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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.

journal_name

Basic Res Cardiol

journal_title

Basic research in cardiology

authors

Dong Y,Undyala VVR,Przyklenk K

doi

10.1007/s00395-016-0578-x

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

issue

eissn

0300-8428

issn

1435-1803

pii

10.1007/s00395-016-0578-x

journal_volume

111

pub_type

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