PGC-1α/ERRα-Sirt3 Pathway Regulates DAergic Neuronal Death by Directly Deacetylating SOD2 and ATP Synthase β

作者：Xuefei Zhang, Xiaoqing Ren, Qi Zhang, Zheyi Li, Shuaipeng Ma, Jintao Bao, Zeyang Li, Xue Bai, Liangjun Zheng, Zhong Zhang, Shujiang Shang, Chen Zhang, Chuangui Wang, Liu Cao, Qingsong Wang, Jianguo Ji · 发表于：Antioxidants and Redox Signaling · 年份：2015 · DOI：10.1089/ars.2015.6403 · 被引用次数：131 · 研究领域：Sirtuins and Resveratrol in Medicine、Nerve injury and regeneration、Genetic Neurodegenerative Diseases

AIMS: Parkinson's disease (PD) heavily affects humans and little is known about its cause and pathogenesis. Sirtuin 3 (Sirt3) plays a key role in regulating mitochondrial dysfunction, which is the main cause of DAergic neuronal loss in PD. We investigated the mechanisms of neuroprotective role of Sirt3 in DAergic neuronal survival. RESULTS: Sirt3 was reduced in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated neurons with its overexpression being neuroprotective. We identified that Sirt3 interacted with manganese superoxide dismutase (SOD2) and adenosine triphosphate (ATP) synthase β and modulated their activities by deacetylating SOD2 (K130) and ATP synthase β (K485) to prevent reactive oxygen species accumulation and ATP depletion, and to alleviate DAergic neuronal death upon MPTP treatment. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) interacted with estrogen-related receptor alpha (ERRα) that bound to the Sirt3 promoter as its transcription factor to regulate Sirt3 expression and DAergic neuronal death. In the mouse midbrain, MPTP administration led to the loss of PGC-1α and Sirt3, high acetylation level of SOD2 and ATP synthase β, and the specific loss of DAergic neurons, while Sirt3 overexpression could protect against DAergic neuronal loss. Sirt3 knockout mice exhibited more sensitive and more DAergic neuronal loss to MPTP treatment. INNOVATION: The study provides new insights into a critical PGC-1α/ERRα-Sirt3 pathway, linking regulat...