.
      • Zolkipli Z.
      • Wang L.
      • Nakayama T.
      • Naviaux J.C.
      • Le T.P.
      • et al.
      Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Zawadzka A.
      • Frontczak-Baniewicz M.
      • Gewartowska M.
      • Dominiak A.
      • et al.
      The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.
      ), MMP (
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Zawadzka A.
      • Frontczak-Baniewicz M.
      • Gewartowska M.
      • Dominiak A.
      • et al.
      The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.
      ,
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      )), and oxidative stress levels (
      • Zhu Y.
      • Carvey P.M.
      • Ling Z.
      Altered glutathione homeostasis in animals prenatally exposed to lipopolysaccharide.
      ,
      • Swanepoel T.
      • Moller M.
      • Harvey B.H.
      N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Zawadzka A.
      • Frontczak-Baniewicz M.
      • Gewartowska M.
      • Dominiak A.
      • et al.
      The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Jesko H.
      • Czapski G.A.
      • Wilkaniec A.
      • Zawadzka A.
      • et al.
      Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.
      ,
      • Al-Amin M.M.
      • Alam T.
      • Hasan S.M.
      • Hasan A.T.
      • Quddus A.H.
      Prenatal maternal lipopolysaccharide administration leads to age- and region-specific oxidative stress in the early developmental stage in offspring.
      ,
      • Briscoe T.
      • Duncan J.
      • Cock M.
      • Choo J.
      • Rice G.
      • Harding R.
      • et al.
      Activation of NF-kappaB transcription factor in the preterm ovine brain and placenta after acute LPS exposure.
      ). Further, unbiased/untargeted proteomics analysis suggested that the top two significant pathways differentiating the brain of MIA-exposed offspring relative to controls were specific to mitochondrial bioenergetic activity (i.e., OXPHOS, tricyclic acid cycle) (
      • Farrelly L.
      • Focking M.
      • Piontkewitz Y.
      • Dicker P.
      • English J.
      • Wynne K.
      • et al.
      Maternal immune activation induces changes in myelin and metabolic proteins, some of which can be prevented with risperidone in adolescence.
      ). Importantly in the majority of reviewed studies (
      • Zhu Y.
      • Carvey P.M.
      • Ling Z.
      Altered glutathione homeostasis in animals prenatally exposed to lipopolysaccharide.
      ,
      • Swanepoel T.
      • Moller M.
      • Harvey B.H.
      N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges.
      ,
      • Naviaux R.K.
      • Zolkipli Z.
      • Wang L.
      • Nakayama T.
      • Naviaux J.C.
      • Le T.P.
      • et al.
      Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
      ,
      • Doehner J.
      • Genoud C.
      • Imhof C.
      • Krstic D.
      • Knuesel I.
      Extrusion of misfolded and aggregated proteins--a protective strategy of aging neurons?.
      ,
      • Anderson A.
      • Genaro-Mattos T.C.
      • Allen L.B.
      • Koczok K.
      • Korade Z.
      • Mirnics K.
      Interaction of maternal immune activation and genetic interneuronal inhibition.
      ,
      • Gyorffy B.A.
      • Gulyassy P.
      • Gellen B.
      • Volgyi K.
      • Madarasi D.
      • Kis V.
      • et al.
      Widespread alterations in the synaptic proteome of the adolescent cerebral cortex following prenatal immune activation in rats.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Zawadzka A.
      • Frontczak-Baniewicz M.
      • Gewartowska M.
      • Dominiak A.
      • et al.
      The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Jesko H.
      • Czapski G.A.
      • Wilkaniec A.
      • Zawadzka A.
      • et al.
      Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.
      ,
      • Farrelly L.
      • Focking M.
      • Piontkewitz Y.
      • Dicker P.
      • English J.
      • Wynne K.
      • et al.
      Maternal immune activation induces changes in myelin and metabolic proteins, some of which can be prevented with risperidone in adolescence.
      ,
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      ), these MIA-induced changes in mitochondria in the brain paralleled changes in brain integrity (e.g., synaptosomal structure (
      • Naviaux R.K.
      • Zolkipli Z.
      • Wang L.
