Next Article in Journal
New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics
Next Article in Special Issue
A Systematic Review and Meta-Analysis of Immunoglobulin G Abnormalities and the Therapeutic Use of Intravenous Immunoglobulins (IVIG) in Autism Spectrum Disorder
Previous Article in Journal
Early Evaluation of Immunotherapy Response in Lymphoma Patients by 18F-FDG PET/CT: A Literature Overview
Previous Article in Special Issue
Paving the Way toward Personalized Medicine: Current Advances and Challenges in Multi-OMICS Approach in Autism Spectrum Disorder for Biomarkers Discovery and Patient Stratification
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JPM
Volume 11
Issue 3
10.3390/jpm11030218
jpm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

by
Richard E. Frye
1,*,
Janet Cakir
2,
Shannon Rose
3,
Raymond F. Palmer
4,
Christine Austin
5,
Paul Curtin
5 and
Manish Arora
5
1
Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ 85016, USA
2
Department of Applied Ecology, North Carolina State University, Raleigh, NC 27695, USA
3
Department of Pediatrics, Arkansas Children’s Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
4
Department of Family and Community Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA
5
Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2021, 11(3), 218; https://doi.org/10.3390/jpm11030218
Received: 5 February 2021 / Revised: 17 March 2021 / Accepted: 17 March 2021 / Published: 18 March 2021
(This article belongs to the Special Issue A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder)
Browse Figures
Versions Notes

Abstract

:
We propose that the mitochondrion, an essential cellular organelle, mediates the long-term prenatal environmental effects of disease in autism spectrum disorder (ASD). Many prenatal environmental factors which increase the risk of developing ASD influence mitochondria physiology, including toxicant exposures, immune activation, and nutritional factors. Unique types of mitochondrial dysfunction have been associated with ASD and recent studies have linked prenatal environmental exposures to long-term changes in mitochondrial physiology in children with ASD. A better understanding of the role of the mitochondria in the etiology of ASD can lead to targeted therapeutics and strategies to potentially prevent the development of ASD.

1. Introduction

Autism spectrum disorder (ASD) is a behaviorally defined disorder [1], with the most recent Center for Disease Control and Prevention estimates suggesting that it affects 1 in 54 children in the United States [2]. Recent studies suggest that inherited single-gene and chromosomal defects account for a minority of ASD cases [3], and that ASD most likely arises from a complicated interaction between genetic predisposition and environmental exposures [4,5]. Given the high recurrent risk in siblings, the prenatal maternal environment has undergone careful study with many prenatal risk factors identified [6,7]. Despite the epidemiological connection between many prenatal risk factors and the development of ASD, the biological mechanisms which link prenatal environmental influences and the increased risk of developing ASD are just beginning to be uncovered.
Three physiological abnormalities which have been increasingly recognized to be associated with ASD are immune system dysfunction, mitochondrial dysfunction, and oxidative stress and redox regulation [1]. Previous reviews examining prenatal physiological abnormalities related to ASD have concentrated on prenatal immune stressors as key and consider mitochondrial dysfunction and oxidative stress to have secondary roles of this “Bad Trio” [8]. In contrast, the current review concentrates on the mitochondria as the central player. Of course, the particular component of the “Bad Trio” that is the initiating culprit may be different for different patients and it is possible that multiple stressors on the various portions of the “Bad Trio” simultaneously may also initiate the pathway to disease.

2. The Mitochondria: Dysfunction Can Be Self-Perpetuating

Mitochondria are essential for a wide range of functions in almost every cell in our body (Figure 1). Best known for their role in the production of adenosine triphosphate (ATP) by oxidative phosphorylation, mitochondria are intimately involved in other cellular functions such as redox metabolism, calcium buffering, lipid homeostasis, and steroid synthesis [9,10,11,12,13]. Mitochondria also have a role in important non-energy-producing metabolic pathways, such as the urea cycle, amino acid and porphyrin production, and as a pathway for the activation of apoptosis. Mitochondria also have important roles in cell signaling, most notably being an essential part of the inflammasome, a complex that initiates immune activation, by releasing damage-associated molecular pattern (DAMP) molecules such as cardiolipin, n-formyl peptides, reactive oxygen species (ROS), and mitochondrial DNA (mtDNA) [14]. Lastly, normal mitochondrial function results in the production of ROS, which can cause cellular injury if not controlled.
Since ATP produced by mitochondria is essential for many cellular systems, abnormal mitochondrial function can disproportionally adversely affect cellular physiology. However, there are several pathways in which abnormal mitochondrial function can result in a self-perpetuating destructive cycle causing sustained pathophysiology. Most notably, interactions between mitochondria, redox metabolism, and the immune system can be mutually detrimental; such detrimental interactions have been documented in ASD (Figure 2) [15].
Mitochondria are both a major producer and target of ROS. Dysfunctional mitochondria produce high amounts of ROS which can result in dysfunction of the electron transport chain (ETC) enzymes, particularly complex I and III, as well as aconitase, the first enzyme in the citric acid cycle (CAC). To compound this problem, reduced glutathione (GSH), the main intracellular and mitochondrial antioxidant, requires ATP for its de novo production. As such, a decrease in ATP production resulting from reduced mitochondrial function will result in lower GSH production, resulting in poorer control of ROS. In fact, a lower GSH redox ratio has been correlated with lower aconitase activity in post-mortem brain from individuals with ASD [16]. Oxidative damage to cellular lipids, proteins, and nucleic acids [17] has been associated with ASD; this is especially important since mtDNA is vulnerable to oxidative damage, and studies have shown that children with ASD demonstrated mtDNA damage in a pattern consistent with oxidative damage [18].
There are several pathways in which dysfunctional mitochondria can cause a wide variety of abnormalities in immune system function. First, cellular damage due to oxidative stress can activate inflammatory pathways [15,16]. Second, as an essential part of the inflammasome, mitochondria release DAMP molecules such as cardiolipin, n-formyl peptides, ROS, and mtDNA [14]. Third, regulatory immune cells are highly dependent on ATP derived from mitochondrial oxidative phosphorylation, while inflammatory cells are highly glycolytic [19]. Thus, once an immune response has been started, the inflammatory response may be difficult to regulate if mitochondrial dysfunction exists. Fourth, inflammation and immune activation upregulate metabolism and recruit physiological processes, but without mitochondrial support, such resources will not be available. Lastly, the immune system produces ROS as a defense mechanism against potential invaders. Such increases in ROS can result in a further detrimental effect on already dysfunctional mitochondria. In fact, mitochondria appear to have a particularly important role in innate immunity [20], which is an area of immune dysfunction that is implicated in ASD. In addition, an increase in proinflammatory cytokine production has been associated with mitochondrial dysfunction in a subset of children with ASD [21].

