title: Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission.
abstract: Mitochondrial dysregulation is strongly implicated in Parkinson disease. Mutations in PTEN-induced kinase 1 (PINK1) are associated with familial parkinsonism and neuropsychiatric disorders. Although overexpressed PINK1 is neuroprotective, less is known about neuronal responses to loss of PINK1 function. We found that stable knockdown of PINK1 induced mitochondrial fragmentation and autophagy in SH-SY5Y cells, which was reversed by the reintroduction of an RNA interference (RNAi)-resistant plasmid for PINK1. Moreover, stable or transient overexpression of wild-type PINK1 increased mitochondrial interconnectivity and suppressed toxin-induced autophagy/mitophagy. Mitochondrial oxidant production played an essential role in triggering mitochondrial fragmentation and autophagy in PINK1 shRNA lines. Autophagy/mitophagy served a protective role in limiting cell death, and overexpressing Parkin further enhanced this protective mitophagic response. The dominant negative Drp1 mutant inhibited both fission and mitophagy in PINK1-deficient cells. Interestingly, RNAi knockdown of autophagy proteins Atg7 and LC3/Atg8 also decreased mitochondrial fragmentation without affecting oxidative stress, suggesting active involvement of autophagy in morphologic remodeling of mitochondria for clearance. To summarize, loss of PINK1 function elicits oxidative stress and mitochondrial turnover coordinated by the autophagic and fission/fusion machineries. Furthermore, PINK1 and Parkin may cooperate through different mechanisms to maintain mitochondrial homeostasis.
authors.affiliation: Department of Pathology and University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Ruben K
authors.initials: RK
authors.lastname: Dagda
authors.affiliation: Department of Pathology and University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Cherra
authors.affiliation: Department of Pathology and University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Kulich
authors.affiliation: Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M55 3H2, Canada.
authors.forename: Anurag
authors.initials: A
authors.lastname: Tandon
authors.affiliation: Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Pathology and University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15213. Electronic address: ctc4@pitt.edu.
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
mesh_terms: D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D055785:Gene Knockdown Techniques; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000071193:Autophagy-Related Protein 7; D008869:Microtubule-Associated Proteins; D011494:Protein Kinases; D044764:Ubiquitin-Activating Enzymes; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C477012:MAP1LC3A protein, human; C111567:parkin protein; C509349:ATG7 protein, human