Abstract
Autism is a neurodevelopmental disorder associated with social deficits and behavioral abnormalities. Recent evidence suggests that mitochondrial dysfunction and oxidative stress may contribute to the etiology of autism. This is the first study to compare the activities of mitochondrial electron transport chain (ETC) complexes (I–V) and pyruvate dehydrogenase (PDH), as well as mitochondrial DNA (mtDNA) copy number in the frontal cortex tissues from autistic and age-matched control subjects. The activities of complexes I, V and PDH were most affected in autism (n=14) being significantly reduced by 31%, 36% and 35%, respectively. When 99% confidence interval (CI) of control group was taken as a reference range, impaired activities of complexes I, III and V were observed in 43%, 29% and 43% of autistic subjects, respectively. Reduced activities of all five ETC complexes were observed in 14% of autistic cases, and the activities of multiple complexes were decreased in 29% of autistic subjects. These results suggest that defects in complexes I and III (sites of mitochondrial free radical generation) and complex V (adenosine triphosphate synthase) are more prevalent in autism. PDH activity was also reduced in 57% of autistic subjects. The ratios of mtDNA of three mitochondrial genes ND1, ND4 and Cyt B (that encode for subunits of complexes I and III) to nuclear DNA were significantly increased in autism, suggesting a higher mtDNA copy number in autism. Compared with the 95% CI of the control group, 44% of autistic children showed higher copy numbers of all three mitochondrial genes examined. Furthermore, ND4 and Cyt B deletions were observed in 44% and 33% of autistic children, respectively. This study indicates that autism is associated with mitochondrial dysfunction in the brain.
Highlights
Autism is a neurodevelopmental disorder associated with social deficits and behavioral abnormalities
If a 99% confidence interval (CI) of control group was taken as the reference range, 6 of the 14 (43%) autistic subjects had less complex I and/or V activities than the lower limit of 99% CI of the control group, suggesting that 6 subjects with autism were affected with deficiencies of complex I and/or V activity (Table 2)
The deficiency of complex III activity in these two autism samples could be caused by the lower activity of complex II, because the whole mitochondria was used, and electrons need to be transferred from complex II to III to produce reduced cytochrome-c in the complex III activity assay
Summary
Autism is a neurodevelopmental disorder associated with social deficits and behavioral abnormalities It belongs to a group of disorders known as autism spectrum disorders (ASDs), which include Asperger’s syndrome and pervasive developmental disorder-not otherwise specified. According to the Centers for Disease Control and Prevention, the prevalence of ASDs in the United States is 1 in 88 children.[1] the cause of autism is elusive, numerous studies suggest that enhanced oxidative stress is a prevalent biochemical condition in autism.[2,3,4,5,6,7,8,9,10,11] A recent metaanalysis study showed prevalence of mitochondrial disorder (MD) in the ASD population to be 5%, which is much higher than observed in general population (B0.01%).[12]. The main function of mitochondria is to generate energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation, a process which requires the action of five electron transport chain (ETC) complexes, that is, complex I (NADH dehydrogenase), complex II (succinate dehydrogenase), complex III (cytochrome bc[1] complex), complex IV (cytochrome-c oxidase) and complex V (ATP synthase).[13,14] Mitochondrial pyruvate dehydrogenase (PDH) occupies a central position in cellular energy metabolism because it catalyzes the conversion of pyruvate to generate acetyl CoA and NADH, thereby linking the glycolysis pathway to tricarboxylic acid cycle and subsequent oxidative phosphorylation to produce ATP in the mitochondria
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