Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex
Darius Ebrahimi-Fakhari,
Afshin Saffari,
Lara Wahlster,
Alessia Di Nardo,
Daria Turner,
Tommy L. Lewis Jr.,
Christopher Conrad,
Jonathan M. Rothberg,
Jonathan O. Lipton,
Stefan Kölker,
Georg F. Hoffmann,
Min-Joon Han,
Franck Polleux,
Mustafa Sahin
Affiliations
Darius Ebrahimi-Fakhari
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Afshin Saffari
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Lara Wahlster
Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
Alessia Di Nardo
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Daria Turner
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Tommy L. Lewis Jr.
Department of Neuroscience, Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, NY 10027, USA
Christopher Conrad
LAM Therapeutics, Guilford, CT 06437, USA
Jonathan M. Rothberg
LAM Therapeutics, Guilford, CT 06437, USA
Jonathan O. Lipton
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Stefan Kölker
Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
Georg F. Hoffmann
Division of Pediatric Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
Min-Joon Han
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Franck Polleux
Department of Neuroscience, Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, NY 10027, USA
Mustafa Sahin
The F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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.
