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

Abstract

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-3β/PGC-1α signaling pathways. We found that PTEN could dephosphorylate AKT to inhibit its activity, leading to decreased GSK3β phosphorylation. This decrease in GSK3β phosphorylation, which could activate itself, increased PGC-1α phosphorylation to promote its degradation and then regulated mitochondrial biogenesis by NRF-1 and TFAM downstream of PGC-1α. In the Valproic acid (VPA) induced autism mouse model, the PTEN protein level was significantly decreased while PGC-1α 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.