title: Interdependence of Parkin-Mediated Mitophagy and Mitochondrial Fission in Adult Mouse Hearts.
abstract: BACKGROUND
  The role of Parkin in hearts is unclear. Germ-line Parkin knockout mice have normal hearts, but Parkin is protective in cardiac ischemia. Parkin-mediated mitophagy is reportedly either irrelevant, or a major factor, in the lethal cardiomyopathy evoked by cardiac myocyte-specific interruption of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission.
  
  
  OBJECTIVE
  To understand the role of Parkin-mediated mitophagy in normal and mitochondrial fission-defective adult mouse hearts.
  
  
  RESULTS
  Parkin mRNA and protein were present at low levels in normal mouse hearts, but were upregulated after cardiac myocyte-directed Drp1 gene deletion in adult mice. Alone, forced cardiac myocyte Parkin overexpression activated mitophagy without adverse effects. Likewise, cardiac myocyte-specific Parkin deletion evoked no adult cardiac phenotype, revealing no essential function for, and tolerance of, Parkin-mediated mitophagy in normal hearts. Concomitant conditional Parkin deletion with Drp1 ablation in adult mouse hearts prevented Parkin upregulation in mitochondria of fission-defective hearts, also increasing 6-week survival, improving ventricular ejection performance, mitigating adverse cardiac remodeling, and decreasing cardiac myocyte necrosis and replacement fibrosis. Underlying the Parkin knockout rescue was suppression of Drp1-induced hyper-mitophagy, assessed as ubiquitination of mitochondrial proteins and mitochondrial association of autophagosomal p62/sequestosome 1 (SQSTM1) and processed microtubule-associated protein 1 light chain 3 (LC3-II). Consequently, mitochondrial content of Drp1-deficient hearts was preserved. Parkin deletion did not alter characteristic mitochondrial enlargement of Drp1-deficient cardiac myocytes.
  
  
  CONCLUSIONS
  Parkin is rare in normal hearts and dispensable for constitutive mitophagic quality control. Ablating Drp1 in adult mouse cardiac myocytes not only interrupts mitochondrial fission, but also markedly upregulates Parkin, thus provoking mitophagic mitochondrial depletion that contributes to the lethal cardiomyopathy.
authors.affiliation: From the Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (M.S., G.G., S.J.M., G.W.D.); Department of Biomedical Sciences, University of Montreal, Quebec, Canada (Y.B.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (A.B.G.); and Departments of Medicine (Cardiology) and Cell Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (R.N.K.).
authors.forename: Moshi
authors.initials: M
authors.lastname: Song
authors.affiliation: From the Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (M.S., G.G., S.J.M., G.W.D.); Department of Biomedical Sciences, University of Montreal, Quebec, Canada (Y.B.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (A.B.G.); and Departments of Medicine (Cardiology) and Cell Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (R.N.K.).
authors.forename: Guohua
authors.initials: G
authors.lastname: Gong
authors.affiliation: From the Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (M.S., G.G., S.J.M., G.W.D.); Department of Biomedical Sciences, University of Montreal, Quebec, Canada (Y.B.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (A.B.G.); and Departments of Medicine (Cardiology) and Cell Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (R.N.K.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Burelle
authors.affiliation: From the Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (M.S., G.G., S.J.M., G.W.D.); Department of Biomedical Sciences, University of Montreal, Quebec, Canada (Y.B.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (A.B.G.); and Departments of Medicine (Cardiology) and Cell Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (R.N.K.).
authors.forename: Åsa B
authors.initials: ÅB
authors.lastname: Gustafsson
authors.affiliation: From the Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (M.S., G.G., S.J.M., G.W.D.); Department of Biomedical Sciences, University of Montreal, Quebec, Canada (Y.B.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (A.B.G.); and Departments of Medicine (Cardiology) and Cell Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (R.N.K.).
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kitsis
authors.affiliation: From the Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (M.S., G.G., S.J.M., G.W.D.); Department of Biomedical Sciences, University of Montreal, Quebec, Canada (Y.B.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (A.B.G.); and Departments of Medicine (Cardiology) and Cell Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (R.N.K.).
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.affiliation: From the Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (M.S., G.G., S.J.M., G.W.D.); Department of Biomedical Sciences, University of Montreal, Quebec, Canada (Y.B.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA (A.B.G.); and Departments of Medicine (Cardiology) and Cell Biology, and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (R.N.K.). gdorn@dom.wustl.edu.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D063306:Mitophagy; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009336:Necrosis; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Parkin protein; cardiomyopathies; mice; mitochondria; mitochondrial degradation; mitochondrial dynamics