Different mechanisms of mitochondrial proton leak in ischaemia/reperfusion injury and preconditioning: implications for pathology and cardioprotection

The mechanisms of mitochondrial proton (H+) leak under various pathophysiological conditions are poorly understood. In the present study it was hypothesized that different mechanisms underlie H+ leak in cardiac IR (ischaemia/reperfusion) injury and IPC (ischaemic preconditioning). Potential H(+) lea...

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Published in:Biochemical journal 2006-05, Vol.395 (3), p.611-618
Main Authors: Nadtochiy, Sergiy M, Tompkins, Andrew J, Brookes, Paul S
Format: Article
Language:English
Subjects:
Animals
Carrier Proteins - metabolism
Cell Membrane Permeability - drug effects
Guanosine Diphosphate - pharmacology
Ischemic Preconditioning, Myocardial
Male
Membrane Potentials - drug effects
Membrane Proteins - metabolism
Mitochondria, Heart - drug effects
Mitochondria, Heart - metabolism
Mitochondrial Membranes - drug effects
Mitochondrial Membranes - metabolism
Myocardial Reperfusion Injury - metabolism
Myocardial Reperfusion Injury - pathology
Myocardial Reperfusion Injury - physiopathology
Oxygen - metabolism
Protons
Rats
Rats, Sprague-Dawley
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container_title Biochemical journal
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creator Nadtochiy, Sergiy M
Tompkins, Andrew J
Brookes, Paul S
description The mechanisms of mitochondrial proton (H+) leak under various pathophysiological conditions are poorly understood. In the present study it was hypothesized that different mechanisms underlie H+ leak in cardiac IR (ischaemia/reperfusion) injury and IPC (ischaemic preconditioning). Potential H(+) leak mechanisms examined were UCPs (uncoupling proteins), allosteric activation of the ANT (adenine nucleotide translocase) by AMP, or the PT (permeability transition) pore. Mitochondria isolated from perfused rat hearts that were subjected to IPC exhibited a greater H+ leak than did controls (202+/-27%, P
doi_str_mv 10.1042/BJ20051927
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In the present study it was hypothesized that different mechanisms underlie H+ leak in cardiac IR (ischaemia/reperfusion) injury and IPC (ischaemic preconditioning). Potential H(+) leak mechanisms examined were UCPs (uncoupling proteins), allosteric activation of the ANT (adenine nucleotide translocase) by AMP, or the PT (permeability transition) pore. Mitochondria isolated from perfused rat hearts that were subjected to IPC exhibited a greater H+ leak than did controls (202+/-27%, P&lt;0.005), and this increased leakage was completely abolished by the UCP inhibitor, GDP, or the ANT inhibitor, CAT (carboxyattractyloside). Mitochondria from hearts subjected to IR injury exhibited a much greater amount of H+ leak than did controls (411+/-28%, P&lt;0.001). The increased leakage after IR was weakly inhibited by GDP, but was inhibited, &gt;50%, by carboxyattractyloside. In addition, it was inhibited by cardioprotective treatment strategies including pre-IR perfusion with the PT pore inhibitors cyclosporin A or sanglifehrin A, the adenylate kinase inhibitor, AP5A (diadenosine pentaphosphate), or IPC. Together these data suggest that the small increase in H+ leak in IPC is mediated by UCPs, while the large increase in H+ leak in IR is mediated by the ANT. Furthermore, under all conditions studied, in situ myocardial O2 efficiency was correlated with isolated mitochondrial H+ leak (r2=0.71). 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In the present study it was hypothesized that different mechanisms underlie H+ leak in cardiac IR (ischaemia/reperfusion) injury and IPC (ischaemic preconditioning). Potential H(+) leak mechanisms examined were UCPs (uncoupling proteins), allosteric activation of the ANT (adenine nucleotide translocase) by AMP, or the PT (permeability transition) pore. Mitochondria isolated from perfused rat hearts that were subjected to IPC exhibited a greater H+ leak than did controls (202+/-27%, P&lt;0.005), and this increased leakage was completely abolished by the UCP inhibitor, GDP, or the ANT inhibitor, CAT (carboxyattractyloside). Mitochondria from hearts subjected to IR injury exhibited a much greater amount of H+ leak than did controls (411+/-28%, P&lt;0.001). The increased leakage after IR was weakly inhibited by GDP, but was inhibited, &gt;50%, by carboxyattractyloside. In addition, it was inhibited by cardioprotective treatment strategies including pre-IR perfusion with the PT pore inhibitors cyclosporin A or sanglifehrin A, the adenylate kinase inhibitor, AP5A (diadenosine pentaphosphate), or IPC. Together these data suggest that the small increase in H+ leak in IPC is mediated by UCPs, while the large increase in H+ leak in IR is mediated by the ANT. Furthermore, under all conditions studied, in situ myocardial O2 efficiency was correlated with isolated mitochondrial H+ leak (r2=0.71). 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subjects Animals
Carrier Proteins - metabolism
Cell Membrane Permeability - drug effects
Guanosine Diphosphate - pharmacology
Ischemic Preconditioning, Myocardial
Male
Membrane Potentials - drug effects
Membrane Proteins - metabolism
Mitochondria, Heart - drug effects
Mitochondria, Heart - metabolism
Mitochondrial Membranes - drug effects
Mitochondrial Membranes - metabolism
Myocardial Reperfusion Injury - metabolism
Myocardial Reperfusion Injury - pathology
Myocardial Reperfusion Injury - physiopathology
Oxygen - metabolism
Protons
Rats
Rats, Sprague-Dawley
title Different mechanisms of mitochondrial proton leak in ischaemia/reperfusion injury and preconditioning: implications for pathology and cardioprotection
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