      • Nakayama T.
      • Naviaux J.C.
      • Le T.P.
      • et al.
      Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
      )) and behavior (e.g., altered inhibitory behavior (
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Jesko H.
      • Czapski G.A.
      • Wilkaniec A.
      • Zawadzka A.
      • et al.
      Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.
      ,
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      ), social behavior (
      • Swanepoel T.
      • Moller M.
      • Harvey B.H.
      N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges.
      ,
      • Naviaux R.K.
      • Zolkipli Z.
      • Wang L.
      • Nakayama T.
      • Naviaux J.C.
      • Le T.P.
      • et al.
      Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Jesko H.
      • Czapski G.A.
      • Wilkaniec A.
      • Zawadzka A.
      • et al.
      Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.
      ), sensorimotor coordination (
      • Naviaux R.K.
      • Zolkipli Z.
      • Wang L.
      • Nakayama T.
      • Naviaux J.C.
      • Le T.P.
      • et al.
      Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
      )).
      Table 1Summary of preclinical MIA prenatal exposure studies
      First AuthorYearAnimal ModelMIA ProtocolMitochondrial Effects in the BrainBrain/Behavior Phenotypes
      Briscoe, T. (
      • Rose S.
      • Niyazov D.M.
      • Rossignol D.A.
      • Goldenthal M.
      • Kahler S.G.
      • Frye R.E.
      Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder.
      )
      2006OvinePrenatal exposure: Gestational day (GD) 95 intravenous bolus dose of lipopolysaccharide (LPS; 1μg/kg) vs. control (saline) directly to fetus (catheter); MIA validation: Direct fetal exposure via catheter, with demonstrated rise in cytokines.oxidative stress in the parietal, temporal, occipital, and thalamus‐basal ganglia regions (measured by ↑lipid peroxide production and 8-Isoprostane) and in the placenta
      Zhu, Y. (
      • Anderson A.
      • Genaro-Mattos T.C.
      • Allen L.B.
      • Koczok K.
      • Korade Z.
      • Mirnics K.
      Interaction of maternal immune activation and genetic interneuronal inhibition.
      )
      2007Sprague-Dawley ratsPrenatal exposure: GD 10.5 intraperitoneal (i.p). injection of LPS (10,000 endotoxin units/kg) vs. control (saline); Postnatal exposure (in separate animals without prenatal exposure): 4 months post-natal acute supranigral injection of LPS (10μg/4μl in saline) vs. control (saline); MIA validation: Not described.oxidative stress in the midbrain (measured by ↓ glutathione (GSH) and ↑ in oxidized GSH and lipid peroxide production) [in both prenatal and postnatal LPS exposure groups]Brain: ↓DA neuron count in the substantia nigra
      Doehner, J. (
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Jesko H.
      • Czapski G.A.
      • Wilkaniec A.
      • Zawadzka A.
      • et al.
      Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.
      )
      2012C57BL/6J micePrenatal exposure: GD17 intravenous injection of Poly(I:C) (5mg/kg) vs. control (saline); MIA validation: Not described.mito density/content in reelin-positive granules in the hippocampusBrain: ↑size and number of reelin-immunoreactive deposits (accumulation of aggregation-prone proteins and peptides)- associated with neuritic swellings
      Naviaux, R.K. (
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Zawadzka A.
      • Frontczak-Baniewicz M.
      • Gewartowska M.
      • Dominiak A.
      • et al.
      The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.
      )
      2013C57BL/6J mice2 Prenatal exposure groups: 1) Single dose i.p. injection of Poly(I:C) on GD12.5 (2 mg/kg); 2) Double dose i.p. injection of Poly(I:C) on GD12.5 (3 mg/kg) & GD17.4 (1.5 mg/kg); all vs. control group (saline) [all results are reported as 2 groups combined]; Postnatal Therapy: 6 weeks postpartum received weekly suramin injection; MIA validation: Not described.mito bioenergetic function in the cerebrum (measured by ↑ complex I and IV activity; no change in Complex II, III activity or complex protein levels) [induced by Poly(I:C) and corrected by APT therapy] No change in mito density/content (measured by citrate synthase)Behavior: ↓social preference, ↓sensorimotor coordination; Brain: ↓cerebellar purkinje cell, ultrastructural synaptic dysmorphology, ERK1/2 and CAMKII signal transduction abnormalities. [All are induced by Poly(I:C) and rescued by APT treatment]
      Farrelly, L. (
      • Buss C.
