Metformin selectively targets redox control of complex I energy transduction.
Metformin selectively targets redox control of complex I energy transduction.
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DOI：
10.1016/j.redox.2017.08.018
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发表时间：
2018-04
期刊：
影响因子：
11.4
通讯作者：
Rena G
中科院分区：
文献类型：
--
作者：
Cameron AR;Logie L;Patel K;Erhardt S;Bacon S;Middleton P;Harthill J;Forteath C;Coats JT;Kerr C;Curry H;Stewart D;Sakamoto K;Repiščák P;Paterson MJ;Hassinen I;McDougall G;Rena G
许多含胍类药物具有抗高血压作用，但大多数药物都表现出毒性，只有双胍类二甲双胍在临床上持续使用。在这里，我们已经分离出二甲双胍独特的线粒体氧化还原控制特性，这可能是造成这种差异的原因。在原代肝细胞和H4 IIE肝癌细胞中，我们发现抗高血糖双胍DG 5-DG 10和双胍苯丙氨酸在细胞信号传导反应、促凋亡启动子表达和肝细胞葡萄糖产生方面的效力比二甲双胍高1000倍。每种药物抑制细胞耗氧量相似，但在其他方面有显着差异。所有双胍类和苯丙氨酸，但不是二甲双胍抑制亚线粒体颗粒中的NADH氧化，指示复合物I抑制，这也与WST-1测量的活细胞中的脱氢酶活性密切对应。与这些发现一致，在分离的线粒体中，DG 8而不是二甲双胍导致NADH/NAD+对随着时间的推移变得更加减少，随后线粒体恶化，表明DG 8的复合物I和线粒体毒性的直接抑制。相比之下，二甲双胍对线粒体NADH/NAD+对产生选择性氧化，而不会引发线粒体退化。总之，我们的研究结果表明，二甲双胍通过选择性诱导复合物I中氧化还原和质子转移结构域不再有效耦合的状态来抑制能量转导。
Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled.
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DOI：
10.1016/j.bbadis.2016.04.015
发表时间：
2016-08
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Cameron AR;Logie L;Patel K;Bacon S;Forteath C;Harthill J;Roberts A;Sutherland C;Stewart D;Viollet B;Sakamoto K;McDougall G;Foretz M;Rena G
通讯作者：
Rena G
DOI：
10.1126/science.1215327
发表时间：
2012-05-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hawley SA;Fullerton MD;Ross FA;Schertzer JD;Chevtzoff C;Walker KJ;Peggie MW;Zibrova D;Green KA;Mustard KJ;Kemp BE;Sakamoto K;Steinberg GR;Hardie DG
通讯作者：
Hardie DG
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X
影响因子：
7.7
作者：
Hunter RW;Treebak JT;Wojtaszewski JF;Sakamoto K
通讯作者：
Sakamoto K
影响因子：
20.1
作者：
Cameron AR;Morrison VL;Levin D;Mohan M;Forteath C;Beall C;McNeilly AD;Balfour DJ;Savinko T;Wong AK;Viollet B;Sakamoto K;Fagerholm SC;Foretz M;Lang CC;Rena G
通讯作者：
Rena G