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

Abstract

Ubiquitous calpains (calpain I and II) are generally recognized as cytosolic proteins. Recently, mitochondrial localized calpain I (μ-calpain) has been identified. Activation of mito-μ-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-μ-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-μ-calpain by calcium overload during ischemia-reperfusion results in decreased AIF content within mitochondria by cleaving AIF. The μ-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 μ-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-μ-calpain using MDL-28170 decreased cardiac injury by preserving AIF content within mitochondria during ischemia-reperfusion. Thus, activation of mito-μ-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-μ-calpain during ischemia-reperfusion.

• Authors: Qun Chen, Melanie Paillard, Ludovic Gomez, Thomas Ross, Ying Hu, Aijun Xu, Edward J Lesnefsky
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 415 Issue 4 Pg. 533-8 (Dec 02 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 22057010 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published by Elsevier Inc.

Chemical References

• Apoptosis Inducing Factor
• Cysteine Proteinase Inhibitors
• Dipeptides
• calpain inhibitor III

Topics

• Animals
• Apoptosis Inducing Factor (metabolism)
• Cysteine Proteinase Inhibitors (pharmacology)
• Dipeptides (pharmacology)
• Enzyme Activation
• Mice
• Mitochondria (enzymology)
• Mitochondria, Heart (enzymology)
• Myocardial Reperfusion Injury (enzymology)