      Maternal oxidative stress during pregnancy and offspring neurodevelopment.
      )
      2015Wistar ratsPrenatal exposure: G15 intravenous injection of Poly(I:C) (4 mg/kg) vs. control (saline); Postnatal Therapy: Postnatal Day (PND) 34–47 i.p. daily injection of risperidone (0.045 mg/kg) vs. control (saline); MIA validation: Not described.mito bioenergetic proteins in the prefrontal cortex (PFC) (measured in unbiased proteomics: top 2 significantly different pathways were related to primarily ↑mitochondrial OXPHOS and tricarboxylic acid cycle (TCA cycle) proteins) [induced by Poly(I:C) with some reversed by risperidone treatment]Brain: Measured 7 myelin and myelin-related proteins in the PFC, 2 were altered by Poly(I:C) (measured in hypothesis driven proteomics analysis- isoform 3 of myelin basic protein and rhombex 29 were altered by Poly(I:C)).
      Al-Amin, M.M. (
      • Naviaux R.K.
      • Curtis B.
      • Li K.
      • Naviaux J.C.
      • Bright A.T.
      • Reiner G.E.
      • et al.
      Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial.
      )
      2016Swiss albino micePrenatal exposure: GD 16 i.p. injection of LPS (50 μg/kg) vs. control (water); MIA validation: Not described.oxidative stress that is age and brain region specific (measured on PND 1- ↑ GSH level, ↓superoxide dismutase activity; PND 7- ↑advanced oxidation of protein product level; PND 14- ↑lipid peroxidation (MDA) and activity of catalase; PND 21- ONLY ↑MDA remains (across all brain regions measured: hippocampus and cerebellum, cortex)
      Györffy, B.A. (
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      )
      2016Wistar ratsPrenatal exposure: GD 13.5 i.p. injection of LPS (20 μg/kg) vs. control (saline); MIA validation: Demonstrated rise in rectal temperature of dams 3hrs post LPS injection.Altered proteins in energy homeostasis/carbohydrate metabolism (proxy for mito bioenergetic function) Altered proteins in oxidative stressBrain: Altered proteins in neurite outgrowth/cytoskeleton and synaptic vesicle exo- and endocytosis.
      Swanepoel, T. (
      • Gyorffy B.A.
      • Gulyassy P.
      • Gellen B.
      • Volgyi K.
      • Madarasi D.
      • Kis V.
      • et al.
      Widespread alterations in the synaptic proteome of the adolescent cerebral cortex following prenatal immune activation in rats.
      )
      2018Sprague-Dawley ratsPrenatal exposure: GD15-16 subcutaneous injection of LPS (100 μg/kg) vs. control (saline); Postnatal challenge & therapy: Postnatal day (PND) 35-50 methamphetamine (MA) with N-acetyl cysteine (NAC) treatment vs control PND 51-64; MIA validation: Not described.oxidative stress in the frontal cortical and striatum (measured by ↑MDA, marker of lipid peroxidation) and ↑in plasma ROS [in both prenatal LPS exposure and LPS + 2nd hit postnatal MA exposure groups; All reversed by NAC therapy]Behavior: ↑social withdrawal, ↓recognition memory, deficit in prepulse inhibition [induced by LPS and LPS+MA; reversed by (mostly) NAC]; Brain: ↑frontal cortical dopamine and noradrenaline [induced by LPS and LPS+MA; reversed by NAC]
      Robicsek, O. (
      • Cattane N.
      • Richetto J.
      • Cattaneo A.
      Prenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder: focus on biological pathways and epigenetic mechanisms.
