Douglas Wallace and his colleagues at the Children’s Hospital of Philadelphia tested the hypothesis that partial defects in mitochondrial bioenergetics are important factors in the etiology of autism. The mitochondria are assembled from genes coded by the maternally inherited, thousand-copy mitochondrial DNA (mtDNA) in addition to the one to two thousand nuclear DNA (nDNA) coded genes that affect mitochondrial structure and function. In addition to generating most of cellular energy by oxidative phosphorylation (OXPHOS), the mitochondria regulate cellular oxidation-reduction status, calcium ion levels, apoptosis, intermediary metabolism and, through high-energy mitochondrial intermediates, the cellular signal transduction pathways and the epigenome.
Because the brain uses 20 percent of our oxygen but is only 2 percent of our body weight, partial reductions in mitochondrial function are more than sufficient to cause neurological symptoms. Wallace and his group found that mtDNA variation, as well as partial defects in nDNA-coded mitochondrial genes resulting from copy number variants (CNVs) or hemizygous mutations, are common features of autism. They also found that increasing numbers of such variants correlate with reduced mitochondrial function.
The potential significance of naturally occurring mtDNA variants in autism and related neuropsychiatric disorders was demonstrated by combining two normal but different mtDNAs within the mouse female germline and demonstrating that this results in hypo-activity, hyperexcitability and learning defects.
To demonstrate that nDNA gene mutations that alter mitochondrial function can cause autism, the researchers studied a mouse model of the syndromic autism disorder Angelman syndrome, caused by an UBE3A gene mutation at chromosome 15q12, as well as the companion Prader-Willi syndrome, caused by deletion of the 15q11-13 imprinting center (IC). The UBE3A mutant mouse has shrunken hippocampal neuronal mitochondria, with reduced synaptic vesicles and a partial brain OXPHOS defect. The IC deletion mouse has systemic mitochondrial structural abnormalities and altered expression of many bioenergetics genes. Studies of mice with known mitochondrial defects also produce behavioral and neuro-anatomical changes consistent with autism.
To determine how partial nDNA and mtDNA mitochondrial defects might interact to generate autism, Wallace and his team studied a series of somatic cell cybrids harboring different percentages of the heteroplasmic pathogenic mtDNA tRNALeu(UUR) nucleotide 3243A>G mutation. This mutation has been associated with diabetes and autism at 20-30 percent 3243G, neuromuscular disease at 50-90 percent 3243G, and Leigh syndrome at 100 percent 3243G.
Biochemical analysis of the various 3243G heteroplasmic cybrids revealed that the 20-30 percent 3243G cybrids have a mild, chronic OXPHOS defect without compensatory induction of glycolysis, the 50-90 percent 3243G cell lines have more severe OXPHOS defects but with up-regulation of glycolysis, while the 100 percent 3243G cells have severe OXPHOS inhibition but without glycolytic compensation1. These alternative bioenergetics states are associated with global phase changes in gene expression generated by alterations in the activities of broad classes of transcription factors and modulation of cellular signal transduction pathways and the epigenome.
Hence, autism is associated with chronic partial mitochondrial bioenergetic deficiency without associated glycolytic compensation, which is consistent with the bioenergetics effects expected for hemizygous nDNA mitochondrial gene mutations, mtDNA variants or heteroplasmic pathogenic mtDNA mutations, and environmental bioenergetics challenges.