title: Convergence of Parkin, PINK1, and α-Synuclein on Stress-induced Mitochondrial Morphological Remodeling.
abstract: Mutations in PARKIN (PARK2), an ubiquitin ligase, cause early onset Parkinson disease. Parkin was shown to bind, ubiquitinate, and target depolarized mitochondria for destruction by autophagy. This process, mitophagy, is considered crucial for maintaining mitochondrial integrity and suppressing Parkinsonism. Here, we report that under moderate mitochondrial stress, parkin does not translocate to mitochondria to induce mitophagy; rather, it stimulates mitochondrial connectivity. Mitochondrial stress-induced fusion requires PINK1 (PARK6), mitofusins, and parkin ubiquitin ligase activity. Upon exposure to mitochondrial toxins, parkin binds α-synuclein (PARK1), and in conjunction with the ubiquitin-conjugating enzyme Ubc13, stimulates K63-linked ubiquitination. Importantly, α-synuclein inactivation phenocopies parkin overexpression and suppresses stress-induced mitochondria fission, whereas Ubc13 inactivation abrogates parkin-dependent mitochondrial fusion. The convergence of parkin, PINK1, and α-synuclein on mitochondrial dynamics uncovers a common function of these PARK genes in the mitochondrial stress response and provides a potential physiological basis for the prevalence of α-synuclein pathology in Parkinson disease.
authors: From the Departments of Pharmacology and Cancer Biology and.
authors: Kristi L
authors: KL
authors: Norris
authors: From the Departments of Pharmacology and Cancer Biology and.
authors: Rui
authors: R
authors: Hao
authors: Neurobiology, Duke University, Medical Center, Durham, North Carolina 27710.
authors: Liang-Fu
authors: LF
authors: Chen
authors: From the Departments of Pharmacology and Cancer Biology and.
authors: Chun-Hsiang
authors: CH
authors: Lai
authors: From the Departments of Pharmacology and Cancer Biology and.
authors: Meghan
authors: M
authors: Kapur
authors: From the Departments of Pharmacology and Cancer Biology and.
authors: Peter J
authors: PJ
authors: Shaughnessy
authors: From the Departments of Pharmacology and Cancer Biology and.
authors: Dennis
authors: D
authors: Chou
authors: From the Departments of Pharmacology and Cancer Biology and.
authors: Jin
authors: J
authors: Yan
authors: the Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors: J Paul
authors: JP
authors: Taylor
authors: the Department of Pharmacology, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel, and.
authors: Simone
authors: S
authors: Engelender
authors: Neurobiology, Duke University, Medical Center, Durham, North Carolina 27710.
authors: Anna E
authors: AE
authors: West
authors: the Department of Physiology, National University of Singapore, Singapore.
authors: Kah-Leong
authors: KL
authors: Lim
authors: From the Departments of Pharmacology and Cancer Biology and tsopang.yao@dm.duke.edu.
authors: Tso-Pang
authors: TP
authors: Yao
mesh_terms: D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000737:chemistry; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D011494:Protein Kinases; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: PTEN-induced putative kinase 1 (PINK1); Parkinson disease; mitochondria; parkin; α-synuclein (a-synuclein)