3. Prenatal Risk Factors for ASD Modulate Mitochondrial Function

Many prenatal factors associated with an increased risk of ASD are associated with mitochondrial dysfunction; these include nutritional agents, both intrinsic and extrinsic stressors, common medications given during pregnancy, modulators of mitochondrial function, and genetic conditions which might affect the fetus (Figure 1).
Folate is an essential vitamin which is well-known to be important during pregnancy to prevent neural tube defects. Folate is also an essential co-factor for adequate mitochondrial function [22]. Several studies have demonstrated that folate supplementation during pregnancy reduces the risk of ASD. Abnormalities in the folate pathway are associated with ASD, including maternal polymorphisms in the reduced folate carrier [23]. Further, mothers of children with ASD have been shown to have the folate receptor alpha autoantibody [24], an abnormality that prevents folate transport across the placenta, resulting in an ASD phenotype in an animal model [25].
Abnormalities in several nutrient metals have been linked to an increased risk of ASD. Studies have associated an increased risk of ASD with atypical pre- and postnatal Zn and Cu metabolism [26] and found that atypical levels of essential (Zn, Mn) and non-essential (Pb) metals during prenatal development and early life in individuals with ASD are associated with long-term physiological and developmental alternations [27]. Studies have associated low maternal iron (Fe) with increased ASD risk [28]. Prenatal Zn and Cu are essential for the function of the cytoplasmic superoxide dismutase (SOD) which is essential for controlling cellular oxidative stress, while Cu is essential for ETC complex IV function. Mn is essential for mitochondrial SOD function, and Fe is an essential component of cytochromes, which are critical components of the ETC.
Carnitine is an essential nutrient for mitochondrial function and fatty acid metabolism [11,29,30]. Abnormalities in carnitine metabolism have been linked to gestational diabetes [31], a risk factor for ASD [32]. A genetic defect in carnitine synthesis is a risk factor for ASD [33], carnitine metabolism is known to be disrupted in ASD [29,30] and a mouse model of ASD is associated with alternations in carnitine biosynthesis [34]. Due to its importance in energy metabolism in neural stem cells of the developing mammalian brain, carnitine deficiency has been proposed to be a prenatal risk factor for ASD [35].
As noted above, increased oxidative stress as well as inflammation is associated with mitochondrial dysfunction. Abnormalities in maternal trans-sulfuration metabolism and chronic oxidative stress are found in mothers of children with ASD during [36] and following [37] pregnancy and, in general, infection during pregnancy is a risk factor for ASD [38]. In fact, the maternal immune activation (MIA) mouse model of ASD demonstrates long-term mitochondrial dysfunction in brain [39] and leukocytes [40] after birth. Pregnancies resulting in a child with ASD have demonstrated increases in proinflammatory cytokines IL-1α [41] and IL-6 [41] in blood, while maternal elevation in IL-17a has been strongly implicated in the MIA model [42]. In laboratory studies, IL-17 [43,44] induces mitochondrial dysfunction through activation of the mitochondria-induced apoptosis pathway and IL-1 suppresses mitochondrial function [45], while IL-6 promotes mitochondrial biogenesis and fatty acid oxidation [46].
Prenatal exposure to many environmental toxicants is linked to an increased risk of developing ASD, including cigarette smoke, phthalates, air pollution, and pesticides such as organophosphate insecticides (e.g., chlorpyrifos) and organochlorine pesticides (e.g., dicofol and endosulfan) [7]. These toxicants have been associated with mitochondrial dysfunction. Organophosphate induces mitochondrial ultrastructure changes and inhibits ETC and CAC enzyme function, while organochlorine pesticides influence mitochondrial dysfunction indirectly by increasing ROS and reactive nitrogen species by altering antioxidant systems including SOD and GSH [47]. Phthalates, common plasticizers present in everyday products, have also been linked to increased oxygen consumption, mitochondrial mass, and fatty-acid metabolism in neonatal rat cardiomyocytes [48] and detrimental changes in mitochondrial membrane potential in human semen [49]. Mitochondrial-derived peptides in cord blood have been associated with prenatal exposure to non-freeway traffic-related air pollution [50]. Cigarette smoke causes mitochondrial dysfunction in the lung epithelium [51].
Several medications commonly used during pregnancy have been linked to an increased risk of developing ASD including acetaminophen [52] and selective serotonin reuptake inhibitors [53]. Acetaminophen has known toxicity by increasing reactive metabolites leading to suppression of mitochondrial function [54]. Fluoxetine, a commonly used selective serotonin reuptake inhibitor, has been shown to inhibit multiple mitochondrial enzymes in several laboratory studies [55] and may result in long-term changes in energy metabolism with neonatal exposure [56]. Other medications commonly used in pregnancy with less certain association with ASD are associated with mitochondrial dysfunction. For example, commonly used antibiotics, including quinolones, aminoglycosides, and β-lactams, can cause mitochondrial dysfunction [57], and commonly used anesthesia may be particularly detrimental to the developing brain, partially through mitochondrial mechanisms [58].
Interestingly, mitochondrial abnormalities have been documented in genetic syndromes associated with ASD such as PTEN mutations [59] and tuberous sclerosis [60,61], Fragile X [62,63], Rett [64,65,66], Phelan–McDermid [67], 15q11-13 duplication [68,69], Angelman [70] and Down [71,72] syndromes as well as septo-optic dysplasia [73]. Thus, a fetus with these genetic changes may already have vulnerable mitochondria that might be sensitive to environmental stressors.
Common nutritional deficiencies are prenatal ASD risk factors which have been suggested to modulate mitochondrial function. Decreased vitamin D in the first [74] or second [75] trimester as well as lifetime [76] is associated with more severe ASD [74,75] or increased ASD risk [76]. Vitamin D deficiency is associated with oxidative stress and reduced mitochondrial respiration that is mediated through the vitamin D receptor [77,78].
Several lines of evidence suggest that ASD is associated with disruption of the microbiome in individuals with ASD as well as their mother during pregnancy [79]. Although a recent landmark study provided preliminary evidence that transplanting the microbiome in individuals with ASD can improve gastrointestinal and ASD symptoms [63], studies in pregnant women are more difficult to conduct, leading to animal studies addressing this possibility. Environmentally induced rodent models of ASD, including the MIA [80] and the valproic acid exposure models [81,82,83], have an altered microbiome. Manipulations which can affect the microbiome have been shown to mitigate the effects of these maternal exposures. Treating pups born from maternal valproic acid exposure demonstrate reduced ASD-like behaviors [84,85] as well as normalization of mitochondrial abnormalities [84], while treatment of pups born from MIA with Bacteroides fragilis normalizes gut permeability and microbial composition and reduces ASD-like behaviors [86]. Interestingly, several prenatal environmental exposures linked to ASD, including air pollution [87], glyphosate [88], prenatal antibiotic use [89], maternal stress [90] and organophosphate herbicides [91], have evidence for disrupting the microbiome, suggesting a potential biological pathway for their effects. The microbiome can influence mitochondrial function through several mechanisms, although the most compelling is through the production of short chain fatty acids [92].

4. Unique Abnormalities in Mitochondrial Function Are Prevalent in ASD

The possibility that environmentally induced mitochondrial dysfunction could have a role in ASD is particularly compelling because abnormal mitochondrial function is one of the most prevalent metabolic disorders found in individuals with ASD, with prevalence ranging from 5% for classically defined mitochondrial disease to 8–47% for biomarkers of mitochondrial dysfunction [11,16], to 62–65% for abnormal ETC/CAC enzymology [93,94], and to 80% for abnormal ETC activity in lymphocytes and granulocytes [95,96]. Particularly compelling is that the great majority of the time, genetic defects cannot explain the mitochondrial abnormalities, suggesting that the abnormality could be acquired as a result of an environmental exposure. There is also a tremendous practical appeal in this hypothesis, as environmental determinants may be particularly amenable to modification.
In classic mitochondrial disease, ETC activity is, by definition, depressed. However, what is unique about abnormalities in mitochondrial function in individuals with ASD is that ETC activity is significantly increased in many cases. The first case reported was a boy with ASD who demonstrated a significant increase in ETC complex I activity while his sister, who was diagnosed with a classic mitochondrial disease known as Leigh syndrome, showed depressed ETC activity [97]. Interestingly, both siblings manifested the same mtDNA mutation, but the sister had a greater genetic mutational load (i.e., higher heteroplasmy). Subsequently, a case-series of five patents with ASD with muscle ETC complex IV activity about 200% of normal was reported [98]. The association of elevated ETC complex IV activity with ASD has subsequently been confirmed in fresh frozen superior temporal gyrus [99], buccal swabs enzymology [93] and lymphoblastoid cell lines (LCLs) using high-resolution respirometry [100].

5. The Significance of Mitochondrial Dysfunction in ASD: Sensitivity to Physiological Stress

Since increased ROS is a key mechanism by which environmental stressors, such as toxicants [101,102,103,104,105,106,107,108] and inflammation [1,11], can disrupt mitochondrial function, an assay has been developed which systematically increases ROS in vitro [109]. This assay, called the Mitochondrial Oxidative Stress Test (MOST), systematically increases ROS in vitro using 2,3–dimethoxy–1,4-napthoquinone (DMNQ), an agent that generates intracellular superoxide and hydrogen peroxide but does not directly deplete thiols [110]. The model was initially developed using LCLs from boys with ASD and age-matched healthy controls (CNT) where DMNQ was shown to increase ROS in CNT and ASD LCLs [110].
In this model, mitochondrial respiratory rates were significantly higher in ASD LCLs as compared to CNT LCLs. Most compelling, indices of mitochondrial health, reserve capacity and maximal respiratory rate, decreased to a greater extent in ASD LCLs when challenged with DMNQ in the MOST assay. Increases in ROS, using the MOST assay, resulted in a depletion of these respiratory parameters at lower DMNQ concentrations in the ASD LCLs, despite these parameters being higher at baseline. This suggests that the ASD LCLs demonstrated a greater vulnerability to ROS.
To determine if these bioenergetics changes were specific to a subset of ASD LCLs, a cluster analysis was used to separated ASD LCLs into those with normal bioenergetics (AD-N) and those with atypical bioenergetics (AD-A) [109]. When the AD-A LCLs were compared to the CNT LCLs, the bioenergetic differences were found to be large. Baseline respiratory rates were ~200% higher in AD-A as compared to the CNT LCLs. Most notably, maximal respiratory capacity and reserve capacity markedly decreased as DMNQ increased, such that reserve capacity was rapidly depleted as DMNQ increased despite being much higher at baseline. This pattern of abnormal respiration in this subset of LCLs has been confirmed over eight studies [61,109,111,112,113,114,115,116].
Despite these experiments, the question remained whether this pattern of mitochondrial dysfunction was specific to ASD or simply a consequence of higher levels of chronic ongoing intrinsic oxidative stress. Since neurotypical siblings (SIBs) of children with ASD manifest similar chronic ongoing elevation in oxidative stress in their LCLs, mitochondrial function was compared between 10 LCLs from boys with ASD and their 10 male SIBs and 10 age-matched CNT males [117]. Mitochondrial function was similar between SIBs and CNTs, but both were different from ASD. In the ASD LCLs, mitochondrial respiration was elevated at baseline and reserve capacity declined more precipitously with increasing DMNQ, as compared to SIB and CNT LCLs. Most notably, the severity of mitochondrial abnormalities in ASD LCLs was related to the severity of stereotyped behaviors and restricted interests as measured on the gold-standard Autism Diagnostic Observation Schedule evaluation years earlier when the blood samples were original collected. Thus, atypical mitochondrial activity in the ASD LCLs is not simply a product of abnormal redox metabolism but rather associated with atypical mitochondrial function specifically. Furthermore, this atypical mitochondrial function is related to more severe core ASD behaviors, suggesting an association with molecular mechanisms of ASD.
Individuals with ASD demonstrate three developmental trajectories: in the early onset subtype, symptoms are obvious from early in infancy, perhaps at birth; in the plateau subtype, infants develop normally throughout the first year of life but then plateau in the rate of gaining skills, followed by the development of ASD symptoms; lastly is a subset that demonstrates neurodevelopmental regression (NDR). The NDR category is intriguing: children attain all their normal developmental milestones but then lose previously attained skills followed by the development of ASD-like behaviors. Often, NDR is associated with a trigger such as seizure [118] and/or fever [119]. NDR is not uncommon in individuals with mitochondrial disease when an illness occurs [120]. Thus, it is not surprising that a meta-analysis showed that NDR was more common in children with ASD that were also diagnosed with mitochondrial disease [11].
Given that the subset of ASD LCLs with elevated respiratory rates have increased vulnerability to physiological stress, a recent study hypothesized that children with ASD and NDR would demonstrate increase mitochondrial respiratory rates. Mitochondrial function was measured in cryopreserved peripheral blood mononuclear cells (PBMCs) from children with ASD, with and without NDR, as well as CNT using the Seahorse XF96 respirometer [121]. Viability was measured and 600 k viable PBMCs were plated per well. As hypothesized, mitochondrial respiration was elevated in children with ASD and NDR. Specifically, the maximal oxygen consumption rate, maximal respiratory capacity, and reserve capacity were higher in the individuals with ASD and NDR as compared to the other groups. Additionally, comparing ASD twins discordant on NDR demonstrated that the twin with NDR showed a significantly elevated maximal oxygen consumption rate. Thus, the NDR ASD phenotype may be a hallmark of abnormal mitochondrial physiology.

