Mitochondrial m-calpain opens the mitochondrial permeability transition pore in ischemia–reperfusion

Abstract Background/objectives : Opening of the mitochondrial permeability transition pore (mPTP) is involved in ischemia–reperfusion injury. Isoforms of Ca 2 + -activated cysteine proteases, calpains, are implicated in the development of myocardial infarction in ischemia–reperfusion. Growing eviden...

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Veröffentlicht in:International journal of cardiology 2015-10, Vol.197, p.26-32
Hauptverfasser: Shintani-Ishida, Kaori, Yoshida, Ken-ichi
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creator Shintani-Ishida, Kaori
Yoshida, Ken-ichi
description Abstract Background/objectives : Opening of the mitochondrial permeability transition pore (mPTP) is involved in ischemia–reperfusion injury. Isoforms of Ca 2 + -activated cysteine proteases, calpains, are implicated in the development of myocardial infarction in ischemia–reperfusion. Growing evidence has revealed the presence of calpains in the mitochondria. We aimed to characterize mitochondrial calpains in the rat heart and to investigate the roles of calpains in mPTP opening after ischemia–reperfusion. Methods and results : Western blotting analysis showed the expression of μ-calpain, m-calpain and calpain 10 in mitochondria isolated from male Sprague-Dawley rats, but casein zymography detected only m-calpain activity. Subcellular fractionation of mitochondria demonstrated the distribution of m-calpain to the matrix fraction. Addition of > 500 μM of Ca 2 + to isolated mitochondria induced mitochondrial swelling, reflecting mPTP opening, and calpain activation. Ca 2 + -induced mitochondrial swelling was inhibited partially by the calpain inhibitor calpeptin. These results support a partial contribution of calpain in the opening of the mPTP. The addition of Ca 2 + to the mitochondria induced inactivation of complex I of the electron transport chain, and cleavage of the ND6 complex I subunit, which were inhibited by calpeptin. Mitochondria isolated from rat hearts that underwent 30 min of coronary occlusion followed by 30 min of reperfusion showed activation of mitochondrial calpains, ND6 cleavage, complex I inactivation, and mPTP opening, which were inhibited by pretreatment with calpain inhibitor 1. Conclusions : We demonstrated for the first time the presence of mitochondrial matrix m-calpain, and its contribution to complex I inactivation and mPTP opening after postischemic reperfusion in the rat heart.
doi_str_mv 10.1016/j.ijcard.2015.06.010
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Isoforms of Ca 2 + -activated cysteine proteases, calpains, are implicated in the development of myocardial infarction in ischemia–reperfusion. Growing evidence has revealed the presence of calpains in the mitochondria. We aimed to characterize mitochondrial calpains in the rat heart and to investigate the roles of calpains in mPTP opening after ischemia–reperfusion. Methods and results : Western blotting analysis showed the expression of μ-calpain, m-calpain and calpain 10 in mitochondria isolated from male Sprague-Dawley rats, but casein zymography detected only m-calpain activity. Subcellular fractionation of mitochondria demonstrated the distribution of m-calpain to the matrix fraction. Addition of &gt; 500 μM of Ca 2 + to isolated mitochondria induced mitochondrial swelling, reflecting mPTP opening, and calpain activation. Ca 2 + -induced mitochondrial swelling was inhibited partially by the calpain inhibitor calpeptin. These results support a partial contribution of calpain in the opening of the mPTP. The addition of Ca 2 + to the mitochondria induced inactivation of complex I of the electron transport chain, and cleavage of the ND6 complex I subunit, which were inhibited by calpeptin. Mitochondria isolated from rat hearts that underwent 30 min of coronary occlusion followed by 30 min of reperfusion showed activation of mitochondrial calpains, ND6 cleavage, complex I inactivation, and mPTP opening, which were inhibited by pretreatment with calpain inhibitor 1. Conclusions : We demonstrated for the first time the presence of mitochondrial matrix m-calpain, and its contribution to complex I inactivation and mPTP opening after postischemic reperfusion in the rat heart.