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

L. Palmieri, V. Papaleo, V. Porcelli, P. Scarcia, L. Gaita, R. Sacco, J. Hager, F. Rousseau, P. Curatolo, B. Manzi, R. Militerni, C. Bravaccio, S. Trillo, C. Schneider, R. Melmed, M. Elia, C. Lenti, M. Saccani, T. Pascucci, S. Puglisi-AllegraK. L. Reichelt, A. M. Persico

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)38-52
Number of pages15
JournalMolecular Psychiatry
Volume15
Issue number1
DOIs
Publication statusPublished - Jan 2010

Keywords

  • Autistic disorder
  • Calcium signaling
  • Chromosome 2q
  • Oxidative stress
  • Pervasive developmental disorders
  • SLC25A12

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Altered calcium homeostasis in autism-spectrum disorders: Evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1'. Together they form a unique fingerprint.

Cite this