Altered calcium homeostasis and mitochondrial dysfunction in autism

Aims: Genetic variants of the brain isoform of the mitochondrial asp/glu carrier (AGC1), were previously found associated with autism. Our initial aim was to investigate asp/glu transport rates and AGC content in post-mortem brains of autistic patients. Methods: Temporocortical gray matter from matched patient-control pairs was used to measure reconstituted AGC1 activity from tissue homogenates or isolated mitochondria.. Protein content and oxidative damage were evaluated by western blotting.and oxyblotting, respectively. The activity of respiratory chain complexes was determined by standard diagnostic procedures. Results: AGC1 transport rates were significantly higher in tissue homogenates from autistic patients, including those with no history of seizures and with normal EEGs prior to death. This increase was consistently blunted by the Ca2+ chelator EGTA; no difference in AGC1 transport rates was found in isolated mitochondria from patients and controls; control mitochondria showed increased AGC1 activity when exposed to the post-mitochondrial supernatant of his/her matched patient than to his/her own supernatant. Complex IV and complex V activities were both increased in autistic patients but no significant difference in their protein abundance as well as in AGC1 content was detected by western blotting; oxidized mitochondrial proteins were markedly increased in the majority but not all of the patients tested. Interestingly, oxidative damage correlated with the reduction of complex I activity. Conclusions: Excessive Ca2+ levels boosts AGC activity in neurons and, to a more variable degree, oxidative stress and OXPHOS dysfunction in autistic brains. The modulation of AGC1 and/or Ca2+ homeostasis could provide new preventive and therapeutic strategies.