title: Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex.
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.
authors.affiliation: The 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.
authors.forename: Darius
authors.initials: D
authors.lastname: Ebrahimi-Fakhari
authors.affiliation: The 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.
authors.forename: Afshin
authors.initials: A
authors.lastname: Saffari
authors.affiliation: Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany; Division of Hematology and Oncology, Stem Cell Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Wahlster
authors.affiliation: The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Di Nardo
authors.affiliation: The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Turner
authors.affiliation: Department of Neuroscience, Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, NY 10027, USA.
authors.forename: Tommy L
authors.initials: TL
authors.lastname: Lewis
authors.affiliation: LAM Therapeutics, Guilford, CT 06437, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Conrad
authors.affiliation: LAM Therapeutics, Guilford, CT 06437, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Rothberg
authors.affiliation: The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan O
authors.initials: JO
authors.lastname: Lipton
authors.affiliation: Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
authors.affiliation: Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Min-Joon
authors.initials: MJ
authors.lastname: Han
authors.affiliation: Department of Neuroscience, Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, NY 10027, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Polleux
authors.affiliation: The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: mustafa.sahin@childrens.harvard.edu.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
mesh_terms: D000818:Animals; D001343:Autophagy; D001369:Axons / Q000378:metabolism; D019069:Cell Respiration; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D063154:Mitochondrial Dynamics; D063306:Mitophagy; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D039904:Pluripotent Stem Cells / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D058570:TOR Serine-Threonine Kinases
keywords: autism; autophagy; axonal transport; carbamazepine; lysosome; mTOR; mTORC1; mitochondria; rapamycin; synapse