Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges.

Cell metabolism Pub Date : 2016-01-12 Epub Date: 2015-11-19 DOI:10.1016/j.cmet.2015.10.013
Aiwu Cheng, Ying Yang, Ye Zhou, Chinmoyee Maharana, Daoyuan Lu, Wei Peng, Yong Liu, Ruiqian Wan, Krisztina Marosi, Magdalena Misiak, Vilhelm A Bohr, Mark P Mattson
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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.

线粒体SIRT3介导神经元对运动、代谢和兴奋性挑战的适应性反应。
线粒体蛋白乙酰化状态对神经元功能和神经系统疾病易感性的影响尚不清楚。在这里,我们表明线粒体蛋白去乙酰化酶SIRT3介导神经元对生物能量、氧化和兴奋性应激的适应性反应。缺乏SIRT3的皮质神经元对谷氨酸诱导的钙超载、兴奋性毒性、氧化和线粒体应激表现出更高的敏感性;aav介导的Sirt3基因传递恢复神经元的应激抗性。在亨廷顿氏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的易感性增加。SIRT3缺乏导致包括超氧化物歧化酶2和嗜环蛋白d在内的几种线粒体蛋白的超乙酰化,跑步轮运动增加了海马神经元中SIRT3的表达,这是由兴奋性谷氨酸能神经传递介导的,对线粒体蛋白乙酰化稳态和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和对变性的抵抗中起着关键作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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