Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex
Year: 2016
Type: article
Abstract: Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon mTORC1 activation, anabolic metabolism, which requires mitochondria, is induced, yet at the same time the principal pathway for mitochondrial turnover, autophagy, is compromised. How mTORC1 activation impacts mitochondrial turnover in neurons remains unknown. Here, we demonstrate impaired mitochondrial homeostasis in neuronal in vitro and in vivo models of TSC. We find that Tsc1/2-deficient neurons accumulate mitochondria in cell bodies, but are depleted of axonal mitochondria, including those supporting presynaptic sites. Axonal and global mitophagy of damaged mitochondria is impaired, suggesting that decreased turnover may act upstream of impaired mitochondrial metabolism. Importantly, blocking mTORC1 or inducing mTOR-independent autophagy restores mitochondrial homeostasis. Our study clarifies the complex relationship between the TSC-mTORC1 pathway, autophagy, and mitophagy, and defines mitochondrial homeostasis as a therapeutic target for TSC and related diseases.
Source: Cell Reports
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Nancy Lurie Marks Family Foundation, Daimler und Benz Stiftung, Studienstiftung des Deutschen Volkes, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, Graduiertenakademie, Technische Universität Dresden, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G2975405632, A kinase pathway required for terminal axon branching and presynaptic function, Sleep and Circadian Rhythms in Tuberous Sclerosis Complex, Boston Intellectual and Developmental Disabilities Research Center, In vivo investigation of mitochondrial dynamics in the mouse brain, LKB1 function in axon development through regulation of mitochondrial trafficking, Intellectual and Developmental Disablities Research Center
OpenAlex ID: W2538495032