6. Unique ASD Mitochondrial Abnormalities May Be Linked to Both Environmental and Genetic Factors

Interestingly, the unique elevations in mitochondrial respiration reported in human tissue have been associated with both genetic and environmentally induced animal models of ASD. Elevated mitochondrial respiration has been documented in genetic syndromes associated with ASD, including Phelan–McDermid [122], Fragile X [62,63], 22q13 dup [67], and Rett [66] syndromes, the PTEN haploinsufficient mouse model of ASD [59] and the Drosophila model of the ASD associated CYFIP1 mutation [123]. Similar changes have been associated with prenatal environmental exposures, specifically prenatal exposure to inflammation as in the MIA mouse, a model of ASD induced by prenatal immune environmental stress [39], and prenatal exposure to toxins as in the maternal valproic acid exposure mouse model of ASD [84].
Consistent with evidence from these prenatal environmental animal models of ASD, several studies have examined the relationship between alternations in long-term mitochondrial function and prenatal environmental stressors in ASD.
Prenatal exposure to air pollution, as measured by average and maximum PM2.5, has been found to be related to mitochondrial respiration in childhood, as measured in PBMCs. The relationship was significantly different for those children with and without a history of NDR. For those with a history of NDR, higher prenatal PM2.5 exposure was associated with higher mitochondrial respiration rates, while for those without a history of NDR, higher prenatal PM2.5 exposure was related to lower mitochondrial respiration [27]. Additional research has linked prenatal air pollution exposure to mitochondrial-derived peptides in cord blood that are associated with long-term changes in mitochondrial physiology [50].
Both prenatal exposures to nutritional and toxic metal were measured in deciduous teeth using laser ablation inductively coupled plasma mass-spectrometry. Prenatal exposure to Mn and Zn was associated with mitochondrial respiration, but only in children with ASD and NDR [29]. The prenatal Cu to Zn ratio was associated with two independent measures of language development in all children with ASD (both those with and without NDR) [29]. This latter study extends previous findings linking prenatal nutrient metal (Zn, Mn, Cu) exposure and ASD [26,27,124,125,126,127].
To determine whether the long-term changes associated with ASD could be induced by exposure to environmental toxicants, one study exposed LCLs to low levels of ROS for a prolonged time (96 h) to simulate chronic ROS exposure which might occur with prolonged exposure to environmental toxicants or other physiological stressors [61]. Prolonged exposure to low levels of ROS induced bioenergetic changes in respiratory parameters involved in ATP production. After prolonged ROS exposure, the LCLs demonstrated increased respiratory rates at baseline, similar to the AD–A LCLs and the ETC activity seen in children with ASD in multiple tissues. These data suggest that a prolonged exposure to a pro-oxidant microenvironment can have chronic effects on the mitochondria.

7. Long-Term Induced Changes in Mitochondrial Function: Adaptive or Maladaptive

Mitochondria undergo long-term adaptive changes in physiology as a result of environmental stressors through a process known as mitoplasticity, which is one compelling mechanism for long-term changes in mitochondrial function associated with prenatal exposures [9]. Several studies may provide insight into the molecular mechanisms associated with long-term changes in mitochondrial function.
Matched typically developing siblings have similar abnormalities in oxidative stress compared to their ASD siblings, but the mitochondria of the ASD siblings appear to have difficulty regulating the mitochondrial ROS (mtROS). mtROS is regulated at the inner mitochondrial membrane through several mechanisms. Uncoupling proteins regulate mtROS by leaking protons across the inner mitochondrial membrane, a process known as proton leak. Studies have demonstrated increased proton leak respiration along with high oxidative stress in both cytoplasm and mitochondria in ASD LCLs [16,128]. Studies have associated ASD with an increase in mechanisms of proton leak. Three previous studies have found an increase in uncoupling protein (UCP2) gene expression [61,116] and protein concentration [109] in LCLs derived from children with ASD, particularly in the LCLs with high respiratory rates (i.e., AD–A LCLs). The adenine nucleotide translocator (ANT) has a significant role in the regulation of inner mitochondrial membrane proton leak. Microdeletion including the SLC25A5 (ANT2) has been associated with non-syndromic intellectual disability with ASD [129]. Heteroplasmic levels of the mtDNA 3243A > G mutation associated with ASD are also associated with significant changes in ANT gene expression [130]. Consistent with this evidence, increased protein leak is also a feature of mitochondrial abnormalities in the Fragile X syndrome mouse, where it is found to directly affect synaptic growth [131]. Thus, dysregulation in inner membrane proton leak seems to be associated with an ASD phenotype.
One of the key processes which maintains optimal mitochondrial function in the face of physiological stress is mitophagy. Several studies have linked ASD to a failure to induce this important process. Mutations in WDFY3 which result in ASD with intellectual disability have been linked to bioenergetic abnormalities in the brain through decreased mitophagy [132], and PARK2, a gene known to be involved in mitophagy, has been identified as a candidate gene for ASD [133]. Examination of the post-mortem temporal cortex has demonstrated ETC activity abnormalities along with alternation in levels of fission (Fis1, Drp1) and fusion (Mfn1, Mfn2 and Opa1) protein essential for regulating mitophagy [134]. Neurons deficient in TSC1/TSC2, a model of tuberous sclerosis, demonstrate impaired mitophagy through a mTORC1 mechanism [60,135]. This is consistent with studies which have demonstrated that ASD LCLs with elevated respiratory rates (i.e., AD–A LCLs) fail to upregulate genes associated with mitophagy through a mTORC1 pathway related mechanism [61]. Recently, ASD-derived fibroblasts were found to have elevated respiratory rates, atypical mitochondrial morphology, and alteration in the mitophagy pathway [136]. Interestingly, a loss of mitophagy can lead to a build-up of cytosolic ROS and mtDNA damage and an increase in proinflammatory cytokines, including IL–1α, IL–1β, IL–18, IFNα, MIF, IL–23, and IL–17 [137].
Alternative to regulatory changes within the body is the possibility that long-term alternation in the microbiome environment (technically outside of the body) could account for long-term changes in mitochondrial function. The connection between the microbiome and mitochondrial dysfunction in ASD is supported by the compelling propionic acid (PPA) rodent model of ASD. Adult rats intraventricularly injected with PPA [138], juvenile rates intraperitoneally injected with PPA [139], and prenatally PPA exposed rodents [140,141] demonstrated ASD-like behaviors. The importance of this model is that fact that enteric microbiome producers of PPA, particularly Clostridia sp, are relatively overrepresented in the ASD microbiome [142]. PPA exposure results in several physiological abnormalities, including mitochondrial dysfunction, particularly disruption of the fatty acid metabolism, as manifested by unique elevations in acyl-carnitines, as well as redox abnormalities as manifested by GSH alternations [142]. Parallel to the unique acyl-carnitine elevations in the rodent model, the same pattern was reported in a case series of ASD patients [143] with the parallel mitochondrial and GSH abnormalities later reported in a more detailed study [144]. Further in vitro studies with ASD LCLs demonstrated the potential detrimental effects of PPA [114] and the protective effect of another prominent enteric microbiome derived short chain fatty acid butyrate [115]. Thus, long-term changes in the microbiome could also account for long-term changes in mitochondrial function in individuals with ASD.

8. Conclusions

One of the critical knowledge gaps in environmental medicine is how an environmental exposure can result in disease when the symptoms arise years after the exposure. Mitochondrial metabolism is a promising mechanism through which the environment can cause long-term effects. For ASD, we have discussed the many prenatal environmental exposures which are linked to ASD and can cause detrimental changes in mitochondrial function. This is compelling because mitochondrial dysfunction is prevalent in ASD. ASD is also associated with a unique type of mitochondrial dysfunction which may be related to environmental exposures. Studies support the notion that specific prenatal exposures linked to ASD, most notably air pollution and prenatal nutritional metal exposure, is associated with long-term alterations in mitochondrial physiology. A better understanding of these biological processes may lead to prevention and treatment strategies.
Prenatal mitochondrial function is important for brain development, as recent animal studies have shown that mitochondrial dysfunction during gestation alters white matter brain connectivity [145] and non-radial interneuron migration [146]. Mitochondrial function is essential for optimal neuronal function and is essential for transport of essential nutrients into the brain such as folate [30]. Mitochondria are also essential for important core metabolic pathways as well as for optimal function of the immune system, which is now known to have an important role in brain development [30]. Thus, mitochondrial dysfunction during the prenatal period can have a profound effect on long-term development.
In this manuscript, we discuss studies with findings that link prenatal environmental exposures to long-term mitochondrial function and ASD. These studies remain intriguing yet preliminary. These findings need to be confirmed and further studies need to be conducted to expand on these findings. One important caveat is a consideration of the measurement of mitochondrial function, as mitochondrial function can differ from tissue to tissue and various assays reflect different aspects of mitochondrial function. For example, the use of PBMCs to measure mitochondrial function is a relatively newly developed biomarker which will require further validation in the future [147].
The applications of these findings may be far reaching, as interventions to correct metabolic and mitochondrial abnormalities are under development, potentially providing targeted treatments for preventing ASD and other diseases from developing if implemented prenatally.

