Different mechanisms of mitochondrial proton leak in ischaemia/reperfusion injury and preconditioning: implications for pathology and cardioprotection
Different mechanisms of mitochondrial proton leak in ischaemia/reperfusion injury and preconditioning: implications for pathology and cardioprotection
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DOI：
10.1042/bj20051927
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发表时间：
2006-05-01
影响因子：
4.1
通讯作者：
Brookes, PS
中科院分区：
文献类型：
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作者：
Nadtochiy, SM;Tompkins, AJ;Brookes, PS
在各种病理生理条件下，线粒体质子（H+）泄漏的机制尚不清楚。在本研究中，假设H+泄漏在心脏缺血/再灌注损伤和缺血预处理中有不同的机制。潜在的H+泄漏机制包括UCPs（解偶联蛋白）、AMP对腺嘌呤核苷酸转位酶（ANT）的变构激活或PT（渗透性转变）孔。从灌注的大鼠心脏中分离出来的线粒体受到IPC的影响，显示出比对照组更大的H+泄漏（202 +/- 27%,P < 0.005），这种增加的泄漏被UCP抑制剂GDP或ANT抑制剂CAT （carboxyattractyloside）完全消除。受到IR损伤的心脏线粒体显示出比对照组更多的H+泄漏（411 +/- 28%,P < 0.001）。GDP对IR后增加的渗漏有微弱的抑制作用，但羧基引诱菌苷对其抑制作用约为50%。此外，心脏保护治疗策略包括ir前灌注PT孔抑制剂cyclosporin A或sanglifehrin A，腺苷酸激酶抑制剂，AP(5)A（二磷酸腺苷）或IPC。这些数据表明，IPC中H+泄漏的少量增加是由UCPs介导的，而IR中H+泄漏的大量增加是由ANT介导的。此外。在所有研究条件下，心肌O-2效率与离体线粒体H+泄漏相关（r(2) = 0.71）。总之，这些数据表明，调节h1泄漏可能对IR损伤的结果有重要影响。
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 < 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 < 0.001). The increased leakage after IR was weakly inhibited by GDP, but was inhibited, > 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, AP(5)A (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 sitit myocardial O-2 efficiency was correlated with isolated mitochondrial H+ leak (r(2) = 0.71). In conclusion, these data suggest that the modulation of H I leak may have important implications for the outcome of IR injury.