Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism.
Research into the metabolic phenotype of autism has been relatively unexplored despite the fact that metabolic abnormalities have been implicated in the pathophysiology of several other neurobehavioral disorders. Plasma biomarkers of oxidative stress have been reported in autistic children; however, intracellular redox status has not yet been evaluated. Lymphoblastoid cells (LCLs) derived from autistic children and unaffected controls were used to assess relative concentrations of reduced glutathione (GSH) and oxidized disulfide glutathione (GSSG) in cell extracts and isolated mitochondria as a measure of intracellular redox capacity. The results indicated that the GSH/GSSG redox ratio was decreased and percentage oxidized glutathione increased in both cytosol and mitochondria in the autism LCLs. Exposure to oxidative stress via the sulfhydryl reagent thimerosal resulted in a greater decrease in the GSH/GSSG ratio and increase in free radical generation in autism compared to control cells. Acute exposure to physiological levels of nitric oxide decreased mitochondrial membrane potential to a greater extent in the autism LCLs, although GSH/GSSG and ATP concentrations were similarly decreased in both cell lines. These results suggest that the autism LCLs exhibit a reduced glutathione reserve capacity in both cytosol and mitochondria that may compromise antioxidant defense and detoxification capacity under prooxidant conditions.
James
S Jill
SJ
Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, 1120 Marshall St., Little Rock, AR 72202, USA. jamesjill@uams.edu
Rose
Shannon
S
Melnyk
Stepan
S
Jernigan
Stefanie
S
Blossom
Sarah
S
Pavliv
Oleksandra
O
Gaylor
David W
DW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000209:etiology / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D003600:Cytosol / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013849:Thimerosal / Q000494:pharmacology; D055815:Young Adult
D005609:Free Radicals; D013849:Thimerosal; D026423:S-Nitroso-N-Acetylpenicillamine; D000255:Adenosine Triphosphate; D005978:Glutathione; D019803:Glutathione Disulfide