SD as reactive oxygen species generated from pro-oxidant environmental toxicants and activated immune cells can result in mitochondrial dysfunction. Four independent case-control studies have documented oxidative 1 Mitochondrial Dysfunction in Autism Cell Lines stress and oxidative damage in plasma, immune cells and postmortem brain from ASD children. Interestingly, resting peripheral blood mononuclear cells and activated lymphocytes and monocytes from children with ASD demonstrate a significant decrease in glutathione redox balance reflecting an intracellular deficit in glutathione-mediated antioxidant and detoxification capacity in these immune cells. An underlying defect in mitochondrial function could be a pivotal deficit in ASD as mitochondrial dysfunction affects high energy demanding organs, particularly the brain and immune system, and could also account for the commonly reported systemic abnormalities associated with ASD, such as immune dysfunction. Diverse immune abnormalities including abnormal lymphocyte activation and monocyte proinflammatory cytokine production have been reproducibly reported in ASD and found to be associated with increased severity of the core and related symptoms of ASD. Indeed, immune cells can be a suitable model for investigating the consequences of mitochondrial abnormalities when nervous tissue cannot be practically studied. We have previously demonstrated that lymphoblastoid cell lines derived from children with autistic disorder produce higher levels of ROS and exhibit a significant decrease in both intracellular and mitochondrial glutathione redox capacity when compared to control LCLs. Furthermore, when challenged with nitrosative stress, the AD LCLs exhibit a greater reduction in mitochondrial membrane potential compared to control LCLs. This evidence suggests that glutathione-mediated redox capacity is insufficient to counter endogenous ROS production in these AD LCLs resulting in increased vulnerability to oxidative damage and mitochondrial dysfunction during pro-oxidant exposures. Mitochondria are both the main producers and main targets of ROS in most cell types; however, redundant mechanisms exist to regulate excessive mitochondrial ROS production to protect electron transport chain complexes, which can be damaged and inactivated by ROS. Uncoupling protein 2 is one of the major control mechanisms for reducing high 1417961 levels of ROS at the inner mitochondrial membrane. In many cell types, including lymphocytes, UCP2 is up-regulated under conditions of chronic mitochondrial oxidative stress to relieve the proton gradient across the inner mitochondrial membrane and reduce mitochondrial ROS production. In this study we hypothesized that a subset of LCLs derived from patients with AD are vulnerable to ROS, such that excessive intracellular ROS results in mitochondrial dysfunction. To this end, we examined mitochondrial respiratory activity in LCLs derived from AD children and age-matched unaffected controls. Specifically we concentrate our studies on MEK162 site reserve capacity, a measure of ability of the mitochondria to respond to physiological stress. Importantly, a reduction in reserve capacity has been linked to aging, heart disease, and neurodegenerative disorders. Hill et al have demonstrated that reserve capacity is important for protecting the cell from acute increases in ROS, but that once reserve capacity is exhausted, cell 22924972 vulnerability is increased and viability is reduced. Thus, we hypothesized SD as reactive oxygen species generated from pro-oxidant environmental toxicants and activated immune cells can result in mitochondrial dysfunction. Four independent case-control studies have documented oxidative 1 Mitochondrial Dysfunction in Autism Cell Lines stress and oxidative damage in plasma, immune cells and postmortem brain from ASD children. Interestingly, resting peripheral blood mononuclear cells and activated lymphocytes and monocytes from children with ASD demonstrate a significant decrease in glutathione redox balance reflecting an intracellular deficit in glutathione-mediated antioxidant and detoxification capacity in these immune cells. An underlying defect in mitochondrial function 18083779 could be a 
pivotal deficit in ASD as mitochondrial dysfunction affects high energy demanding organs, particularly the brain and immune system, and could also account for the commonly reported systemic abnormalities associated with ASD, such as immune dysfunction. Diverse immune abnormalities including abnormal lymphocyte activation and monocyte proinflammatory cytokine production have been reproducibly reported in ASD and found to be associated with increased severity of the core and related symptoms of ASD. Indeed, immune cells can be a suitable model for investigating the consequences of mitochondrial abnormalities when nervous tissue cannot be practically studied. We have previously demonstrated that lymphoblastoid cell lines derived from children with autistic disorder produce higher levels of ROS and exhibit a significant decrease in both intracellular and mitochondrial glutathione redox capacity when compared to control LCLs. Furthermore, when challenged with nitrosative stress, the AD LCLs exhibit a greater reduction in mitochondrial membrane potential compared to control LCLs. This evidence suggests that glutathione-mediated redox capacity is insufficient to counter endogenous ROS production in these AD LCLs resulting in increased vulnerability to oxidative damage and mitochondrial dysfunction during pro-oxidant exposures. Mitochondria are both the main producers and main targets of ROS in most cell types; however, redundant mechanisms exist to regulate excessive mitochondrial ROS production to protect electron transport chain complexes, which can be damaged and inactivated by ROS. Uncoupling protein 2 is one of the major control mechanisms for reducing high levels of ROS at the inner mitochondrial membrane. In many cell types, including lymphocytes, UCP2 is up-regulated under conditions of chronic mitochondrial oxidative stress to relieve the proton gradient across the inner mitochondrial membrane and reduce mitochondrial ROS production. In this study we hypothesized that a subset of LCLs derived from patients with AD are vulnerable to ROS, such that excessive intracellular ROS results in mitochondrial dysfunction. To this end, we examined mitochondrial respiratory activity in LCLs derived from AD children and age-matched unaffected controls. Specifically we concentrate our studies on reserve capacity, a measure of ability of the mitochondria to respond to physiological stress. Importantly, a reduction in reserve capacity has been linked to aging, heart disease, 1417961 and neurodegenerative disorders. Hill et al have demonstrated that reserve capacity is important for protecting the cell from acute increases in ROS, but that once reserve capacity is exhausted, cell vulnerability is increased and viability is reduced. Thus, we hypothesized
