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

• Published in: Cell reports (Cambridge) Vol. 17; no. 4; pp. 1053 - 1070
• Main Authors: Ebrahimi-Fakhari, Darius, Saffari, Afshin, Wahlster, Lara, Di Nardo, Alessia, Turner, Daria, Lewis, Tommy L., Conrad, Christopher, Rothberg, Jonathan M., Lipton, Jonathan O., Kölker, Stefan, Hoffmann, Georg F., Han, Min-Joon, Polleux, Franck, Sahin, Mustafa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.10.2016; Elsevier
• Subjects: Animals; autism; Autophagy; axonal transport; Axons - metabolism; carbamazepine; Cell Respiration; Humans; lysosome; Lysosomes - metabolism; Membrane Potential, Mitochondrial; Mice; mitochondria; Mitochondrial Degradation; Mitochondrial Dynamics; Models, Biological; mTOR; mTORC1; Mutation - genetics; Neurons - metabolism; Neurons - pathology; Pluripotent Stem Cells - metabolism; Presynaptic Terminals - metabolism; rapamycin; synapse; TOR Serine-Threonine Kinases - metabolism; Tuberous Sclerosis - metabolism; Tuberous Sclerosis - pathology; Tumor Suppressor Proteins - metabolism; autophagy; mitochondria; mTOR; axonal transport; synapse; mTORC1; lysosome; autism; rapamycin; carbamazepine
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.09.054

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. [Display omitted] •Mitochondria, some of which are dysfunctional, accumulate in Tsc2-deficient neurons•Axonal mitochondria, including those captured at presynaptic sites, are depleted•Spatiotemporal dynamics of axonal mitophagy and global mitophagic flux are impaired•Enhancing mTOR-dependent and -independent autophagy restores mitochondrial turnover Ebrahimi-Fakhari et al. show that mitochondrial dynamics and mitophagy are impaired in neuronal models of tuberous sclerosis complex. Axonal transport, turnover, and presynaptic capturing of mitochondria are compromised. Enhancing autophagic flux through mTORC1-dependent and -independent mechanisms restores mitochondrial homeostasis.