Author Contributions

All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

This research was supported by the Arkansas Biosciences Institute (Little Rock, AR, USA), The Jonty Foundation (St Paul, MN, USA), The Autism Research Institute (San Diego, CA, USA), the Gupta Family Foundation (Atherton, CA, USA), The Jane Bostford Johnson Foundation (New York, NY, USA) and the Jager Family Foundation (Chicago, IL, USA).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Rossignol, D.A.; Frye, R.E. A review of research trends in physiological abnormalities in autism spectrum disorders: Immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol. Psychiatry 2012, 17, 389–401. [Google Scholar] [CrossRef] [PubMed][Green Version]
  2. Maenner, M.J.; Shaw, K.A.; Baio, J.; Washington, A.; Patrick, M.; DiRienzo, M.; Christensen, D.L.; Wiggins, L.D.; Pettygrove, S.; Andrews, J.G.; et al. Prevalence of autism spectrum disorder among children aged 8 years—Autism and developmental disabilities monitoring network, 11 sites, United States, 2016. Morb. Mortal. Wkly. Rep. Surveill. Summ. 2020, 69, 1–12. [Google Scholar] [CrossRef] [PubMed]
  3. Schaefer, G.B.; Mendelsohn, N.J. Professional Practice Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet. Med. 2013, 15, 399–407. [Google Scholar] [CrossRef] [PubMed][Green Version]
  4. Hallmayer, J.; Cleveland, S.; Torres, A.; Phillips, J.; Cohen, B.; Torigoe, T.; Miller, J.; Fedele, A.; Collins, J.; Smith, K.; et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch. Gen. Psychiatry 2011, 68, 1095–1102. [Google Scholar] [CrossRef]
  5. Sandin, S.; Lichtenstein, P.; Kuja-Halkola, R.; Larsson, H.; Hultman, C.M.; Reichenberg, A. The familial risk of autism. JAMA 2014, 311, 1770–1777. [Google Scholar] [CrossRef]
  6. Hertz-Picciotto, I.; Schmidt, R.J.; Krakowiak, P. Understanding environmental contributions to autism: Causal concepts and the state of science. Autism Res. Off. J. Int. Soc. Autism Res. 2018, 11, 554–586. [Google Scholar] [CrossRef]
  7. Rossignol, D.A.; Genuis, S.J.; Frye, R.E. Environmental toxicants and autism spectrum disorders: A systematic review. Transl. Psychiatry 2014, 4, e360. [Google Scholar] [CrossRef] [PubMed]
  8. Panisi, C.; Guerini, F.R.; Abruzzo, P.M.; Balzola, F.; Biava, P.M.; Bolotta, A.; Brunero, M.; Burgio, E.; Chiara, A.; Clerici, M.; et al. Autism spectrum disorder from the womb to adulthood: Suggestions for a paradigm shift. J. Pers. Med. 2021, 11, 70. [Google Scholar] [CrossRef]
  9. Jose, C.; Melser, S.; Benard, G.; Rossignol, R. Mitoplasticity: Adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis. Antioxid. Redox Signal. 2013, 18, 808–849. [Google Scholar] [CrossRef]
  10. Frye, R.E.; Rossignol, D.A. Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr. Res. 2011, 69, 41R–47R. [Google Scholar] [CrossRef]
  11. Rossignol, D.A.; Frye, R.E. Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis. Mol. Psychiatry 2012, 17, 290–314. [Google Scholar] [CrossRef] [PubMed][Green Version]
  12. Frye, R.E.; Rossignol, D. Mitochondrial physiology and autism spectrum disorder. OA Autism 2013, 1. [Google Scholar] [CrossRef][Green Version]
  13. Wallace, D.C.; Fan, W. Energetics, epigenetics, mitochondrial genetics. Mitochondrion 2010, 10, 12–31. [Google Scholar] [CrossRef][Green Version]
  14. Banoth, B.; Cassel, S.L. Mitochondria in innate immune signaling. Transl. Res. 2018, 202, 52–68. [Google Scholar] [CrossRef] [PubMed]
  15. Rossignol, D.A.; Frye, R.E. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front. Physiol. 2014, 5, 150. [Google Scholar] [CrossRef][Green Version]
  16. Rose, S.; Melnyk, S.; Pavliv, O.; Bai, S.; Nick, T.G.; Frye, R.E.; James, S.J. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl. Psychiatry 2012, 2, e134. [Google Scholar] [CrossRef] [PubMed][Green Version]
  17. Frustaci, A.; Neri, M.; Cesario, A.; Adams, J.B.; Domenici, E.; Dalla Bernardina, B.; Bonassi, S. Oxidative stress-related biomarkers in autism: Systematic review and meta-analyses. Free Radic. Biol. Med. 2012, 52, 2128–2141. [Google Scholar] [CrossRef]
  18. Napoli, E.; Wong, S.; Giulivi, C. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Mol. Autism 2013, 4, 2. [Google Scholar] [CrossRef][Green Version]
  19. O’Neill, L.A.; Kishton, R.J.; Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 2016, 16, 553–565. [Google Scholar] [CrossRef] [PubMed][Green Version]
  20. West, A.P.; Shadel, G.S.; Ghosh, S. Mitochondria in innate immune responses. Nat. Rev. Immunol. 2011, 11, 389–402. [Google Scholar] [CrossRef] [PubMed][Green Version]
  21. Jyonouchi, H.; Geng, L.; Rose, S.; Bennuri, S.C.; Frye, R.E. Variations in mitochondrial respiration differ in IL-1ß/IL-10 ratio based subgroups in autism spectrum disorders. Front. Psychiatry 2019, 10, 71. [Google Scholar] [CrossRef] [PubMed][Green Version]
  22. Delhey, L.M.; Nur Kilinc, E.; Yin, L.; Slattery, J.C.; Tippett, M.L.; Rose, S.; Bennuri, S.C.; Kahler, S.G.; Damle, S.; Legido, A.; et al. The effect of mitochondrial supplements on mitochondrial activity in children with autism spectrum disorder. J. Clin. Med. 2017, 6, 18. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. James, S.J.; Melnyk, S.; Jernigan, S.; Pavliv, O.; Trusty, T.; Lehman, S.; Seidel, L.; Gaylor, D.W.; Cleves, M.A. A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism. Am. J. Med Genet. Part B Neuropsychiatr. Genet. Off. Publ. Int. Soc. Psychiatr. Genet. 2010, 153b, 1209–1220. [Google Scholar] [CrossRef][Green Version]
  24. Quadros, E.V.; Sequeira, J.M.; Brown, W.T.; Mevs, C.; Marchi, E.; Flory, M.; Jenkins, E.C.; Velinov, M.T.; Cohen, I.L. Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents. Autism Res. Off. J. Int. Soc. Autism Res. 2018, 11, 707–712. [Google Scholar] [CrossRef]
  25. Sequeira, J.M.; Desai, A.; Berrocal-Zaragoza, M.I.; Murphy, M.M.; Fernandez-Ballart, J.D.; Quadros, E.V. Exposure to folate receptor alpha antibodies during gestation and weaning leads to severe behavioral deficits in rats: A pilot study. PLoS ONE 2016, 11, e0152249. [Google Scholar] [CrossRef]
  26. Curtin, P.; Austin, C.; Curtin, A.; Gennings, C.; Arora, M.; Tammimies, K.; Willfors, C.; Berggren, S.; Siper, P.; Rai, D.; et al. Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Sci. Adv. 2018, 4, eaat1293. [Google Scholar] [CrossRef][Green Version]
  27. Frye, R.E.; Cakir, J.; Rose, S.; Delhey, L.; Bennuri, S.C.; Tippett, M.; Melnyk, S.; James, S.J.; Palmer, R.F.; Austin, C.; et al. Prenatal air pollution influences neurodevelopment and behavior in autism spectrum disorder by modulating mitochondrial physiology. Mol. Psychiatry 2020. [Google Scholar] [CrossRef]
  28. Zhong, C.; Tessing, J.; Lee, B.K.; Lyall, K. Maternal dietary factors and the risk of autism spectrum disorders: A systematic review of existing evidence. Autism Res. Off. J. Int. Soc. Autism Res. 2020. [Google Scholar] [CrossRef]
  29. Frye, R.E. Mitochondrial dysfunction in autism spectrum disorder: Unique abnormalities and targeted treatments. Semin. Pediatr. Neurol. 2020, 35, 100829. [Google Scholar] [CrossRef] [PubMed]
  30. 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. Mol. Diagn. Ther. 2018, 22, 571–593. [Google Scholar] [CrossRef][Green Version]
  31. Sun, M.; Zhao, B.; He, S.; Weng, R.; Wang, B.; Ding, Y.; Huang, X.; Luo, Q. The alteration of carnitine metabolism in second trimester in GDM and a nomogram for predicting macrosomia. J. Diabetes Res. 2020, 2020, 4085757. [Google Scholar] [CrossRef] [PubMed]
  32. Wan, H.; Zhang, C.; Li, H.; Luan, S.; Liu, C. Association of maternal diabetes with autism spectrum disorders in offspring: A systemic review and meta-analysis. Medicine 2018, 97, e9438. [Google Scholar] [CrossRef] [PubMed]
