title: Nitric oxide induction of Parkin translocation in PTEN-induced putative kinase 1 (PINK1) deficiency: functional role of neuronal nitric oxide synthase during mitophagy.
abstract: The failure to trigger mitophagy is implicated in the pathogenesis of familial Parkinson disease that is caused by PINK1 or Parkin mutations. According to the prevailing PINK1-Parkin signaling model, mitophagy is promoted by the mitochondrial translocation of Parkin, an essential PINK1-dependent step that occurs via a previously unknown mechanism. Here we determined that critical concentrations of NO was sufficient to induce the mitochondrial translocation of Parkin even in PINK1 deficiency, with apparent increased interaction of full-length PINK1 accumulated during mitophagy, with neuronal nitric oxide synthase (nNOS). Specifically, optimum levels of NO enabled PINK1-null dopaminergic neuronal cells to regain the mitochondrial translocation of Parkin, which appeared to be significantly suppressed by nNOS-null mutation. Moreover, nNOS-null mutation resulted in the same mitochondrial electron transport chain (ETC) enzyme deficits as PINK1-null mutation. The involvement of mitochondrial nNOS activation in mitophagy was further confirmed by the greatly increased interactions of full-length PINK1 with nNOS, accompanied by mitochondrial accumulation of phospho-nNOS (Ser(1412)) during mitophagy. Of great interest is that the L347P PINK1 mutant failed to bind to nNOS. The loss of nNOS phosphorylation and Parkin accumulation on PINK1-deficient mitochondria could be reversed in a PINK1-dependent manner. Finally, non-toxic levels of NO treatment aided in the recovery of PINK1-null dopaminergic neuronal cells from mitochondrial ETC enzyme deficits. In summary, we demonstrated the full-length PINK1-dependent recruitment of nNOS, its activation in the induction of Parkin translocation, and the feasibility of NO-based pharmacotherapy for defective mitophagy and ETC enzyme deficits in Parkinson disease.
authors.affiliation: From the Department of Brain and Cognitive Sciences, Brain Disease Research Institute.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Han
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, and.
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: From the Department of Brain and Cognitive Sciences, Brain Disease Research Institute.
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.affiliation: From the Department of Brain and Cognitive Sciences, Brain Disease Research Institute.
authors.forename: Pyung-Lim
authors.initials: PL
authors.lastname: Han
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, and.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Ha
authors.affiliation: From the Department of Brain and Cognitive Sciences, Brain Disease Research Institute, Graduate School of Pharmaceutical Sciences, College of Pharmacy, and hjson@ewha.ac.kr.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Son
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D004579:Electron Transport; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics*; D009569:Nitric Oxide / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011485:Protein Binding; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics*; D021381:Protein Transport; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C496321:Nos1 protein, mouse; C111567:parkin protein
keywords: Mitophagy; Nitric Oxide; PTEN-induced Putative Kinase 1 (PINK1); Parkin; Parkinson Disease; nNOS