Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation.
Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation.
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抑制线粒体复合物 I 可改善葡萄糖代谢，与 AMPK 激活无关
DOI：
10.1111/jcmm.13432
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发表时间：
2018-03
影响因子：
5.3
通讯作者：
Jia WP
中科院分区：
文献类型：
--
作者：
Hou WL;Yin J;Alimujiang M;Yu XY;Ai LG;Bao YQ;Liu F;Jia WP
越来越多的证据表明，二甲双胍和小檗碱（众所周知的降糖药）能够抑制线粒体复合物I的电子传递链。在这项研究中，我们的目的是探讨的抗高血压作用的复合物I抑制。用鱼藤酮、异戊巴比妥和NDUFA 13基因沉默抑制复合物I。对db/db小鼠进行腹腔葡萄糖耐量试验和胰岛素耐量试验。测定乳酸释放和葡萄糖消耗以研究HepG 2肝细胞和C2 C12肌管中的葡萄糖代谢。在原代肝细胞中测量葡萄糖输出。利用化合物C和表达显性负性AMP活化蛋白激酶（AMPK）α1/2的腺病毒来阻断AMPK途径。测定细胞NAD +/NADH比值，评价细胞能量转化和氧化还原状态。鱼藤酮改善db/db小鼠的高血糖和胰岛素抵抗。它诱导葡萄糖消耗和糖酵解，并减少肝脏葡萄糖输出。鱼藤酮还激活AMPK。此外，它对AMPK失活仍然有效。增强的糖酵解和抑制的糖异生与细胞NAD +/NADH比率的降低相关，这是由复合物I抑制引起的。异戊巴比妥，另一个代表性的复合物I抑制剂，刺激葡萄糖消耗和减少肝脏葡萄糖输出体外。当用基因沉默敲低复合物I的亚基NDUFA 13的表达时，观察到类似的变化。这些发现表明线粒体复合物I已成为糖尿病治疗的关键药物靶点。复合物I的抑制通过非AMPK途径改善葡萄糖稳态，这可能与细胞NAD +/NADH比率的抑制有关。
Accumulating evidences showed metformin and berberine, well‐known glucose‐lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes. Glucose output was measured in primary hepatocytes. Compound C and adenoviruses expressing dominant negative AMP‐activated protein kinase (AMPK) α1/2 were exploited to inactivate AMPK pathway. Cellular NAD +/NADH ratio was assayed to evaluate energy transforming and redox state. Rotenone ameliorated hyperglycaemia and insulin resistance in db/db mice. It induced glucose consumption and glycolysis and reduced hepatic glucose output. Rotenone also activated AMPK. Furthermore, it remained effective with AMPK inactivation. The enhanced glycolysis and repressed gluconeogenesis correlated with a reduction in cellular NAD +/NADH ratio, which resulted from complex I suppression. Amobarbital, another representative complex I inhibitor, stimulated glucose consumption and decreased hepatic glucose output in vitro, too. Similar changes were observed while expression of NDUFA13, a subunit of complex I, was knocked down with gene silencing. These findings reveal mitochondrial complex I emerges as a key drug target for diabetes treatment. Inhibition of complex I improves glucose homoeostasis via non‐AMPK pathway, which may relate to the suppression of the cellular NAD +/NADH ratio.
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影响因子：
56.9
作者：
Shaw, RJ;Lamia, KA;Cantley, LC
通讯作者：
Cantley, LC
DOI：
10.1124/jpet.105.091702
发表时间：
2006-01-01
影响因子：
3.5
作者：
Chen, Q;Hoppel, CL;Lesnefsky, EJ
通讯作者：
Lesnefsky, EJ
影响因子：
6.5
作者：
Brusq, Jean-Marie;Ancellin, Nicolas;Issandou, Marc
通讯作者：
Issandou, Marc
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X