</description><identifier>ISSN: 0167-5273</identifier><identifier>EISSN: 1874-1754</identifier><identifier>DOI: 10.1016/j.ijcard.2015.06.010</identifier><identifier>PMID: 26113472</identifier><language>eng</language><publisher>Netherlands: Elsevier Ireland Ltd</publisher><subject>Animals ; Blotting, Western ; Calcium ; Calcium - pharmacology ; Calpain ; Calpain - antagonists &amp; inhibitors ; Calpain - pharmacology ; Cardiovascular ; Dipeptides - pharmacology ; Female ; Humans ; Ischemia–reperfusion injury ; Male ; Middle Aged ; Mitochondria ; Mitochondria, Heart - enzymology ; Mitochondrial Membrane Transport Proteins - metabolism ; Mitochondrial permeability transition pore ; Myocardial Reperfusion Injury - enzymology ; Rats ; Rats, Sprague-Dawley ; Young Adult</subject><ispartof>International journal of cardiology, 2015-10, Vol.197, p.26-32</ispartof><rights>Elsevier Ireland Ltd</rights><rights>2015 Elsevier Ireland Ltd</rights><rights>Copyright © 2015 Elsevier Ireland Ltd. 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Isoforms of Ca 2 + -activated cysteine proteases, calpains, are implicated in the development of myocardial infarction in ischemia–reperfusion. Growing evidence has revealed the presence of calpains in the mitochondria. We aimed to characterize mitochondrial calpains in the rat heart and to investigate the roles of calpains in mPTP opening after ischemia–reperfusion. Methods and results : Western blotting analysis showed the expression of μ-calpain, m-calpain and calpain 10 in mitochondria isolated from male Sprague-Dawley rats, but casein zymography detected only m-calpain activity. Subcellular fractionation of mitochondria demonstrated the distribution of m-calpain to the matrix fraction. Addition of &gt; 500 μM of Ca 2 + to isolated mitochondria induced mitochondrial swelling, reflecting mPTP opening, and calpain activation. Ca 2 + -induced mitochondrial swelling was inhibited partially by the calpain inhibitor calpeptin. These results support a partial contribution of calpain in the opening of the mPTP. The addition of Ca 2 + to the mitochondria induced inactivation of complex I of the electron transport chain, and cleavage of the ND6 complex I subunit, which were inhibited by calpeptin. Mitochondria isolated from rat hearts that underwent 30 min of coronary occlusion followed by 30 min of reperfusion showed activation of mitochondrial calpains, ND6 cleavage, complex I inactivation, and mPTP opening, which were inhibited by pretreatment with calpain inhibitor 1. 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Isoforms of Ca 2 + -activated cysteine proteases, calpains, are implicated in the development of myocardial infarction in ischemia–reperfusion. Growing evidence has revealed the presence of calpains in the mitochondria. We aimed to characterize mitochondrial calpains in the rat heart and to investigate the roles of calpains in mPTP opening after ischemia–reperfusion. Methods and results : Western blotting analysis showed the expression of μ-calpain, m-calpain and calpain 10 in mitochondria isolated from male Sprague-Dawley rats, but casein zymography detected only m-calpain activity. Subcellular fractionation of mitochondria demonstrated the distribution of m-calpain to the matrix fraction. Addition of &gt; 500 μM of Ca 2 + to isolated mitochondria induced mitochondrial swelling, reflecting mPTP opening, and calpain activation. Ca 2 + -induced mitochondrial swelling was inhibited partially by the calpain inhibitor calpeptin. 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subjects Animals
Blotting, Western
Calcium
Calcium - pharmacology
Calpain
Calpain - antagonists & inhibitors
Calpain - pharmacology
Cardiovascular
Dipeptides - pharmacology
Female
Humans
Ischemia–reperfusion injury
Male
Middle Aged
Mitochondria
Mitochondria, Heart - enzymology
Mitochondrial Membrane Transport Proteins - metabolism
Mitochondrial permeability transition pore
Myocardial Reperfusion Injury - enzymology
Rats
Rats, Sprague-Dawley
Young Adult
title Mitochondrial m-calpain opens the mitochondrial permeability transition pore in ischemia–reperfusion
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