  33. Celestino-Soper, P.B.; Violante, S.; Crawford, E.L.; Luo, R.; Lionel, A.C.; Delaby, E.; Cai, G.; Sadikovic, B.; Lee, K.; Lo, C.; et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc. Natl. Acad. Sci. USA 2012, 109, 7974–7981. [Google Scholar] [CrossRef] [PubMed][Green Version]
  34. Lee, H.; Kim, H.K.; Kwon, J.T.; Park, S.; Park, H.J.; Kim, S.K.; Park, J.K.; Kang, W.S.; Kim, Y.J.; Chung, J.H.; et al. BBOX1 is down-regulated in maternal immune-activated mice and implicated in genetic susceptibility to human schizophrenia. Psychiatry Res. 2018, 259, 197–202. [Google Scholar] [CrossRef] [PubMed]
  35. Bankaitis, V.A.; Xie, Z. The neural stem cell/carnitine malnutrition hypothesis: New prospects for effective reduction of autism risk? J. Biol. Chem. 2019, 294, 19424–19435. [Google Scholar] [CrossRef][Green Version]
  36. Hollowood, K.; Melnyk, S.; Pavliv, O.; Evans, T.; Sides, A.; Schmidt, R.J.; Hertz-Picciotto, I.; Elms, W.; Guerrero, E.; Kruger, U.; et al. Maternal metabolic profile predicts high or low risk of an autism pregnancy outcome. Res. Autism Spectr. Disord. 2018, 56, 72–82. [Google Scholar] [CrossRef]
  37. James, S.J.; Melnyk, S.; Jernigan, S.; Hubanks, A.; Rose, S.; Gaylor, D.W. Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism. J. Autism Dev. Disord. 2008, 38, 1966–1975. [Google Scholar] [CrossRef]
  38. Bauman, M.D.; Van de Water, J. Translational opportunities in the prenatal immune environment: Promises and limitations of the maternal immune activation model. Neurobiol. Dis. 2020, 141, 104864. [Google Scholar] [CrossRef]
  39. Naviaux, R.K.; Zolkipli, Z.; Wang, L.; Nakayama, T.; Naviaux, J.C.; Le, T.P.; Schuchbauer, M.A.; Rogac, M.; Tang, Q.; Dugan, L.L.; et al. Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PLoS ONE 2013, 8, e57380. [Google Scholar] [CrossRef]
  40. Giulivi, C.; Napoli, E.; Schwartzer, J.; Careaga, M.; Ashwood, P. Gestational exposure to a viral mimetic poly(i:C) results in long-lasting changes in mitochondrial function by leucocytes in the adult offspring. Mediat. Inflamm. 2013, 2013, 609602. [Google Scholar] [CrossRef][Green Version]
  41. Jones, K.L.; Croen, L.A.; Yoshida, C.K.; Heuer, L.; Hansen, R.; Zerbo, O.; DeLorenze, G.N.; Kharrazi, M.; Yolken, R.; Ashwood, P.; et al. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol. Psychiatry 2017, 22, 273–279. [Google Scholar] [CrossRef] [PubMed][Green Version]
  42. Wong, H.; Hoeffer, C. Maternal IL-17A in autism. Exp. Neurol. 2018, 299, 228–240. [Google Scholar] [CrossRef] [PubMed]
  43. Kim, E.K.; Kwon, J.E.; Lee, S.Y.; Lee, E.J.; Kim, D.S.; Moon, S.J.; Lee, J.; Kwok, S.K.; Park, S.H.; Cho, M.L. IL-17-mediated mitochondrial dysfunction impairs apoptosis in rheumatoid arthritis synovial fibroblasts through activation of autophagy. Cell Death Dis. 2017, 8, e2565. [Google Scholar] [CrossRef]
  44. Kakareko, M.; Jabłońska, E.; Ratajczak-Wrona, W. Role of rhIL-17 in regulating the mitochondrial pathway proteins in peripheral blood neutrophils. Clin. Lab. 2015, 61, 345–351. [Google Scholar] [CrossRef]
  45. Zhou, H.; Wang, H.; Yu, M.; Schugar, R.C.; Qian, W.; Tang, F.; Liu, W.; Yang, H.; McDowell, R.E.; Zhao, J.; et al. IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes. Nat. Immunol. 2020, 21, 1219–1231. [Google Scholar] [CrossRef]
  46. Xu, Y.; Zhang, Y.; Ye, J. IL-6: A potential role in cardiac metabolic homeostasis. Int. J. Mol. Sci. 2018, 19, 2474. [Google Scholar] [CrossRef][Green Version]
  47. Karami-Mohajeri, S.; Abdollahi, M. Toxic influence of organophosphate, carbamate, and organochlorine pesticides on cellular metabolism of lipids, proteins, and carbohydrates: A systematic review. Hum. Exp. Toxicol. 2011, 30, 1119–1140. [Google Scholar] [CrossRef]
  48. Posnack, N.G.; Swift, L.M.; Kay, M.W.; Lee, N.H.; Sarvazyan, N. Phthalate exposure changes the metabolic profile of cardiac muscle cells. Environ. Health Perspect. 2012, 120, 1243–1251. [Google Scholar] [CrossRef] [PubMed]
  49. Pant, N.; Shukla, M.; Kumar Patel, D.; Shukla, Y.; Mathur, N.; Kumar Gupta, Y.; Saxena, D.K. Correlation of phthalate exposures with semen quality. Toxicol. Appl. Pharmacol. 2008, 231, 112–116. [Google Scholar] [CrossRef]
  50. Breton, C.V.; Song, A.Y.; Xiao, J.; Kim, S.J.; Mehta, H.H.; Wan, J.; Yen, K.; Sioutas, C.; Lurmann, F.; Xue, S.; et al. Effects of air pollution on mitochondrial function, mitochondrial DNA methylation, and mitochondrial peptide expression. Mitochondrion 2019, 46, 22–29. [Google Scholar] [CrossRef]
  51. Aghapour, M.; Remels, A.H.V.; Pouwels, S.D.; Bruder, D.; Hiemstra, P.S.; Cloonan, S.M.; Heijink, I.H. Mitochondria: At the crossroads of regulating lung epithelial cell function in chronic obstructive pulmonary disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 2020, 318, L149–l164. [Google Scholar] [CrossRef]
  52. Bauer, A.Z.; Kriebel, D.; Herbert, M.R.; Bornehag, C.G.; Swan, S.H. Prenatal paracetamol exposure and child neurodevelopment: A review. Horm. Behav. 2018, 101, 125–147. [Google Scholar] [CrossRef]
  53. Andalib, S.; Emamhadi, M.R.; Yousefzadeh-Chabok, S.; Shakouri, S.K.; Høilund-Carlsen, P.F.; Vafaee, M.S.; Michel, T.M. Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review. Eur. Psychiatry J. Assoc. Eur. Psychiatr. 2017, 45, 161–166. [Google Scholar] [CrossRef]
  54. Ramachandran, A.; Jaeschke, H. Acetaminophen hepatotoxicity: A mitochondrial perspective. Adv. Pharmacol. 2019, 85, 195–219. [Google Scholar] [CrossRef] [PubMed]
  55. De Oliveira, M.R. Fluoxetine and the mitochondria: A review of the toxicological aspects. Toxicol. Lett. 2016, 258, 185–191. [Google Scholar] [CrossRef] [PubMed]
  56. Da L.D. Barros, M.; Manhães-de-Castro, R.; Alves, D.T.; Quevedo, O.G.; Toscano, A.E.; Bonnin, A.; Galindo, L. Long term effects of neonatal exposure to fluoxetine on energy balance: A systematic review of experimental studies. Eur. J. Pharmacol. 2018, 833, 298–306. [Google Scholar] [CrossRef]
  57. Kalghatgi, S.; Spina, C.S.; Costello, J.C.; Liesa, M.; Morones-Ramirez, J.R.; Slomovic, S.; Molina, A.; Shirihai, O.S.; Collins, J.J. Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in Mammalian cells. Sci. Transl. Med. 2013, 5, 192ra85. [Google Scholar] [CrossRef][Green Version]
  58. Bodolea, C. Anaesthesia in early childhood—Is the development of the immature brain in danger? Rom. J. Anaesth. Intensive Care 2016, 23, 33–40. [Google Scholar] [CrossRef][Green Version]
  59. Napoli, E.; Ross-Inta, C.; Wong, S.; Hung, C.; Fujisawa, Y.; Sakaguchi, D.; Angelastro, J.; Omanska-Klusek, A.; Schoenfeld, R.; Giulivi, C. Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: Interplay between Pten and p53. PLoS ONE 2012, 7, e42504. [Google Scholar] [CrossRef][Green Version]
  60. Ebrahimi-Fakhari, D.; Saffari, A.; Wahlster, L.; Sahin, M. Using tuberous sclerosis complex to understand the impact of MTORC1 signaling on mitochondrial dynamics and mitophagy in neurons. Autophagy 2017, 13, 754–756. [Google Scholar] [CrossRef] [PubMed]
  61. Bennuri, S.C.; Rose, S.; Frye, R.E. Mitochondrial dysfunction is inducible in lymphoblastoid cell lines from children with autism and may involve the TORC1 pathway. Front. Psychiatry Mol. Psychiatry 2019, 10, 269. [Google Scholar] [CrossRef][Green Version]
  62. D’Antoni, S.; de Bari, L.; Valenti, D.; Borro, M.; Bonaccorso, C.M.; Simmaco, M.; Vacca, R.A.; Catania, M.V. Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome. Biol. Chem. 2020, 401, 497–503. [Google Scholar] [CrossRef]
  63. Griffiths, K.K.; Wang, A.; Wang, L.; Tracey, M.; Kleiner, G.; Quinzii, C.M.; Sun, L.; Yang, G.; Perez-Zoghbi, J.F.; Licznerski, P.; et al. Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2020, 34, 7404–7426. [Google Scholar] [CrossRef][Green Version]
