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Mitochondrial Etiology of Neuropsychiatric Disorders

A Mitochondrial Etiology of Autism: Implications for Neuropsychiatric Disorders.
Douglas C. Wallace, Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia.
Mitochondrial dysfunction is a common observation in a wide range of neuropsychiatric disorders. However, it has traditionally been assumed that these partial defects are secondary to some other genetic disorder.
The mitochondrial genes are dispersed across the nuclear DNA (nDNA) and the mitochondrial DNA (mtDNA) with the mtDNA coding exclusively for proteins involved in the mitochondrial bioenergetic process, oxidative phosphorylation (OXPHOS). Specific mtDNA mutations have been associated with autism such as the mtDNA tRNALeu(UUR) m.32432A>G mutation, and we have reported that several European mtDNA lineages (haplogroups) are at increased risk for autism with odds ratios of approximately 2, half the effect of male versus female.
However, to prove a causal relationship between mtDNA mutations and neuropsychiatric disorders, we needed to create in a mouse a specific mtDNA mutation and show that the mouse developed a neuropsychiatric disease. Accordingly, we created two mice harboring single nucleotide changes in mtDNA OXPHOS complex I (NADH dehydrogenase) genes, one in the MT-ND5 gene 12353C>T, S204F (ND5S204F) and the other in the MT-ND6 gene m.13997G>A, P25L (ND6P25L). The ND6P25 mutation causes a 60% reduction in complex I in association with increased mitochondrial reactive species production (mROS), while the ND5S204F mutation causes an approximately 30-40% reduction in complex I. Both, mtDNA mutations alter the mouse electroretinogram response. However, the ND6P25 mutation caused and autism phenotype while the ND5S204F did not. Behavioral analysis of the ND6P25 mouse revealed impaired social interactions, increased repetitive behaviors, decreased seizure threshold, and EEG alterations. Moreover, the male ND6P25 mice displayed a robust autism phenotype while the female ND6P25 displayed only minor behavioral alterations.
Thus, a single mtDNA nucleotide change is sufficient to cause a neuropsychiatric disorder, in this case autism. However, the differences in OXPHOS defects that cause different neuropsychiatric phenotypes are subtle.