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Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha ( PGC-1 α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation ( p  < 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely  PGC-1 α,  STOML2 ,  MFN2 ,  FIS1 ,  OPA1 , and  GABPA. PGC-1 α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) ( p  = 1 × 10 –6 ). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated ( p  = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the  PGC-1 α promoter and there was a positive correlation between methylation at  PGC-1 α CpG#1 and mtDNA copy number (Spearman’s  r  = 0.2,  n  = 49,  p  = 0.04) in ASD. Furthermore, DNA methylation at  PGC-1 α CpG#1 and mtDNA copy number correlated significantly ( p  < 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on  PGC-1 α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the  PGC-1 α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.

DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder