Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) affects ~ 2% of children in the United States. The etiology of ASD likely involves environmental factors triggering physiological abnormalities in genetically sensitive individuals. One of these major physiological abnormalities is mitochondrial dysfunction, which may affect a significant subset of children with ASD. Here we systematically review the literature on human studies of mitochondrial dysfunction related to ASD. Clinical aspects of mitochondrial dysfunction in ASD include unusual neurodevelopmental regression, especially if triggered by an inflammatory event, gastrointestinal symptoms, seizures, motor delays, fatigue and lethargy. Traditional biomarkers of mitochondrial disease are widely reported to be abnormal in ASD, but appear non-specific. Newer biomarkers include buccal cell enzymology, biomarkers of fatty acid metabolism, non-mitochondrial enzyme function, apoptosis markers and mitochondrial antibodies. Many genetic abnormalities are associated with mitochondrial dysfunction in ASD, including chromosomal abnormalities, mitochondrial DNA mutations and large-scale deletions, and mutations in both mitochondrial and non-mitochondrial nuclear genes. Mitochondrial dysfunction has been described in immune and buccal cells, fibroblasts, muscle and gastrointestinal tissue and the brains of individuals with ASD. Several environmental factors, including toxicants, microbiome metabolites and an oxidized microenvironment are shown to modulate mitochondrial function in ASD tissues. Investigations of treatments for mitochondrial dysfunction in ASD are promising but preliminary. The etiology of mitochondrial dysfunction and how to define it in ASD is currently unclear. However, preliminary evidence suggests that the mitochondria may be a fruitful target for treatment and prevention of ASD. Further research is needed to better understand the role of mitochondrial dysfunction in the pathophysiology of ASD.

Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

“…In general, some evidences indicated an impaired activity of mitochondrial respiratory chain coupled with decreased protein and/or gene expression of the ETC complexes in different cells and tissues from ASD individuals 6 . However, other studies in skin, brain, muscle, buccal epithelium, and lymphoblastoid cells highlighted an increased ETC activity, rather than decreased in ASD patients, 26 corroborating our data on the mitochondrial complexes expression.…”

“…Indeed, similarly to our results, when examined in basal condition, ASD lymphoblastoid cells exhibited abnormally high maximal respiratory capacity, reserve capacity, and proton‐leak respiration coupled with higher glycolysis and glycolytic reserve 22‐25 . Of note, among the children with ASD, the authors recognized a subset in which mitochondria appear to become overactive and more vulnerable when the levels of oxidants increase (ie, greater drop of maximal respiratory capacity and reserve capacity under stress conditions) 26 . Moreover, these findings were confirmed also in a different cell type such as peripheral blood mononuclear cells (PBMC) that displayed an altered mitochondrial respiration (ie, higher maximal respiratory capacity and reserve capacity) associated with changes in cytokine profile in ASD children, suggesting that abnormalities in immune and mitochondrial functions are phenomena closely interrelated in ASD 27 .…”

Angelman syndrome: a journey through the brain

“…Interestingly, altered mitochondrial function and oxidative stress are well‐described pathophysiological mechanisms in neurodegenerative and autism spectrum disorders (for a review, see Ref. ). Thus, it is not surprising that the mitochondrial function also seems to be impaired in AS.…”

Developmental regression and mitochondrial function in children with autism

“…Other studies suggest that up to 80% of individuals with ASD show abnormal ETC activity in lymphocytes and granulocytes 6,7 as well as postmortem brain 8 . Thus, it is hypothesized that individual with ASD have unique changes in mitochondrial function that may be distinct from classically defined mitochondrial disease 4,9 . For example, rather than significant decreases is ETC complex activity, individuals with ASD have been found to have significant elevations in ETC complex activity in multiple tissues 8,10–14 .…”

“…We hypothesize that children with ASD and DR have marginal but adequate mitochondrial function until a trigger increases physiological stress that overwhelms the capacity of mitochondria to function, resulting in clinically observed DR. Marginal mitochondrial function could be represented by very low mitochondrial activity, as seen in mitochondrial disease, but we believe that marginal mitochondrial function could also be represented by very high mitochondrial activity, as seen in the LCL model since such elevated respiratory rates could represent a state in which the mitochondria is close to its maximum ability to function, making mitochondria sensitivity to physiological stress 9,15,16 . To this end, this study examined mitochondrial function and mitochondrial DNA (mtDNA) damage and copy number in peripheral blood mononuclear cells (PBMCs) from three age‐matched groups of children: those with ASD, with and without DR, and non‐ASD controls.…”