      )
      2018Wistar rats (in-vivo model); see manuscript for in-vitro modelPrenatal exposure: GD15, injected into the tail vein with poly-I:C (4 mg/kg/ml) vs. control (saline); Postnatal therapy: PNDs 34–46 isolated active normal mitochondria (IAN-MIT) (100 μg/4.5μl), injected into the medial prefrontal cortex; MIA validation: Not described.mito bioenergetic function in frontal cortex neurons (measured by mitochondrial membrane potential (MMP)) [induced by Poly(I:C) and rescued by IAN-MIT therapy] No change in mitochondrial distribution and network connectivityBehavior: Latent inhibition was absent in Poly(I:C) exposed mice, but was rescued by IAN-MIT postnatal therapy.
      Cieślik, M. (
      • Briscoe T.
      • Duncan J.
      • Cock M.
      • Choo J.
      • Rice G.
      • Harding R.
      • et al.
      Activation of NF-kappaB transcription factor in the preterm ovine brain and placenta after acute LPS exposure.
      )
      2020Wistar ratsPrenatal exposure: GD9.5 i.p. injection of LPS (100 μg/kg) vs. control (saline); MIA validation: Demonstrated maternal sickness behavior up to 24hrs post LPS injection.Altered mitochondrial structure/morphology in cerebral cortex (measured by ultrastructural changes (cristae blurring)) ↑oxidative stress in the cerebral cortex (measured by ↑12-lipoxygenase and cyclooxygenase-2 mRNA levels, ↑DCF fluorescence (to quantify ROS), ↑oxidized GSH (GSSG),↓GSH/GSSG ratio)Behavior: ↑ heterogeneity in intensity of play behavior, ↓social interaction (no change in locomotor and exploratory activity, anxiety-related behavior); Brain: ↓Formation and turnover of synaptic vesicles (protein levels), disturbed synaptic membranes & changed myelin (via ultrastructural measurement)
      Anderson, A. (
      • Farrelly L.
      • Focking M.
      • Piontkewitz Y.
      • Dicker P.
      • English J.
      • Wynne K.
      • et al.
      Maternal immune activation induces changes in myelin and metabolic proteins, some of which can be prevented with risperidone in adolescence.
      )
      2021Wild type (WT) rats

      (see manuscript for transgenic models)
      Prenatal exposure: GD12.5 i.p. injection of Poly(I:C) (100 μL/10g) vs. control (saline) [Poly(I:C) exposure given to WT and transgenic mice- only WT discussed here]; MIA validation: Not described, but cite previous studies conducted by lab with demonstrated cytokine rise.Altered energy metabolism and acylcarnitine species in the neocortex (authors argue proxy for mitochondrial metabolism)
      Cieślik, M. (
      • Al-Amin M.M.
      • Alam T.
      • Hasan S.M.
      • Hasan A.T.
      • Quddus A.H.
      Prenatal maternal lipopolysaccharide administration leads to age- and region-specific oxidative stress in the early developmental stage in offspring.
      )
      2021Wistar ratsPrenatal exposure: GD9.5 i.p. injection of LPS (100 μg/kg) vs. control (saline); MIA validation: Demonstrated maternal sickness behavior up to 24hrs post LPS injection.mito bioenergetic function in the hippocampus (measured by ↓ gene expression for Complex I (mt-Nd1) and Complex IV (mt-Co1), ↓protein level for ND1 (CI), ↓ CI enzyme activity (no change CIV), and ↓ MMP) Altered mitochondrial structure/morphology in the hippocampus (measured by ultrastructural changes of synaptic mitochondria ("swollen" mitochondria) ↑oxidative stress in the hippocampus (measured by ↓reduced/oxidized glutathione ratio (indicates enhanced generation of ROS); ↓ total GSH; ↑oxidized DCF (proxy for ROS); ↓mito antioxidant enzymes(Sod1 and Sod2))Brain: ↑ size of synaptic cleft (no change in size and # of synaptic vesicles (SVs)), ultrastructural changes in synapses (↓packing density of SVs in the presynaptic area, blurred and thickened structure of the synaptic cleft), altered synaptic proteins
      Two recent studies strengthening the empirical support for an association between preclinical MIA and offspring brain mitochondrial dysfunction are of particular relevance. The first, employed multiple layered measures of mitochondrial structure and function in the hippocampus of adolescent offspring born to dams exposed to lipopolysaccahride during pregnancy (gestation day 9.5) to demonstrate a comprehensive decrease in gene expression, protein level and enzymatic activity specific to mitochondrial electron transport chain Complex I, that also corresponded with a holistic decrease in bioenergetic function, measured by MMP (
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Zawadzka A.
