Impaired Mitochondrial Dynamics And Mitophagy In Neuronal Models Of Tuberous Sclerosis Complex

摘要: Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon activation, anabolic metabolism, which requires mitochondria, induced, yet at same time principal pathway for mitochondrial turnover, autophagy, compromised. How impacts turnover in neurons remains unknown. Here, we demonstrate impaired homeostasis neuronal in vitro in vivo models TSC. We find that Tsc1/2-deficient accumulate mitochondria cell bodies, but are depleted axonal including those supporting presynaptic sites. Axonal global mitophagy damaged impaired, suggesting decreased may act upstream metabolism. Importantly, blocking inducing mTOR-independent autophagy restores homeostasis. Our study clarifies relationship between TSC-mTORC1 pathway, mitophagy, defines as therapeutic target TSC related diseases.