title: PGC-1α/ERRα-Sirt3 Pathway Regulates DAergic Neuronal Death by Directly Deacetylating SOD2 and ATP Synthase β.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The study provides new insights into a critical PGC-1α/ERRα-Sirt3 pathway, linking regulation of mitochondrial protein acetylation and DAergic neuronal death in PD pathogenesis, which provide a potential therapeutic strategy and target in PD treatment.
  
  
  CONCLUSIONS
  These results provide a vital PGC-1α/ERRα-Sirt3 pathway that protects against DAergic neuronal death by directly deacetylating SOD2 (K130) and ATP synthase β (K485) in PD.
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Xuefei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Ren
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Zheyi
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Shuaipeng
authors.initials: S
authors.lastname: Ma
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Jintao
authors.initials: J
authors.lastname: Bao
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Zeyang
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Liangjun
authors.initials: L
authors.lastname: Zheng
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 2 State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University , Beijing, China .
authors.forename: Shujiang
authors.initials: S
authors.lastname: Shang
authors.affiliation: 2 State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University , Beijing, China .
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: 3 Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China .
authors.forename: Chuangui
authors.initials: C
authors.lastname: Wang
authors.affiliation: 4 Institute of Translational Medicine, China Medical University , Shenyang, China .
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 1 State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University , Beijing, China .
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor; D000099156:Superoxide Dismutase 2
chemical_list: D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D013481:Superoxides; D000097983:ERRalpha Estrogen-Related Receptor; D000099156:Superoxide Dismutase 2