title: Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress.
abstract: BACKGROUND
  Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood.
  
  
  OBJECTIVE
  We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart.
  
  
  RESULTS
  Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout mice. Although left ventricular function in cardiac-specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice.
  
  
  CONCLUSIONS
  Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion.
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shirakabe
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Sciarretta
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Toli
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Mihara
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohishi
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.).
authors.forename: Maha
authors.initials: M
authors.lastname: Abdellatif
authors.affiliation: From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark (Y.I., A.S., Y.M., P.Z., S.S., J.T., M.A., J.S.); IRCCS Neuromed, Pozzilli, Italy (S.S.); Department of Medicine and Bioregulatory Science (M.N.), Department of Molecular Biology (K.M.), Department of Cardiovascular Medicine, Department of Cardiovascular Research, Development, and Translational Medicine (K.E.), Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan; and Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan (M.O.). sadoshju@njms.rutgers.edu.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D034281:Dynamins / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Drp1 protein, mouse; autophagy; heart; ischemia/reperfusion injury; mitochondria