Original Article

Molecular Psychiatry (2010) 15, 38–52; doi:10.1038/mp.2008.63; published online 8 July 2008

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

L Palmieri1,2, V Papaleo3,4,16, V Porcelli1,16, P Scarcia1, L Gaita3,4, R Sacco3,4, J Hager5, F Rousseau5, P Curatolo6, B Manzi6, R Militerni7, C Bravaccio7, S Trillo8, C Schneider9, R Melmed10, M Elia11, C Lenti12, M Saccani12, T Pascucci13,14, S Puglisi-Allegra13,14, K-L Reichelt15 and A M Persico3,4

  1. 1Laboratory of Biochemistry and Molecular Biology, Department of Pharmaco-Biology, University of Bari, Bari, Italy
  2. 2Consiglio Nazionale delle Ricerche, Institute of Biomembranes and Bioenergetics, Bari, Italy
  3. 3Laboratory of Molecular Psychiatry and Neurogenetics, University ‘Campus Bio-Medico’, Rome, Italy
  4. 4Laboratory of Molecular Psychiatry and Psychiatric Genetics, Department of Experimental Neurosciences, I.R.C.C.S. ‘Fondazione Santa Lucia’, Rome, Italy
  5. 5IntegraGen SA. Genopole, Evry, France
  6. 6Department of Child Neuropsychiatry, University ‘Tor Vergata’, Rome, Italy
  7. 7Department of Child Neuropsychiatry, University of Naples Federico II, Naples, Italy
  8. 8ASL RM/B, Rome, Italy
  9. 9Center for Autism Research and Education, Phoenix, AZ, USA
  10. 10Southwest Autism Research and Resource Center, Phoenix, AZ, USA
  11. 11Unit of Neurology and Clinical Neurophysiopathology, I.R.C.C.S. ‘Oasi Maria S.S.’, Enna, Italy
  12. 12Department of Child Neuropsychiatry, University of Milan, Milan, Italy
  13. 13Department of Psychology, University ‘La Sapienza’, Rome, Italy
  14. 14Laboratory of Behavioral Neurobiology, Department of Experimental Neurosciences, I.R.C.C.S. ‘Fondazione Santa Lucia’, Rome, Italy
  15. 15Department of Pediatric Research, Rikshospitalet, University of Oslo, Oslo, Norway

Correspondence: Professor AM Persico, Laboratory of Molecular Psychiatry and Neurogenetics, University ‘Campus Bio-Medico’, Via Alvaro del Portillo 21, I-00128 Rome, Italy. E-mail: a.persico@unicampus.it; Professor L Palmieri, Laboratory of Biochemistry and Molecular Biology, Department of Pharmaco-Biology, University of Bari, Via Orabona 4, Bari 70125, Italy. E-mail: lpalm@farmbiol.uniba.it

16These authors contributed equally to this work.

Received 20 July 2007; Revised 7 April 2008; Accepted 16 May 2008; Published online 8 July 2008.

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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 (Ca2+). 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 Ca2+ chelator ethylene glycol tetraacetic acid; neocortical Ca2+ 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 Ca2+-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 Ca2+ levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca2+ homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.

Keywords:

autistic disorder; calcium signaling; chromosome 2q; oxidative stress; pervasive developmental disorders; SLC25A12

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