Activation of mitochondrial μ-calpain increases AIF cleavage in cardiac mitochondria during ischemia-reperfusion

被引:77
作者
Chen, Qun [1 ]
Paillard, Melanie [1 ,3 ]
Gomez, Ludovic [1 ,3 ]
Ross, Thomas [1 ]
Hu, Ying [1 ]
Xu, Aijun [1 ]
Lesnefsky, Edward J. [1 ,2 ,4 ]
机构
[1] Virginia Commonwealth Univ, Dept Med, Div Cardiol, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA
[3] Univ Lyon 1, INSERM, U 8864, F-69365 Lyon, France
[4] Vet Affairs Med Ctr, McGuire Dept, Richmond, VA 23249 USA
基金
美国国家卫生研究院;
关键词
Mitochondria; Calpastatin; Calpain; Ischemia-reperfusion; Calcium; APOPTOSIS-INDUCING FACTOR; ELECTRON-TRANSPORT; MYOCARDIAL ISCHEMIA/REPERFUSION; PERMEABILITY TRANSITION; CELL-DEATH; PROTECTS; INJURY; TRANSLOCATION; RESPIRATION; SENSITIZES;
D O I
10.1016/j.bbrc.2011.10.037
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ubiquitous calpains (calpain I and II) are generally recognized as cytosolic proteins. Recently, mitochondrial localized calpain I (mu-calpain) has been identified. Activation of mito-mu-calpain cleaves apoptosis inducing factor (AIF), a flavoprotein located within the mitochondrial intermembrane space, in liver mitochondria, but not in brain mitochondria. We first tested if activation of mito-mu-calpain cleaves AIF in isolated heart mitochondria. A decrease in AIF content within mitochondria increases cardiac injury during ischemia-reperfusion by augmenting oxidative stress. We hypothesize that the activation of mito-mu-calpain by calcium overload during ischemia-reperfusion results in decreased AIF content within mitochondria by cleaving AIF. The mu-calpain was present within mouse heart mitochondria, mostly in the intermembrane space. Exogenous calcium treatment induced a calpain-dependent decrease of mitochondrial AIF content in isolated mouse heart mitochondria. This process was blocked by a calpain inhibitor (MDL-28170). The Mitochondrial mu-calpain activity was increased by 160 +/- 15% during ischemia-reperfusion compared to time control. In contrast, the mitochondrial AIF content was decreased by 52 +/- 7% during reperfusion vs. time control in the buffer perfused mouse heart. Inhibition of mito-mu-calpain using MDL-28170 decreased cardiac injury by preserving AIF content within mitochondria during ischemia-reperfusion. Thus, activation of mito-mu-calpain is required to release AIF from cardiac mitochondria. Inhibition of calpains using MDL-28170 decreases cardiac injury by inhibiting both cytosolic calpains and mito-mu-calpain during ischemia-reperfusion. Published by Elsevier Inc.
引用
收藏
页码:533 / 538
页数:6
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