      • Frontczak-Baniewicz M.
      • Gewartowska M.
      • Dominiak A.
      • et al.
      The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.
      ). Furthermore, this study demonstrated mitochondrial specific increases in oxidative stress (mROS) and decreases in mitochondrial specific antioxidant levels, which is consistent with the increase in oxidative stress reported across all studies that assessed MIA-induced oxidative damage (
      • Zhu Y.
      • Carvey P.M.
      • Ling Z.
      Altered glutathione homeostasis in animals prenatally exposed to lipopolysaccharide.
      ,
      • Swanepoel T.
      • Moller M.
      • Harvey B.H.
      N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Zawadzka A.
      • Frontczak-Baniewicz M.
      • Gewartowska M.
      • Dominiak A.
      • et al.
      The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.
      ,
      • Cieslik M.
      • Gassowska-Dobrowolska M.
      • Jesko H.
      • Czapski G.A.
      • Wilkaniec A.
      • Zawadzka A.
      • et al.
      Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.
      ,
      • Al-Amin M.M.
      • Alam T.
      • Hasan S.M.
      • Hasan A.T.
      • Quddus A.H.
      Prenatal maternal lipopolysaccharide administration leads to age- and region-specific oxidative stress in the early developmental stage in offspring.
      ,
      • Briscoe T.
      • Duncan J.
      • Cock M.
      • Choo J.
      • Rice G.
      • Harding R.
      • et al.
      Activation of NF-kappaB transcription factor in the preterm ovine brain and placenta after acute LPS exposure.
      ). Previous work has highlighted ROS as a mediator of fetal neurodevelopmental programming (
      • Buss C.
      Maternal oxidative stress during pregnancy and offspring neurodevelopment.
      ,
      • Cattane N.
      • Richetto J.
      • Cattaneo A.
      Prenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder: focus on biological pathways and epigenetic mechanisms.
      ), and we bring the focus here to mitochondria, as the primary source of ROS, particularly in response to inflammatory insults (
      • Park J.
      • Min J.S.
      • Kim B.
      • Chae U.B.
      • Yun J.W.
      • Choi M.S.
      • et al.
      Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways.
      ). The second study presents the first empirical evidence to inform more directly on the cause-effect-relationship between MIA-dependent programming of mitochondrial dysfunction and behavior. Specifically, Robiscek et al. (2018) demonstrate decreased mitochondrial bioenergetic function (measured by MMP) in cortical neurons in MIA-exposed rats which parallel behavioral deficits (
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      ). Interestingly, both of these features are rescued by postnatal mitochondrial therapy via intracranial injections of isolated active normal mitochondria (
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      ). The promise of mitochondrial therapy is further supported by the successful treatment of human neurons derived from schizophrenic patients using isolated active normal mitochondria (
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      ), which normalized cellular oxygen consumption and MMP to the levels observed in neurons from control patients. Similarly, Naviaux et al. (2013) had previously employed a postnatal therapy in MIA-exposed offspring that targets the extracellular release of mitochondrial molecules (i.e., mitokines), and was able to rescue cerebral mitochondrial function and core social deficits (
      • Naviaux R.K.
      • Zolkipli Z.
      • Wang L.
      • Nakayama T.
      • Naviaux J.C.
      • Le T.P.
      • et al.
      Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
      ). The same mitokine therapy was employed in a recent human phase I/II randomized control trial in children with autism, and improved scores on the Autism Diagnostic Observation Schedule (
      • Naviaux R.K.
      • Curtis B.
      • Li K.
      • Naviaux J.C.
      • Bright A.T.
      • Reiner G.E.
      • et al.
      Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial.
      ). The efficacy of such mitochondrial targeted treatments supports the premise that mitochondrial activity is sufficient to induce, and potentially rescue, neurodevelopmental disorders.