  64. Grosser, E.; Hirt, U.; Janc, O.A.; Menzfeld, C.; Fischer, M.; Kempkes, B.; Vogelgesang, S.; Manzke, T.U.; Opitz, L.; Salinas-Riester, G.; et al. Oxidative burden and mitochondrial dysfunction in a mouse model of Rett syndrome. Neurobiol. Dis. 2012, 48, 102–114. [Google Scholar] [CrossRef]
  65. Gibson, J.H.; Slobedman, B.; KN, H.; Williamson, S.L.; Minchenko, D.; El-Osta, A.; Stern, J.L.; Christodoulou, J. Downstream targets of methyl CpG binding protein 2 and their abnormal expression in the frontal cortex of the human Rett syndrome brain. BMC Neurosci. 2010, 11, 53. [Google Scholar] [CrossRef][Green Version]
  66. Condie, J.; Goldstein, J.; Wainwright, M.S. Acquired microcephaly, regression of milestones, mitochondrial dysfunction, and episodic rigidity in a 46,XY male with a de novo MECP2 gene mutation. J. Child Neurol. 2010, 25, 633–636. [Google Scholar] [CrossRef] [PubMed]
  67. Frye, R.E. Mitochondrial disease in 22q13 duplication syndrome. J. Child Neurol. 2012, 27, 942–949. [Google Scholar] [CrossRef] [PubMed]
  68. Frye, R.E. 15q11.2-13 duplication, mitochondrial dysfunction, and developmental disorders. J. Child Neurol. 2009, 24, 1316–1320. [Google Scholar] [CrossRef] [PubMed][Green Version]
  69. Filipek, P.A.; Juranek, J.; Smith, M.; Mays, L.Z.; Ramos, E.R.; Bocian, M.; Masser-Frye, D.; Laulhere, T.M.; Modahl, C.; Spence, M.A.; et al. Mitochondrial dysfunction in autistic patients with 15q inverted duplication. Ann. Neurol. 2003, 53, 801–804. [Google Scholar] [CrossRef]
  70. Su, H.; Fan, W.; Coskun, P.E.; Vesa, J.; Gold, J.A.; Jiang, Y.H.; Potluri, P.; Procaccio, V.; Acab, A.; Weiss, J.H.; et al. Mitochondrial dysfunction in CA1 hippocampal neurons of the UBE3A deficient mouse model for Angelman syndrome. Neurosci. Lett. 2011, 487, 129–133. [Google Scholar] [CrossRef][Green Version]
  71. Pagano, G.; Castello, G. Oxidative stress and mitochondrial dysfunction in Down syndrome. Adv. Exp. Med. Biol. 2012, 724, 291–299. [Google Scholar] [CrossRef] [PubMed]
  72. Pallardo, F.V.; Lloret, A.; Lebel, M.; d’Ischia, M.; Cogger, V.C.; Le Couteur, D.G.; Gadaleta, M.N.; Castello, G.; Pagano, G. Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-telangiectasia, Down syndrome, Fanconi anaemia and Werner syndrome. Biogerontology 2010, 11, 401–419. [Google Scholar] [CrossRef]
  73. Schuelke, M.; Krude, H.; Finckh, B.; Mayatepek, E.; Janssen, A.; Schmelz, M.; Trefz, F.; Trijbels, F.; Smeitink, J. Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation. Ann. Neurol. 2002, 51, 388–392. [Google Scholar] [CrossRef] [PubMed]
  74. Chen, J.; Xin, K.; Wei, J.; Zhang, K.; Xiao, H. Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring. J. Psychosom. Res. 2016, 89, 98–101. [Google Scholar] [CrossRef]
  75. Vinkhuyzen, A.A.E.; Eyles, D.W.; Burne, T.H.J.; Blanken, L.M.E.; Kruithof, C.J.; Verhulst, F.; White, T.; Jaddoe, V.W.; Tiemeier, H.; McGrath, J.J. Gestational vitamin D deficiency and autism spectrum disorder. Bjpsych. Open 2017, 3, 85–90. [Google Scholar] [CrossRef]
  76. Magnusson, C.; Lundberg, M.; Lee, B.K.; Rai, D.; Karlsson, H.; Gardner, R.; Kosidou, K.; Arver, S.; Dalman, C. Maternal vitamin D deficiency and the risk of autism spectrum disorders: Population-based study. Bjpsych. Open 2016, 2, 170–172. [Google Scholar] [CrossRef][Green Version]
  77. Dzik, K.P.; Kaczor, J.J. Mechanisms of vitamin D on skeletal muscle function: Oxidative stress, energy metabolism and anabolic state. Eur. J. Appl. Physiol. 2019, 119, 825–839. [Google Scholar] [CrossRef][Green Version]
  78. Silvagno, F.; Pescarmona, G. Spotlight on vitamin D receptor, lipid metabolism and mitochondria: Some preliminary emerging issues. Mol. Cell. Endocrinol. 2017, 450, 24–31. [Google Scholar] [CrossRef] [PubMed]
  79. Slattery, J.; MacFabe, D.F.; Kahler, S.G.; Frye, R.E. Enteric ecosystem disruption in autism spectrum disorder: Can the microbiota and macrobiota be restored? Curr. Pharm. Des. 2016, 22, 6107–6121. [Google Scholar] [CrossRef][Green Version]
  80. Lammert, C.R.; Frost, E.L.; Bolte, A.C.; Paysour, M.J.; Shaw, M.E.; Bellinger, C.E.; Weigel, T.K.; Zunder, E.R.; Lukens, J.R. Cutting edge: Critical roles for microbiota-mediated regulation of the immune system in a prenatal immune activation model of autism. J. Immunol. 2018, 201, 845–850. [Google Scholar] [CrossRef][Green Version]
  81. Liu, F.; Horton-Sparks, K.; Hull, V.; Li, R.W.; Martínez-Cerdeño, V. The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism. Mol. Autism 2018, 9, 61. [Google Scholar] [CrossRef] [PubMed][Green Version]
  82. Wang, J.P.; Xu, Y.C.; Hou, J.Q.; Li, J.Y.; Xing, J.; Yang, B.X.; Zhang, Z.H.; Zhang, B.L.; Li, H.H.; Li, P. Effects of dietary fat profile on gut microbiota in valproate animal model of autism. Front. Med. 2020, 7, 151. [Google Scholar] [CrossRef]
  83. De Theije, C.G.; Wopereis, H.; Ramadan, M.; van Eijndthoven, T.; Lambert, J.; Knol, J.; Garssen, J.; Kraneveld, A.D.; Oozeer, R. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav. Immun. 2014, 37, 197–206. [Google Scholar] [CrossRef] [PubMed]
  84. Ahn, Y.; Narous, M.; Tobias, R.; Rho, J.M.; Mychasiuk, R. The ketogenic diet modifies social and metabolic alterations identified in the prenatal valproic acid model of autism spectrum disorder. Dev. Neurosci. 2014, 36, 371–380. [Google Scholar] [CrossRef]
  85. Castro, K.; Baronio, D.; Perry, I.S.; Riesgo, R.D.S.; Gottfried, C. The effect of ketogenic diet in an animal model of autism induced by prenatal exposure to valproic acid. Nutr. Neurosci. 2017, 20, 343–350. [Google Scholar] [CrossRef] [PubMed]
  86. Hsiao, E.Y.; McBride, S.W.; Hsien, S.; Sharon, G.; Hyde, E.R.; McCue, T.; Codelli, J.A.; Chow, J.; Reisman, S.E.; Petrosino, J.F.; et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013, 155, 1451–1463. [Google Scholar] [CrossRef][Green Version]
  87. Vallès, Y.; Francino, M.P. Air pollution, early life microbiome, and development. Curr. Environ. Health Rep. 2018, 5, 512–521. [Google Scholar] [CrossRef] [PubMed][Green Version]
  88. Pu, Y.; Yang, J.; Chang, L.; Qu, Y.; Wang, S.; Zhang, K.; Xiong, Z.; Zhang, J.; Tan, Y.; Wang, X.; et al. Maternal glyphosate exposure causes autism-like behaviors in offspring through increased expression of soluble epoxide hydrolase. Proc. Natl. Acad. Sci. USA 2020, 117, 11753–11759. [Google Scholar] [CrossRef]
  89. Hamad, A.F.; Alessi-Severini, S.; Mahmud, S.M.; Brownell, M.; Kuo, I.F. Prenatal antibiotics exposure and the risk of autism spectrum disorders: A population-based cohort study. PLoS ONE 2019, 14, e0221921. [Google Scholar] [CrossRef][Green Version]
  90. Beversdorf, D.Q.; Stevens, H.E.; Margolis, K.G.; Van de Water, J. Prenatal stress and maternal immune dysregulation in autism spectrum disorders: Potential points for intervention. Curr. Pharm. Des. 2019, 25, 4331–4343. [Google Scholar] [CrossRef]
  91. Dong, T.; Guan, Q.; Hu, W.; Zhang, M.; Zhang, Y.; Chen, M.; Wang, X.; Xia, Y. Prenatal exposure to glufosinate ammonium disturbs gut microbiome and induces behavioral abnormalities in mice. J. Hazard. Mater. 2020, 389, 122152. [Google Scholar] [CrossRef]
  92. Frye, R.E.; Rose, S.; Slattery, J.; MacFabe, D.F. Gastrointestinal dysfunction in autism spectrum disorder: The role of the mitochondria and the enteric microbiome. Microb. Ecol. Health Dis. 2015, 26, 27458. [Google Scholar] [CrossRef]
  93. Delhey, L.; Kilinc, E.N.; Yin, L.; Slattery, J.; Tippett, M.; Wynne, R.; Rose, S.; Kahler, S.; Damle, S.; Legido, A.; et al. Bioenergetic variation is related to autism symptomatology. Metab. Brain Dis. 2017, 32, 2021–2031. [Google Scholar] [CrossRef][Green Version]
  94. Goldenthal, M.J.; Damle, S.; Sheth, S.; Shah, N.; Melvin, J.; Jethva, R.; Hardison, H.; Marks, H.; Legido, A. Mitochondrial enzyme dysfunction in autism spectrum disorders; a novel biomarker revealed from buccal swab analysis. Biomark. Med. 2015, 9, 957–965. [Google Scholar] [CrossRef]
