Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1

Abstract

Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient-control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca(2+)). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca(2+) chelator ethylene glycol tetraacetic acid; neocortical Ca(2+) levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca(2+)-containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca(2+) levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca(2+) homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies. Molecular Psychiatry (2010) 15, 38-52; doi: 10.1038/mp.2008.63; published online 8 July 200

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“…Another vulnerability gene, MET, was identified by Campbell and Levitt collaborating with our group for the genetic studies involved in this project [80,81]. In addition, we have identified other new vulnerability genes and confirmed associations initially reported in other samples for several genes, including ADA [82], APOE [83], HOXA1 [84,85], ITG-B3 [86], PON1 [87], PRKCB1 [88], SLC6A4 [89,90], SLC-25A12 [91].…”

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“…excessive intracellular Ca 2+ spikes can in turn interfere both with neurodevelopment and with energy production, modulating the activity of the mitochondrial aspartate-glutamate carrier AGC1. Interestingly, also the SlC25A12 gene, which encodes for AGC1, encompasses genetic variants able to influence disease risk in autism (Palmieri et al, 2010). Genetic vulnerability at the ATP2B2 and SLC25A12 loci could be exacerbated by prenatal environmental exposure to PCBs, important endocrine disruptors also able to promote Ca 2+ entry from the extracellular space, and Ca 2+ release from the endoplasmic reticulum (Pessah et al, 2010).…”