Glucose Modulates Respiratory Complex I Activity in Response to Acute Mitochondrial Dysfunction
Glucose Modulates Respiratory Complex I Activity in Response to Acute Mitochondrial Dysfunction
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DOI：
10.1074/jbc.m112.386060
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发表时间：
2012-11-09
影响因子：
4.8
通讯作者：
Dufour, Eric
中科院分区：
文献类型：
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作者：
Cannino, Giuseppe;El-Khoury, Riyad;Dufour, Eric
糖酵解和呼吸之间的适当协调是必不可少的，但参与感知呼吸链缺陷和相应地修改线粒体功能的调节机制尚不清楚。为了研究这种调节的性质，我们将呼吸旁路酶引入培养的人（HEK293T）细胞中，并研究了线粒体对呼吸链抑制的反应。在没有呼吸链抑制剂的情况下，替代呼吸酶的表达没有可检测地改变细胞生理学或线粒体功能。然而，在透化细胞NDI1（替代NADH脱氢酶）绕过复合物I抑制，而替代氧化酶（AOX）绕过复合物III或IV抑制。相反，在完整的细胞中，AOX旁路的作用受到葡萄糖生长的抑制，而NDI 1产生的作用则不受影响。此外，NDI1废除葡萄糖抑制AOX驱动的呼吸，牵连复合物I作为这种调节的目标。快速复合物I下调在长时间呼吸抑制后部分释放，表明它提供了一个"紧急关闭"系统来调节代谢以响应氧化磷酸化功能障碍。该系统是独立的HIF 1，线粒体超氧化物，或ATP合酶的调节。我们的发现揭示了一种适应线粒体功能障碍的新途径，并可能为对抗疾病提供新的机会。
Proper coordination between glycolysis and respiration is essential, yet the regulatory mechanisms involved in sensing respiratory chain defects and modifying mitochondrial functions accordingly are unclear. To investigate the nature of this regulation, we introduced respiratory bypass enzymes into cultured human (HEK293T) cells and studied mitochondrial responses to respiratory chain inhibition. In the absence of respiratory chain inhibitors, the expression of alternative respiratory enzymes did not detectably alter cell physiology or mitochondrial function. However, in permeabilized cells NDI1 (alternative NADH dehydrogenase) bypassed complex I inhibition, whereas alternative oxidase (AOX) bypassed complex III or IV inhibition. In contrast, in intact cells the effects of the AOX bypass were suppressed by growth on glucose, whereas those produced by NDI1 were unaffected. Moreover, NDI1 abolished the glucose suppression of AOX-driven respiration, implicating complex I as the target of this regulation. Rapid Complex I down-regulation was partly released upon prolonged respiratory inhibition, suggesting that it provides an "emergency shutdown" system to regulate metabolism in response to dysfunctions of the oxidative phosphorylation. This system was independent of HIF1, mitochondrial superoxide, or ATP synthase regulation. Our findings reveal a novel pathway for adaptation to mitochondrial dysfunction and could provide new opportunities for combatting diseases.