  95. Giulivi, C.; Zhang, Y.F.; Omanska-Klusek, A.; Ross-Inta, C.; Wong, S.; Hertz-Picciotto, I.; Tassone, F.; Pessah, I.N. Mitochondrial dysfunction in autism. JAMA 2010, 304, 2389–2396. [Google Scholar] [CrossRef][Green Version]
  96. Napoli, E.; Wong, S.; Hertz-Picciotto, I.; Giulivi, C. Deficits in bioenergetics and impaired immune response in granulocytes from children with autism. Pediatrics 2014, 133, e1405–e1410. [Google Scholar] [CrossRef] [PubMed][Green Version]
  97. Graf, W.D.; Marin-Garcia, J.; Gao, H.G.; Pizzo, S.; Naviaux, R.K.; Markusic, D.; Barshop, B.A.; Courchesne, E.; Haas, R.H. Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation. J. Child Neurol. 2000, 15, 357–361. [Google Scholar] [CrossRef]
  98. Frye, R.E.; Naviaux, R.K. Autistic disorder with complex IV overactivity: A new mitochondrial syndrome. J. Pediatr. Neurol. 2011, 9, 427–434. [Google Scholar]
  99. Palmieri, L.; Papaleo, V.; Porcelli, V.; Scarcia, P.; Gaita, L.; Sacco, R.; Hager, J.; Rousseau, F.; Curatolo, P.; Manzi, B.; et al. Altered calcium homeostasis in autism-spectrum disorders: Evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Mol. Psychiatry 2010, 15, 38–52. [Google Scholar] [CrossRef] [PubMed][Green Version]
  100. Hassan, H.; Gnaiger, E.; Zakaria, F.; Makpol, S.; Karim, N.A. Alterations in mitocohndrial respiratiory capacity and membrane potential: A link between mitochondrial dysregulation and autism. MitoFit 2020, in press. [Google Scholar]
  101. Fowler, B.A.; Woods, J.S. Ultrastructural and biochemical changes in renal mitochondria during chronic oral methyl mercury exposure: The relationship to renal function. Exp. Mol. Pathol. 1977, 27, 403–412. [Google Scholar] [CrossRef]
  102. Shenker, B.J.; Guo, T.L.; O, I.; Shapiro, I.M. Induction of apoptosis in human T-cells by methyl mercury: Temporal relationship between mitochondrial dysfunction and loss of reductive reserve. Toxicol. Appl. Pharmacol. 1999, 157, 23–35. [Google Scholar] [CrossRef] [PubMed]
  103. Goyer, R.A. Toxic and essential metal interactions. Annu. Rev. Nutr. 1997, 17, 37–50. [Google Scholar] [CrossRef]
  104. Pourahmad, J.; Mihajlovic, A.; O’Brien, P.J. Hepatocyte lysis induced by environmental metal toxins may involve apoptotic death signals initiated by mitochondrial injury. Adv. Exp. Med. Biol. 2001, 500, 249–252. [Google Scholar] [CrossRef]
  105. Hiura, T.S.; Li, N.; Kaplan, R.; Horwitz, M.; Seagrave, J.C.; Nel, A.E. The role of a mitochondrial pathway in the induction of apoptosis by chemicals extracted from diesel exhaust particles. J. Immunol. 2000, 165, 2703–2711. [Google Scholar] [CrossRef][Green Version]
  106. Wong, P.W.; Garcia, E.F.; Pessah, I.N. Ortho-substituted PCB95 alters intracellular calcium signaling and causes cellular acidification in PC12 cells by an immunophilin-dependent mechanism. J. Neurochem. 2001, 76, 450–463. [Google Scholar] [CrossRef] [PubMed]
  107. Sherer, T.B.; Richardson, J.R.; Testa, C.M.; Seo, B.B.; Panov, A.V.; Yagi, T.; Matsuno-Yagi, A.; Miller, G.W.; Greenamyre, J.T. Mechanism of toxicity of pesticides acting at complex I: Relevance to environmental etiologies of Parkinson’s disease. J. Neurochem. 2007, 100, 1469–1479. [Google Scholar] [CrossRef] [PubMed]
  108. Yamano, T.; Morita, S. Effects of pesticides on isolated rat hepatocytes, mitochondria, and microsomes II. Arch. Environ. Contam. Toxicol. 1995, 28, 1–7. [Google Scholar] [CrossRef]
  109. Rose, S.; Frye, R.E.; Slattery, J.; Wynne, R.; Tippett, M.; Pavliv, O.; Melnyk, S.; James, S.J. Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort. PLoS ONE 2014, 9, e85436. [Google Scholar] [CrossRef]
  110. Hill, B.G.; Higdon, A.N.; Dranka, B.P.; Darley-Usmar, V.M. Regulation of vascular smooth muscle cell bioenergetic function by protein glutathiolation. Biochim. Biophys. Acta 2010, 1797, 285–295. [Google Scholar] [CrossRef][Green Version]
  111. Frye, R.E.; Rose, S.; Wynne, R.; Bennuri, S.C.; Blossom, S.; Gilbert, K.M.; Heilbrun, L.; Palmer, R.F. Oxidative stress challenge uncovers trichloroacetaldehyde hydrate-induced mitoplasticity in autistic and control lymphoblastoid cell lines. Sci. Rep. 2017, 7, 4478. [Google Scholar] [CrossRef] [PubMed][Green Version]
  112. Rose, S.; Frye, R.E.; Slattery, J.; Wynne, R.; Tippett, M.; Melnyk, S.; James, S.J. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl. Psychiatry 2015, 5, e526. [Google Scholar] [CrossRef] [PubMed][Green Version]
  113. Rose, S.; Wynne, R.; Frye, R.E.; Melnyk, S.; James, S.J. Increased susceptibility to ethylmercury-induced mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines. J. Toxicol. 2015, 2015, 573701. [Google Scholar] [CrossRef] [PubMed]
  114. Frye, R.E.; Rose, S.; Chacko, J.; Wynne, R.; Bennuri, S.C.; Slattery, J.C.; Tippett, M.; Delhey, L.; Melnyk, S.; Kahler, S.G.; et al. Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. Transl. Psychiatry 2016, 6, e927. [Google Scholar] [CrossRef]
  115. Rose, S.; Bennuri, S.C.; Davis, J.E.; Wynne, R.; Slattery, J.C.; Tippett, M.; Delhey, L.; Melnyk, S.; Kahler, S.G.; MacFabe, D.F.; et al. Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism. Transl. Psychiatry 2018, 8, 42. [Google Scholar] [CrossRef] [PubMed]
  116. Rose, S.; Bennuri, S.C.; Wynne, R.; Melnyk, S.; James, S.J.; Frye, R.E. Mitochondrial and redox abnormalities in autism lymphoblastoid cells: A sibling control study. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2017, 31, 904–909. [Google Scholar] [CrossRef][Green Version]
  117. Melnyk, S.; Fuchs, G.J.; Schulz, E.; Lopez, M.; Kahler, S.G.; Fussell, J.J.; Bellando, J.; Pavliv, O.; Rose, S.; Seidel, L.; et al. Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. J. Autism Dev. Disord. 2012, 42, 367–377. [Google Scholar] [CrossRef][Green Version]
  118. Canitano, R.; Zappella, M. Autistic epileptiform regression. Funct. Neurol. 2006, 21, 97–101. [Google Scholar]
  119. Shoffner, J.; Hyams, L.; Langley, G.N.; Cossette, S.; Mylacraine, L.; Dale, J.; Ollis, L.; Kuoch, S.; Bennett, K.; Aliberti, A.; et al. Fever plus mitochondrial disease could be risk factors for autistic regression. J. Child Neurol. 2010, 25, 429–434. [Google Scholar] [CrossRef]
  120. Edmonds, J.L.; Kirse, D.J.; Kearns, D.; Deutsch, R.; Spruijt, L.; Naviaux, R.K. The otolaryngological manifestations of mitochondrial disease and the risk of neurodegeneration with infection. Arch. Otolaryngol. Head Neck Surg. 2002, 128, 355–362. [Google Scholar] [CrossRef][Green Version]
  121. Singh, K.; Singh, I.N.; Diggins, E.; Connors, S.L.; Karim, M.A.; Lee, D.; Zimmerman, A.W.; Frye, R.E. Developmental regression and mitochondrial function in children with autism. Ann. Clin. Transl. Neurol. 2020, 7, 683–694. [Google Scholar] [CrossRef]
  122. Frye, R.E.; Cox, D.; Slattery, J.; Tippett, M.; Kahler, S.; Granpeesheh, D.; Damle, S.; Legido, A.; Goldenthal, M.J. Mitochondrial dysfunction may explain symptom variation in Phelan-McDermid syndrome. Sci. Rep. 2016, 6, 19544. [Google Scholar] [CrossRef][Green Version]
  123. Kanellopoulos, A.K.; Mariano, V.; Spinazzi, M.; Woo, Y.J.; McLean, C.; Pech, U.; Li, K.W.; Armstrong, J.D.; Giangrande, A.; Callaerts, P.; et al. Aralar sequesters GABA into hyperactive mitochondria, causing social behavior deficits. Cell 2020, 180, 1178–1197.e20. [Google Scholar] [CrossRef]
  124. Curtin, P.; Curtin, A.; Austin, C.; Gennings, C.; Tammimies, K.; Bolte, S.; Arora, M. Recurrence quantification analysis to characterize cyclical components of environmental elemental exposures during fetal and postnatal development. PLoS ONE 2017, 12, e0187049. [Google Scholar] [CrossRef][Green Version]