      3.3 Mitochondrial dysfunction in the context of human neurodevelopmental disorders

      Further support for the role of mitochondrial function as a potential mediator of the association between MIA during pregnancy and mental health risk comes from clinical epidemiological studies that suggest a relationship between mitochondrial dysfunction and neurodevelopmental disorders, for which maternal infection/immune activation during pregnancy is an established risk factor. Brain mitochondrial dysfunction has been reported in autism spectrum disorder (
      • Rose S.
      • Niyazov D.M.
      • Rossignol D.A.
      • Goldenthal M.
      • Kahler S.G.
      • Frye R.E.
      Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder.
      ,
      • Minshew N.J.
      • Goldstein G.
      • Dombrowski S.M.
      • Panchalingam K.
      • Pettegrew J.W.
      A preliminary 31P MRS study of autism: evidence for undersynthesis and increased degradation of brain membranes.
      ,
      • Tang G.
      • Gutierrez Rios P.
      • Kuo S.H.
      • Akman H.O.
      • Rosoklija G.
      • Tanji K.
      • et al.
      Mitochondrial abnormalities in temporal lobe of autistic brain.
      ), attention deficit hyperactivity disorder (
      • Nguyen Nguyen H.T.
      • Kato H.
      • Sato H.
      • Yamaza H.
      • Sakai Y.
      • Ohga S.
      • et al.
      Positive effect of exogenous brain-derived neurotrophic factor on impaired neurite development and mitochondrial function in dopaminergic neurons derived from dental pulp stem cells from children with attention deficit hyperactivity disorder.
      ), and schizophrenia (
      • Roberts R.C.
      Postmortem studies on mitochondria in schizophrenia.
      ,
      • Eltokhi A.
      • Santuy A.
      • Merchan-Perez A.
      • Sprengel R.
      Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies.
      ). Specifically, patients differed from healthy controls in mitochondrial density/localization (
      • Minshew N.J.
      • Goldstein G.
      • Dombrowski S.M.
      • Panchalingam K.
      • Pettegrew J.W.
      A preliminary 31P MRS study of autism: evidence for undersynthesis and increased degradation of brain membranes.
      ,
      • Nguyen Nguyen H.T.
      • Kato H.
      • Sato H.
      • Yamaza H.
      • Sakai Y.
      • Ohga S.
      • et al.
      Positive effect of exogenous brain-derived neurotrophic factor on impaired neurite development and mitochondrial function in dopaminergic neurons derived from dental pulp stem cells from children with attention deficit hyperactivity disorder.
      ,
      • Roberts R.C.
      Postmortem studies on mitochondria in schizophrenia.
      ,
      • Eltokhi A.
      • Santuy A.
      • Merchan-Perez A.
      • Sprengel R.
      Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies.
      ), bioenergetic function (
      • Rose S.
      • Niyazov D.M.
      • Rossignol D.A.
      • Goldenthal M.
      • Kahler S.G.
      • Frye R.E.
      Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder.
      ,
      • Tang G.
      • Gutierrez Rios P.
      • Kuo S.H.
      • Akman H.O.
      • Rosoklija G.
      • Tanji K.
      • et al.
      Mitochondrial abnormalities in temporal lobe of autistic brain.
      ,
      • Nguyen Nguyen H.T.
      • Kato H.
      • Sato H.
      • Yamaza H.
      • Sakai Y.
      • Ohga S.
      • et al.
      Positive effect of exogenous brain-derived neurotrophic factor on impaired neurite development and mitochondrial function in dopaminergic neurons derived from dental pulp stem cells from children with attention deficit hyperactivity disorder.
      ), fission/fusion dynamics (
      • Tang G.
      • Gutierrez Rios P.
      • Kuo S.H.
      • Akman H.O.
      • Rosoklija G.
      • Tanji K.
      • et al.
      Mitochondrial abnormalities in temporal lobe of autistic brain.
      ), and structure/morphology (
      • Nguyen Nguyen H.T.
      • Kato H.
      • Sato H.
      • Yamaza H.
      • Sakai Y.
      • Ohga S.
      • et al.
