title: Inhibition of mitochondrial fission as a molecular target for cardioprotection: critical importance of the timing of treatment.
abstract: Recent attention has focused on the concept that mitochondrial dynamics-that is, the balance between mitochondrial fusion and fission (fragmentation)-may play a pivotal role in determining cell fate in the setting of myocardial ischemia-reperfusion injury. In this regard, there is an emerging consensus that: (1) ischemia-reperfusion favors mitochondrial fragmentation and (2) strategies aimed at inhibiting the translocation of dynamin-related protein 1 (DRP1: the 'master regulator' of fission) from the cytosol to the mitochondria, when initiated as a pretreatment, are cardioprotective. However, direct molecular evidence of a cause-and-effect relationship between mitochondrial fission and cardiomyocyte death has not been established. To address this issue, we used a well-characterized in vitro, immortal cultured cardiomyocyte model to establish whether subcellular redistribution of DRP1 to mitochondria: (1) is triggered by hypoxia-reoxygenation; (2) plays a causal role in hypoxia-reoxygenation-induced cytochrome c release (harbinger of apoptosis) and cardiomyocyte death; and (3) represents a molecular mechanism that can be targeted in a clinically relevant time frame to render cells resistant to lethal hypoxia-reoxygenation injury. Our results provide direct evidence that the redistribution of DRP1 to mitochondria contributes to cardiomyocyte death, and corroborate the previous observations that the pre-ischemic inhibition of DRP1 translocation is cardioprotective. Moreover, we report the novel finding that-in marked contrast to the data obtained with pretreatment-inhibition of DRP1 translocation initiated at the time of reoxygenation had complex, unexpected and unfavorable consequences: i.e., attenuated cardiomyocyte apoptosis but exacerbated total cell death, possibly via concurrent upregulation of necroptosis.
authors: Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.|Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA.|Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, USA.
authors: Yi
authors: Y
authors: Dong
authors: Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.|Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA.
authors: Vishnu V R
authors: VVR
authors: Undyala
authors: Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA. karinp@wayne.edu.|Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA. karinp@wayne.edu.|Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI, USA. karinp@wayne.edu.
authors: Karin
authors: 0000-0002-9602-6349
authors: K
authors: Przyklenk
mesh_terms: D000818:Animals; D016923:Cell Death; D034281:Dynamins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D051379:Mice; D063154:Mitochondrial Dynamics / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport / Q000502:physiology
chemical_list: C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Apoptosis; Dynamin-related protein 1; HL-1 cell; Hypoxia–reoxygenation; Ischemia–reperfusion; Mitochondrial fission