title: Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain.
abstract: Mitochondrial dynamics and mitophagy have been linked to cardiovascular and neurodegenerative diseases. Here, we demonstrate that the mitochondrial division dynamin Drp1 and the Parkinson's disease-associated E3 ubiquitin ligase parkin synergistically maintain the integrity of mitochondrial structure and function in mouse heart and brain. Mice lacking cardiac Drp1 exhibited lethal heart defects. In Drp1KO cardiomyocytes, mitochondria increased their connectivity, accumulated ubiquitinated proteins, and decreased their respiration. In contrast to the current views of the role of parkin in ubiquitination of mitochondrial proteins, mitochondrial ubiquitination was independent of parkin in Drp1KO hearts, and simultaneous loss of Drp1 and parkin worsened cardiac defects. Drp1 and parkin also play synergistic roles in neuronal mitochondrial homeostasis and survival. Mitochondrial degradation was further decreased by combination of Drp1 and parkin deficiency, compared with their single loss. Thus, the physiological importance of parkin in mitochondrial homeostasis is revealed in the absence of mitochondrial division in mammals.
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kageyama
authors.affiliation: Center for Research in Biological Systems and Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kinya
authors.initials: K
authors.lastname: Seo
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Sysa-Shah
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Johns Hopkins University School of Medicine, Baltimore, MD, USA Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
authors.forename: Shaida A
authors.initials: SA
authors.lastname: Andrabi
authors.affiliation: Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Weiran
authors.initials: W
authors.lastname: Chen
authors.affiliation: Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Höke
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Johns Hopkins University School of Medicine, Baltimore, MD, USA Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Johns Hopkins University School of Medicine, Baltimore, MD, USA Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabrielson
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Miho
authors.initials: M
authors.lastname: Iijima
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA hsesaki@jhmi.edu.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D055032:Electron Microscope Tomography; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C584019:Myh6 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D018995:Myosin Heavy Chains; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: mice; mitochondria; organelle division; respiration