      Positive effect of exogenous brain-derived neurotrophic factor on impaired neurite development and mitochondrial function in dopaminergic neurons derived from dental pulp stem cells from children with attention deficit hyperactivity disorder.
      ,
      • Eltokhi A.
      • Santuy A.
      • Merchan-Perez A.
      • Sprengel R.
      Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies.
      ). Furthermore, inherited mtDNA mutations are associated with increased risk for neurodevelopmental disorders (
      • Pons R.
      • Andreu A.L.
      • Checcarelli N.
      • Vila M.R.
      • Engelstad K.
      • Sue C.M.
      • et al.
      Mitochondrial DNA abnormalities and autistic spectrum disorders.
      ,
      • Patowary A.
      • Nesbitt R.
      • Archer M.
      • Bernier R.
      • Brkanac Z.
      Next Generation Sequencing Mitochondrial DNA Analysis in Autism Spectrum Disorder.
      ,
      • Ichikawa T.
      • Arai M.
      • Miyashita M.
      • Arai M.
      • Obata N.
      • Nohara I.
      • et al.
      Schizophrenia: maternal inheritance and heteroplasmy of mtDNA mutations.
      ,
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      • Pizzo S.
      • Naviaux R.K.
      • Markusic D.
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      Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation.
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      • Napoli E.
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      Beyond autophagy: a novel role for autism-linked Wdfy3 in brain mitophagy.
      ), which supports the premise that mitochondrial dysfunction may be a cause rather than a secondary consequence of these disorders. Moreover, in preclinical murine models where mitochondrial specific defects can be induced through mutations or overexpression, and temporality can be established, mild mitochondrial dysfunction has proven sufficient to cause autism spectrum disorder (
      • Yardeni T.
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      • McCoy A.J.
      • Schaefer P.M.
      • McManus M.J.
      • Marsh E.D.
      • et al.
      An mtDNA mutant mouse demonstrates that mitochondrial deficiency can result in autism endophenotypes.
      ), schizophrenia (

      Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, et al. (2008): Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. 13(2): 173-186.

      ,
      • Uzuneser T.C.
      • Speidel J.
      • Kogias G.
      • Wang A.L.
      • de Souza Silva M.A.
      • Huston J.P.
      • et al.
      Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats.
      ), and broad neurodevelopmental disorder (
      • Fernandez A.
      • Meechan D.W.
      • Karpinski B.A.
      • Paronett E.M.
      • Bryan C.A.
      • Rutz H.L.
      • et al.
      Mitochondrial Dysfunction Leads to Cortical Under-Connectivity and Cognitive Impairment.
      ) phenotypes. Thus, there is empirical evidence supporting a causal role for the integrity of mitochondrial structure and function in early brain development. Because mitochondria regulate and are regulated by inflammatory processes, there is furthermore a basis for concluding a causal role of mitochondria in MIA-induced changes in brain development and risk for neurodevelopmental disorders.

      4. Conclusions and future directions

      Convergent evidence supporting the obligatory role of mitochondria in brain development and the role of mitochondria as mediators and initiators of inflammatory processes, as well as evidence of mitochondrial dysfunction in pre-clinical MIA exposure models and human neurodevelopmental disorders, suggests that mitochondria play a pivotal role in MIA-induced alterations in brain development.
      While the conceptual model presented here is supported by empirical evidence, we address below two major limitations (i.e., knowledge gaps) presenting opportunities for future research. First, preclinical studies demonstrate that mitochondrial dysfunction is induced by MIA, and parallels MIA-induced changes in brain development and behavior; however, evidence to support clear cause-and-effect of mitochondrial function in this pathway is still limited (
      • Naviaux R.K.
      • Zolkipli Z.
      • Wang L.
      • Nakayama T.
      • Naviaux J.C.
      • Le T.P.
      • et al.
      Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
      ,
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      ). Further empirical evidence is needed to support which aspects of mitochondrial function are sufficient and necessary for MIA-induced alterations in neurodevelopment, with parallel evidence that these aspects can be mitigated by mitochondrial targeted therapies. Novel insights from such studies could lead to potential therapeutic targets, that may be applied prenatally, or even postnatally while the brain retains a high degree of neuroplasticity, as has successfully been done in first pioneer studies (
      • Naviaux R.K.
