Inhibition of mitochondrial fission as a molecular target for cardioprotection: critical importance of the timing of treatment

Yi Dong, Vishnu V.R. Undyala, Karin Przyklenk

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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.

Original languageEnglish
Article number59
JournalBasic Research in Cardiology
Volume111
Issue number5
DOIs
StatePublished - Sep 1 2016

Keywords

  • Apoptosis
  • Dynamin-related protein 1
  • HL-1 cell
  • Hypoxia–reoxygenation
  • Ischemia–reperfusion
  • Mitochondrial fission

Fingerprint

Dive into the research topics of 'Inhibition of mitochondrial fission as a molecular target for cardioprotection: critical importance of the timing of treatment'. Together they form a unique fingerprint.

Cite this