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パーキンソン病とその類縁疾患 1
Parkinson's Disease and Related Disorders 1

開催日 2014/9/12
時間 17:10 - 18:10
会場 Room I(311+312)
Chairperson(s) 小澤 健太郎 / Kentaro Ozawa (奈良県立医科大学 / Nara Medical University, Japan)
山門 穂高 / Hodaka Yamakado (京都大学大学院医学研究科 臨床神経学  / Department of Neurology, Kyoto University Graduate School of Medicine, Japan)

Nitric oxide regulates degradation of depolarized mitochondria via S-nitrosylation of parkin

  • O2-I-5-2
  • 小澤 健太郎 / Kentaro Ozawa:1 趙 晶 / Jing Zhao:1 京谷 陽司 / Yoji Kyotani:1 伊藤 都裕 / Satoyasu Ito:1 長山 功佑 / Kosuke Nagayama:1 辻 優一 / Yuichi Tsuji:1 吉栖 正典 / Masanori Yoshizumi:1 
  • 1:奈良県立医科大学 / Dept Pharmacol., Nara Med. Univ., Nara, Japan 

Parkin, a ring between ring fingers E3 ubiquitin ligase with a ubiquitin-like domain at the N-terminus, its mutations cause a familial form of Parkinson's disease (PD) known as autosomal recessive juvenile parkinsonism. Recently a series of reports revealed parkin plays an important role in mitochondrial quality control. When the mitochondria are depolarized, parkin is recruited from the cytosol to mitochondria, activated, and ubiquitinates proteins on mitochondrial outer membrane, which leads to mitochondrial degradation via an autophagic event known as mitophagy. It is well-establised how parkin is recruited to depolarized mitochondria, however, molecular mechanism to regulate the activity of parkin is not well-understood.
We hypothesized that the activity of parkin might be regulated by S-nitrosylation, the covalent incorporation of a nitric oxide moiety into thiol groups. S-nitrosylation is enhanced in brain tissues of patients with PD and cultured cells treated with the mitochondrial respiratory chain complex I, however, its pathophysiological significance is still controversial. Here we identified a S-nitrosylated cysteine residue in parkin, and revealed S-nitrosylation of parkin increases E3 ligase activity by comparing with cysteine-to-serine mutant. Furthermore we revealed S-nitrosylation of parkin plays an important role in degradation of depolarized mitochondria. Finally we showed peroxynitrite, which is produced by the reaction of nitric oxide with superoxide, denitrosylated and nitrated parkin and decreased mitochondrial degradation, which can account for the negative effect of NO on mitochondrial quality control. We would propose that our results provide insight that S-nitrosylation plays important roles in mitochondrial quality control, which is possibly involved in the pathogenesis of PD.

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