Cheng Aiwu, Yang Ying, Zhou Ye, Maharana Chinmoyee, Lu Daoyuan, Peng Wei, Liu Yong, Wan Ruiqian, Marosi Krisztina, Misiak Magdalena, Bohr Vilhelm A, Mattson Mark P
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA; Department of Neurology, Wuhan University, Wuhan, Hubei 430071, China.
Cell Metab. 2016 Jan 12;23(1):128-42. doi: 10.1016/j.cmet.2015.10.013. Epub 2015 Nov 19.
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.
线粒体蛋白乙酰化状态对神经元功能及对神经疾病易感性的影响尚不清楚。在此我们表明，线粒体蛋白脱乙酰酶SIRT3介导神经元对生物能、氧化和兴奋性应激的适应性反应。缺乏SIRT3的皮层神经元对谷氨酸诱导的钙超载、兴奋毒性以及氧化和线粒体应激表现出更高的敏感性；腺相关病毒介导的Sirt3基因递送可恢复神经元的应激抗性。在与亨廷顿舞蹈病和癫痫相关的模型中，Sirt3(-/-)小鼠分别表现出纹状体和海马神经元更高的易损性。SIRT3缺乏导致几种线粒体蛋白的超乙酰化，包括超氧化物歧化酶2和亲环蛋白D。跑步锻炼可增加海马神经元中Sirt3的表达，这由兴奋性谷氨酸能神经传递介导，并且对于线粒体蛋白乙酰化稳态以及跑步的神经保护作用至关重要。我们的研究结果表明，SIRT3在神经元对生理挑战的适应性反应及抗变性中起关键作用。
