PTEN Regulates Mitochondria! Biogenesis via the AKT/GSK-3β/PGC-1α Pathway in Autism

Autism spectrum disorder (ASD) is a widespread, complex and serious neurodevelopmental disorder. Complex genetic and environmental factors are thought to contribute to the development of ASD. Genome-wide association analysis has identified multiple autism-related genes. Mutation of the phosphatase and tensin homolog (Pten) is closely related to autism and accounts for 5-17% of cases of autism. However, the detailed mechanism is still unclear. Recently, mitochondrial dysfunction was tightly associated with ASD pathogenesis, such as developmental degeneration, learning and various behavioral disorders. The mitochondrial DNA (mtDNA) copy number in children with autism is also significantly increased. The correlation between Pten and mitochondrial dysfunction in autism is still unknown. In this study, we examined how Pten regulates mitochondrial biogenesis through the AKT/GSK-3 beta/PGC-1 alpha signaling pathways. We found that PTEN could dephosphorylate AKT to inhibit its activity, leading to decreased GSK3 beta phosphorylation. This decrease in GSK3 beta phosphorylation, which could activate itself, increased PGC-1 alpha phosphorylation to promote its degradation and then regulated mitochondrial biogenesis by NRF-1 and TFAM downstream of PGC-1 alpha. In the Valproic acid (VPA) induced autism mouse model, the PTEN protein level was significantly decreased while PGC-1 alpha and COX IV levels were increased in the hippocampus and cortex. Our data suggest that there is a correlation between PTEN and mitochondrial dysfunction and this correlation may be a potential mechanism of ASD. (C) 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

Autism spectrum disorder is a complex neurodevelopmental disorder with genetic and environmental factors playing a role in its development. Studies have shown a correlation between mutations in the phosphatase and tensin homolog (Pten) gene and autism, as well as a connection to mitochondrial dysfunction.