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Published on: February 9, 2020
Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex
Darius Ebrahimi-Fakhari1, Afshin Saffari1, Lara Wahlster2
1The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
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.
Insights
Tuberous sclerosis complex (TSC) impairs mitochondrial health in neurons by disrupting turnover. Restoring autophagy or blocking mTORC1 can fix this, highlighting mitochondrial homeostasis as a therapeutic target for TSC.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Tuberous sclerosis complex (TSC) is a genetic neurodevelopmental disorder caused by mutations in TSC1 or TSC2 genes.
- These mutations lead to the hyperactivation of the mTORC1 pathway, promoting anabolic metabolism and requiring mitochondria.
- However, TSC also compromises autophagy, the primary pathway for mitochondrial turnover, creating a metabolic paradox.
Purpose of the Study:
- To investigate the impact of mTORC1 activation on mitochondrial turnover in neurons in Tuberous Sclerosis Complex (TSC).
- To elucidate the mechanisms underlying impaired mitochondrial homeostasis in TSC neuronal models.
- To identify potential therapeutic targets for TSC by understanding the interplay between the TSC-mTORC1 pathway, autophagy, and mitophagy.
Main Methods:
- Utilized in vitro and in vivo neuronal models of TSC (Tsc1/2-deficient).
- Assessed mitochondrial distribution, accumulation, and depletion in neuronal compartments (cell bodies and axons).
- Evaluated mitophagy (autophagy of mitochondria) and global autophagy levels.
- Intervened by blocking mTORC1 signaling or inducing mTOR-independent autophagy.
Main Results:
- Demonstrated impaired mitochondrial homeostasis in TSC neuronal models.
- Observed accumulation of mitochondria in neuronal cell bodies and depletion in axons, including presynaptic sites.
- Found impaired axonal and global mitophagy, suggesting decreased turnover precedes metabolic dysfunction.
- Showed that blocking mTORC1 or enhancing autophagy restores mitochondrial homeostasis.
Conclusions:
- mTORC1 hyperactivation in TSC disrupts neuronal mitochondrial homeostasis by impairing mitophagy.
- Impaired mitochondrial turnover, rather than metabolism, is a key early defect in TSC neurons.
- Restoring mitochondrial homeostasis through mTORC1 inhibition or autophagy induction presents a promising therapeutic strategy for TSC.
