title: S-nitrosylation regulates mitochondrial quality control via activation of parkin.
abstract: Parkin, a ubiquitin E3 ligase of the ring between ring fingers family, has been implicated in mitochondrial quality control. A series of recent reports have suggested that the recruitment of parkin is regulated by phosphorylation. However, the molecular mechanism that activates parkin to induce mitochondrial degradation is not well understood. Here, and in contrast to previous reports that S-nitrosylation of parkin is exclusively inhibitory, we identify a previously unrecognized site of S-nitrosylation in parkin (Cys323) that induces mitochondrial degradation. We demonstrate that endogenous S-nitrosylation of parkin is in fact responsible for activation of its E3 ligase activity to induce aggregation and degradation. We further demonstrate that mitochondrial uncoupling agents result in denitrosylation of parkin, and that prevention of denitrosylation restores mitochondrial degradation. Our data indicates that NO both positive effects on mitochondrial quality control, and suggest that targeted S-nitrosylation could provide a novel therapeutic strategy against Parkinson's disease.
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Japan. ko12@naramedu.ac.jp
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ozawa
authors.forename: Akira T
authors.initials: AT
authors.lastname: Komatsubara
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Sawada
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kawafune
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsumoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tsuji
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kyotani
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshizumi
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015027:Zebrafish
chemical_list: D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D003545:Cysteine