Mitochondrial pathways to autism

Autism is a severe pervasive developmental disorder characterized by variable degrees of impairment in language, communication and social skills, as well as by repetitive and stereotypic patterns of behaviour. Despite strong familial components, clinical and genetic complexities have posed a major challenge to our understanding of autism pathogenesis. A significant subset of autistic patients display biochemical or neuropathological evidence of mitochondrial dysfunction and/or oxidative stress. However, only in a very few cases abnormal energy metabolism could be linked to a specific genetic defect. Interest in assessing the role of mitochondria in this disorder has been revitalized by the association between autism and variants of the SLC25A12 gene [1], which encodes the predominant isoform of the mitochondrial aspartate/glutamate carrier (AGC) in brain [2]. Cytosolic Ca2+ can rapidly activate AGC transport through four “EF-hand” domains located at its N-terminus, thereby increasing the NADH/NAD ratio in the mitochondrial matrix and consequently boosting electron flow through the respiratory chain and ATP generation by oxidative phosphorylation [3]. Post-mortem studies of temporocortical gray matter from matched patient–control pairs revealed that AGC transport rates were significantly higher in brains from autistic patients [4]. This difference was blunted by Ca2+ chelator EGTA and direct fluorimetric measurements confirmed significantly higher Ca2+ levels in the patients, compared to their matched controls [4]. Oxidized mitochondrial proteins were markedly increased in the majority of the patients tested. Interestingly, oxidative damage correlated with the reduction of complex I activity indicating that excessive Ca2+ levels boost AGC activity in neurons and, to a more variable degree, cause oxidative stress and mitochondrial dysfunction in autistic brains. Furthermore, we identified a protective SLC25A12 gene variant in a sizable group of unaffected siblings modulating AGC1 mRNA levels and protein activity. Our results suggest that mitochondria may play a critical role in the cascade of signalling events leading to autism and in determining to what extent different prenatal triggers will derange neurodevelopment and yield abnormal postnatal behaviour.