      • Zolkipli Z.
      • Wang L.
      • Nakayama T.
      • Naviaux J.C.
      • Le T.P.
      • et al.
      Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.
      ,
      • Robicsek O.
      • Ene H.M.
      • Karry R.
      • Ytzhaki O.
      • Asor E.
      • McPhie D.
      • et al.
      Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder.
      ). Second, confirmatory analyses in humans are necessary to demonstrate the generalization of the consequences of MIA exposures during pregnancy for offspring mitochondrial function, generally and specifically in the brain. Human studies in living patients have been limited to accessible peripheral tissues that serve as a proxy to mitochondrial function in the brain (methods reviewed in (
      • Picard M.
      • Trumpff C.
      • Burelle Y.
      Mitochondrial Psychobiology: Foundations and Applications.
      )), yet we highlight some methodological advances for areas of potential future clinical research. Specifically, novel non-invasive indirect measurement (magnetic resonance and positron emission tomography imaging) of mitochondrial bioenergetic function (
      • Tsukada H.
      • Nishiyama S.
      • Fukumoto D.
      • Kanazawa M.
      • Harada N.
      Novel PET probes 18F-BCPP-EF and 18F-BCPP-BF for mitochondrial complex I: a PET study in comparison with 18F-BMS-747158-02 in rat brain.
      ,
      • Tsukada H.
      • Ohba H.
      • Kanazawa M.
      • Kakiuchi T.
      • Harada N.
      Evaluation of 18F-BCPP-EF for mitochondrial complex 1 imaging in the brain of conscious monkeys using PET.
      ) and mROS production (
      • Zhelev Z.
      • Bakalova R.
      • Aoki I.
      • Lazarova D.
      • Saga T.
      Imaging of superoxide generation in the dopaminergic area of the brain in Parkinson's disease, using mito-TEMPO.
      ) in the brain have been demonstrated in pre-clinical animal models and are potential tools for future in-vivo research in human studies. Furthermore, recent advances in induced pluripotent stem cell and umbilical mesenchymal stem cells (uMSCs) research would allow for collection of non-invasive tissues at birth (e.g., umbilical cord) and/or early in life (e.g., hair follicles) with demonstrated potential for differentiation to neuronal cell-lineages (
      • Re S.
      • Dogan A.A.
      • Ben-Shachar D.
      • Berger G.
      • Werling A.M.
      • Walitza S.
      • et al.
      Improved Generation of Induced Pluripotent Stem Cells From Hair Derived Keratinocytes - A Tool to Study Neurodevelopmental Disorders as ADHD.
      ,
      • Fu Y.S.
      • Cheng Y.C.
      • Lin M.Y.
      • Cheng H.
      • Chu P.M.
      • Chou S.C.
      • et al.
      Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism.
      ,
      • Chen S.
      • Zhang W.
      • Wang J.M.
      • Duan H.T.
      • Kong J.H.
      • Wang Y.X.
      • et al.
      Differentiation of isolated human umbilical cord mesenchymal stem cells into neural stem cells.
      ). Such tissues could be utilized for 2D and 3D differentiation research studies of the central nervous system under varying inflammatory conditions, and in particular, progress in using human primary cell cultures to generate more complex 3D brain organoids (
      • Chen S.
      • Zhang W.
      • Wang J.M.
      • Duan H.T.
      • Kong J.H.
      • Wang Y.X.
      • et al.
      Differentiation of isolated human umbilical cord mesenchymal stem cells into neural stem cells.
      ) now allows for improved ex-vivo modeling of inflammation-induced mitochondrial deficits in the developing brain and to examine treatment options.
      In summary, we argue that mitochondrial function is a promising mechanism through which maternal immune activation/inflammation during pregnancy, can impact the risk for neurodevelopmental and psychiatric disorders. Elucidating the role of mitochondria as a mediator of MIA-induced alterations in brain development and neurodevelopmental disease risk may not only provide new insight into the pathophysiology of mental health disorders, but may also offer new therapeutic targets.

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      Supplementary Material

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