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Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex. | LitMetric

AI Article Synopsis

  • Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder linked to mutations in TSC1 or TSC2 genes, resulting in activation of the mTORC1 kinase, which affects cellular metabolism and mitochondrial function.
  • Research shows that neurons lacking Tsc1/2 accumulate mitochondria in their cell bodies but lack them in axons, notably at presynaptic sites, indicating disrupted mitochondrial distribution and function.
  • The study highlights that impaired mitophagy, or the removal of damaged mitochondria, due to mTORC1 activation leads to mitochondrial imbalance, but targeting mTORC1 or promoting autophagy can restore this balance, suggesting potential therapy avenues for TSC and similar conditions.

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078873PMC
http://dx.doi.org/10.1016/j.celrep.2016.09.054DOI Listing

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