Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder

Abstract

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder and has a high prevalence in children. Recently, mitochondrial oxidative stress has been proposed to be associated with ASD. Besides, SIRT1/PGC-1α signaling plays an important role in combating oxidative stress. In this study, we sought to determine the role of SIRT1/PGC-1α signaling in the ASD lymphoblastoid cell lines (LCLs). In this study, the mRNA and protein expressions of SIRT1/PGC-1α axis genes were assessed in 35 children with ASD and 35 healthy controls (matched for age, gender, and IQ). An immortalized LCL was established by transforming lymphocytes with Epstein–Barr virus. Next, we used ASD LCLs and control LCLs to detect SIRT1/PGC-1α axis genes expression and oxidative damage. Finally, the effect of overexpression of PGC-1α on oxidative injury in the ASD LCLs was determined. SIRT1/PGC-1α axis genes expression was downregulated at RNA and protein levels in ASD patients and LCLs. Besides, the translocation of cytochrome c and DIABLO from mitochondria to the cytosol was found in the ASD LCLs. Moreover, the intracellular reactive oxygen species (ROS) and mitochondrial ROS and cell apoptosis were increased in the ASD LCLs. However, overexpression of PGC-1α upregulated the SIRT1/PGC-1α axis genes expression and reduced cytochrome c and DIABLO release in the ASD LCLs. Also, overexpression of PGC-1α reduced the ROS generation and cell apoptosis in the ASD LCLs. Overexpression of PGC-1α could reduce the oxidative injury in the ASD LCLs, and PGC-1α may act as a target for treatment.

Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder

“…Since several studies suggested mitochondrial dysfunction as one of the main metabolic abnormalities observed in ASD physiopathology, 6 in the current study, we first wanted to confirm the presence of possible mitochondrial defects in our cellular model, examining mitochondrial superoxide production. Consistent with another study in immortalized lymphoblastoid cell lines from ASD patients, 21 we observed an increased mitochondrial superoxide production in our fibroblast model, thus supporting a role for mitochondria in ASD redox imbalance. Higher mitochondrial ROS levels could be related to an increased electron leak from a defective ETC during oxidative phosphorylation process 12 .…”

Social behavior, neuroimmune markers and glutamic acid decarboxylase levels in a rat model of valproic acid-induced autism

“…It was proposed that mitochondrial oxidative stress is involved in the development of ASD. A recent study indicated that the intracellular reactive oxygen species (ROS) and mitochondrial ROS, and cell apoptosis were increased in the autism lymphoblastic cell lines (Bu et al, 2017). In our present study, the plasma levels of a potent oxidative stress marker, 8OHdG, were significantly increased in male VPA-exposed rats as compared to the control rats.…”

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

“…Autism is often associated with mitochondrial disease and abnormalities in energy generation (Bu et al, ; Hollis, Kanellopoulos, & Bagni, ). Chronic injection of PPA is known to provoke aquired mitochondrial dysfunctions, the level of which depends on the character of treatment (Choi et al, ; Frye et al, , ; MacFabe, ).…”