  125. Arora, M.; Bradman, A.; Austin, C.; Vedar, M.; Holland, N.; Eskenazi, B.; Smith, D.R. Determining fetal manganese exposure from mantle dentine of deciduous teeth. Environ. Sci. Technol. 2012, 46, 5118–5125. [Google Scholar] [CrossRef][Green Version]
  126. Arora, M.; Hare, D.; Austin, C.; Smith, D.R.; Doble, P. Spatial distribution of manganese in enamel and coronal dentine of human primary teeth. Sci. Total Environ. 2011, 409, 1315–1319. [Google Scholar] [CrossRef]
  127. Arora, M.; Reichenberg, A.; Willfors, C.; Austin, C.; Gennings, C.; Berggren, S.; Lichtenstein, P.; Anckarsater, H.; Tammimies, K.; Bolte, S. Fetal and postnatal metal dysregulation in autism. Nat. Commun. 2017, 8, 15493. [Google Scholar] [CrossRef] [PubMed]
  128. Rose, S.; Melnyk, S.; Trusty, T.A.; Pavliv, O.; Seidel, L.; Li, J.; Nick, T.; James, S.J. Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism. Autism Res. Treat. 2012, 2012, 986519. [Google Scholar] [CrossRef] [PubMed][Green Version]
  129. Vandewalle, J.; Bauters, M.; Van Esch, H.; Belet, S.; Verbeeck, J.; Fieremans, N.; Holvoet, M.; Vento, J.; Spreiz, A.; Kotzot, D.; et al. The mitochondrial solute carrier SLC25A5 at Xq24 is a novel candidate gene for non-syndromic intellectual disability. Hum. Genet. 2013, 132, 1177–1185. [Google Scholar] [CrossRef] [PubMed]
  130. Picard, M.; Zhang, J.; Hancock, S.; Derbeneva, O.; Golhar, R.; Golik, P.; O’Hearn, S.; Levy, S.; Potluri, P.; Lvova, M.; et al. Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. Proc. Natl. Acad. Sci. USA 2014, 111, E4033–E4042. [Google Scholar] [CrossRef] [PubMed][Green Version]
  131. Licznerski, P.; Park, H.A.; Rolyan, H.; Chen, R.; Mnatsakanyan, N.; Miranda, P.; Graham, M.; Wu, J.; Cruz-Reyes, N.; Mehta, N.; et al. ATP Synthase c-subunit leak causes aberrant cellular metabolism in fragile X syndrome. Cell 2020, 182, 1170–1185.e9. [Google Scholar] [CrossRef]
  132. Napoli, E.; Song, G.; Panoutsopoulos, A.; Riyadh, M.A.; Kaushik, G.; Halmai, J.; Levenson, R.; Zarbalis, K.S.; Giulivi, C. Beyond autophagy: A novel role for autism-linked Wdfy3 in brain mitophagy. Sci. Rep. 2018, 8, 11348. [Google Scholar] [CrossRef] [PubMed][Green Version]
  133. Yin, C.-L.; Chen, H.-I.; Li, L.-H.; Chien, Y.-L.; Liao, H.-M.; Chou, M.C.; Chou, W.-J.; Tsai, W.-C.; Chiu, Y.-N.; Wu, Y.-Y.; et al. Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder. Mol. Autism 2016, 7, 23. [Google Scholar] [CrossRef] [PubMed][Green Version]
  134. Tang, G.; Gutierrez Rios, P.; Kuo, S.-H.; Akman, H.O.; Rosoklija, G.; Tanji, K.; Dwork, A.; Schon, E.A.; Dimauro, S.; Goldman, J.; et al. Mitochondrial abnormalities in temporal lobe of autistic brain. Neurobiol. Dis. 2013, 54, 349–361. [Google Scholar] [CrossRef][Green Version]
  135. Ebrahimi-Fakhari, D.; Saffari, A.; Wahlster, L.; Di Nardo, A.; Turner, D.; Lewis, T.L., Jr.; Conrad, C.; Rothberg, J.M.; Lipton, J.O.; Kölker, S.; et al. Impaired mitochondrial dynamics and mitophagy in neuronal models of tuberous sclerosis complex. Cell Rep. 2016, 17, 1053–1070. [Google Scholar] [CrossRef][Green Version]
  136. Pecorelli, A.; Ferrara, F.; Messano, N.; Cordone, V.; Schiavone, M.L.; Cervellati, F.; Woodby, B.; Cervellati, C.; Hayek, J.; Valacchi, G. Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2020, 34, 6521–6538. [Google Scholar] [CrossRef] [PubMed]
  137. Harris, J.; Deen, N.; Zamani, S.; Hasnat, M.A. Mitophagy and the release of inflammatory cytokines. Mitochondrion 2018, 41, 2–8. [Google Scholar] [CrossRef]
  138. Meeking, M.M.; MacFabe, D.F.; Mepham, J.R.; Foley, K.A.; Tichenoff, L.J.; Boon, F.H.; Kavaliers, M.; Ossenkopp, K.P. Propionic acid induced behavioural effects of relevance to autism spectrum disorder evaluated in the hole board test with rats. Prog. Neuro Psychopharmacol. Biol. Psychiatry 2020, 97, 109794. [Google Scholar] [CrossRef] [PubMed]
  139. Shams, S.; Foley, K.A.; Kavaliers, M.; MacFabe, D.F.; Ossenkopp, K.P. Systemic treatment with the enteric bacterial metabolic product propionic acid results in reduction of social behavior in juvenile rats: Contribution to a rodent model of autism spectrum disorder. Dev. Psychobiol. 2019, 61, 688–699. [Google Scholar] [CrossRef]
  140. Foley, K.A.; MacFabe, D.F.; Kavaliers, M.; Ossenkopp, K.P. Sexually dimorphic effects of prenatal exposure to lipopolysaccharide, and prenatal and postnatal exposure to propionic acid, on acoustic startle response and prepulse inhibition in adolescent rats: Relevance to autism spectrum disorders. Behav. Brain Res. 2015, 278, 244–256. [Google Scholar] [CrossRef]
  141. Foley, K.A.; MacFabe, D.F.; Vaz, A.; Ossenkopp, K.P.; Kavaliers, M. Sexually dimorphic effects of prenatal exposure to propionic acid and lipopolysaccharide on social behavior in neonatal, adolescent, and adult rats: Implications for autism spectrum disorders. Int. J. Dev. Neurosci. Off. J. Int. Soc. Dev. Neurosci. 2014, 39, 68–78. [Google Scholar] [CrossRef] [PubMed]
  142. Macfabe, D. Autism: Metabolism, mitochondria, and the microbiome. Glob. Adv. Health Med. 2013, 2, 52–66. [Google Scholar] [CrossRef] [PubMed][Green Version]
  143. Frye, R.E. Biomarkers of abnormal energy metabolism in children with autism spectrum disorder. N. Am. J. Med. Sci. 2012, 5, 141–147. [Google Scholar] [CrossRef]
  144. Frye, R.E.; Melnyk, S.; Macfabe, D.F. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl. Psychiatry 2013, 3, e220. [Google Scholar] [CrossRef] [PubMed][Green Version]
  145. Fernandez, A.; Meechan, D.W.; Karpinski, B.A.; Paronett, E.M.; Bryan, C.A.; Rutz, H.L.; Radin, E.A.; Lubin, N.; Bonner, E.R.; Popratiloff, A.; et al. Mitochondrial dysfunction leads to cortical under-connectivity and cognitive impairment. Neuron 2019, 102, 1127–1142.e3. [Google Scholar] [CrossRef]
  146. 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. Cell Rep. 2016, 15, 229–237. [Google Scholar] [CrossRef][Green Version]
  147. Chacko, B.K.; Kramer, P.A.; Ravi, S.; Benavides, G.A.; Mitchell, T.; Dranka, B.P.; Ferrick, D.; Singal, A.K.; Ballinger, S.W.; Bailey, S.M.; et al. The Bioenergetic Health Index: A new concept in mitochondrial translational research. Clin. Sci. 2014, 127, 367–373. [Google Scholar] [CrossRef][Green Version]
Jpm 11 00218 g001 550
Figure 1. The mitochondria can be negatively affected by many environmental and biological factors associated with autism spectrum disorder (left orange panel) and has many critical roles in cellular physiology (right blue panel). ETC: electron transport chain; DAMP: damage-associated molecular pattern
Figure 1. The mitochondria can be negatively affected by many environmental and biological factors associated with autism spectrum disorder (left orange panel) and has many critical roles in cellular physiology (right blue panel). ETC: electron transport chain; DAMP: damage-associated molecular pattern
Jpm 11 00218 g001
Jpm 11 00218 g002 550
Figure 2. Self-perpetuating destructive cycles which can result in mitochondrial dysfunction.
Figure 2. Self-perpetuating destructive cycles which can result in mitochondrial dysfunction.
Jpm 11 00218 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Frye, R.E.; Cakir, J.; Rose, S.; Palmer, R.F.; Austin, C.; Curtin, P.; Arora, M. Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder. J. Pers. Med. 2021, 11, 218. https://doi.org/10.3390/jpm11030218

AMA Style

Frye RE, Cakir J, Rose S, Palmer RF, Austin C, Curtin P, Arora M. Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder. Journal of Personalized Medicine. 2021; 11(3):218. https://doi.org/10.3390/jpm11030218

Chicago/Turabian Style

Frye, Richard E., Janet Cakir, Shannon Rose, Raymond F. Palmer, Christine Austin, Paul Curtin, and Manish Arora. 2021. "Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder" Journal of Personalized Medicine 11, no. 3: 218. https://doi.org/10.3390/jpm11030218

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop