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Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism

S. Jill James^*,1, Shannon Rose^*, Stepan Melnyk^*, Stefanie Jernigan^*, Sarah Blossom^*, Oleksandra Pavliv^* and David W. Gaylor

^* Department of Pediatrics; and

Department of Biostatistics, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital Research Institute, Little Rock, Arkansas, USA

¹ Correspondence: Arkansas Children’s Hospital Research Institute, 1120 Marshall St., Slot 512-41B, Little Rock, AR 72202, USA. E-mail: jamesjill{at}uams.edu

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. J., Rose, S., Melnyk, S., Jernigan, S., Blossom, S., Pavliv, O., Gaylor, D. W. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism.

Key Words: autistic disorder • oxidative stress • nitric oxide