title: Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges.
abstract: The impact of mitochondrial protein acetylation status on neuronal function and vulnerability to neurological disorders is unknown. Here we show that the mitochondrial protein deacetylase SIRT3 mediates adaptive responses of neurons to bioenergetic, oxidative, and excitatory stress. Cortical neurons lacking SIRT3 exhibit heightened sensitivity to glutamate-induced calcium overload and excitotoxicity and oxidative and mitochondrial stress; AAV-mediated Sirt3 gene delivery restores neuronal stress resistance. In models relevant to Huntington's disease and epilepsy, Sirt3(-/-) mice exhibit increased vulnerability of striatal and hippocampal neurons, respectively. SIRT3 deficiency results in hyperacetylation of several mitochondrial proteins, including superoxide dismutase 2 and cyclophilin D. Running wheel exercise increases the expression of Sirt3 in hippocampal neurons, which is mediated by excitatory glutamatergic neurotransmission and is essential for mitochondrial protein acetylation homeostasis and the neuroprotective effects of running. Our findings suggest that SIRT3 plays pivotal roles in adaptive responses of neurons to physiological challenges and resistance to degeneration.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. Electronic address: chengai@mail.nih.gov.
authors.forename: Aiwu
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA; Department of Neurology, Wuhan University, Wuhan, Hubei 430071, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Chinmoyee
authors.initials: C
authors.lastname: Maharana
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Daoyuan
authors.initials: D
authors.lastname: Lu
authors.affiliation: Laboratory of Genetics, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Ruiqian
authors.initials: R
authors.lastname: Wan
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Marosi
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA; Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Misiak
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: mark.mattson@nih.gov.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000107:Acetylation; D000222:Adaptation, Physiological; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004734:Energy Metabolism; D006624:Hippocampus / Q000166:cytology; D053078:Membrane Potential, Mitochondrial; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D017072:Neostriatum / Q000166:cytology; D009410:Nerve Degeneration / Q000201:enzymology; D009474:Neurons / Q000502:physiology*; D010805:Physical Conditioning, Animal; D065840:Protective Factors; D011499:Protein Processing, Post-Translational; D012420:Running / Q000502:physiology; D056566:Sirtuin 3 / Q000502:physiology*; D013312:Stress, Physiological
chemical_list: D024101:Mitochondrial Proteins; C525046:Sirt3 protein, mouse; D056566:Sirtuin 3; D002118:Calcium
keywords: CypD; ROS; SOD2; excitotoxicity; mPTP; mitochondria; neurodegeneration; voluntary exercise