Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation.
Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation.
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DOI：
10.1074/jbc.ra117.001254
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发表时间：
2018-05-11
期刊：
影响因子：
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通讯作者：
James DE
中科院分区：
文献类型：
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作者：
Fazakerley DJ;Minard AY;Krycer JR;Thomas KC;Stöckli J;Harney DJ;Burchfield JG;Maghzal GJ;Caldwell ST;Hartley RC;Stocker R;Murphy MP;James DE
线粒体氧化应激、线粒体功能障碍或两者都与胰岛素抵抗有关。然而，分离这些过程在胰岛素抵抗中的单独作用一直是困难的，因为它们往往是同时发生的，而且还缺乏有选择地增加氧化剂产生而不损害线粒体呼吸的工具。利用过氧化还蛋白亚型的二聚体/单体状态作为隔室过氧化氢负荷的指标，我们提供了证据，证明氧化应激局限于小鼠胰岛素抵抗的3T3-L1脂肪细胞和脂肪组织的线粒体。为了将氧化应激与氧化磷酸化受损分离开来，并研究线粒体氧化应激本身是否会导致胰岛素抵抗，我们使用线粒体靶向百草枯(MitoPQ)在线粒体内产生超氧化物，而不直接破坏呼吸链。在≤10μm，mitoPQ特异性地增加线粒体超氧化物歧化和过氧化氢，而不改变完整细胞的线粒体呼吸。在此条件下，MitoPQ抑制了胰岛素刺激的葡萄糖摄取和葡萄糖转运蛋白4(GLUT4)在脂肪细胞和肌管中向质膜的转位。MitoPQ概括了在其他实验模型中发现的胰岛素抵抗的许多特征，包括线粒体而不是胞浆中氧化剂的增加；对葡萄糖运输的影响比对其他胰岛素调节过程的影响更深远，例如蛋白质合成和脂肪分解；胰岛素信号没有明显的缺陷；以及缺陷的胰岛素但不是AMP激活的蛋白激酶(AMPK)调节的GLUT4移位。我们的结论是，线粒体氧化剂的升高迅速削弱了胰岛素调节的GLUT4易位，并显著促进了胰岛素抵抗，并且MitoPQ是研究线粒体氧化应激与调节的GLUT4转运之间联系的理想工具。
Mitochondrial oxidative stress, mitochondrial dysfunction, or both have been implicated in insulin resistance. However, disentangling the individual roles of these processes in insulin resistance has been difficult because they often occur in tandem, and tools that selectively increase oxidant production without impairing mitochondrial respiration have been lacking. Using the dimer/monomer status of peroxiredoxin isoforms as an indicator of compartmental hydrogen peroxide burden, we provide evidence that oxidative stress is localized to mitochondria in insulin-resistant 3T3-L1 adipocytes and adipose tissue from mice. To dissociate oxidative stress from impaired oxidative phosphorylation and study whether mitochondrial oxidative stress per se can cause insulin resistance, we used mitochondria-targeted paraquat (MitoPQ) to generate superoxide within mitochondria without directly disrupting the respiratory chain. At ≤10 μm, MitoPQ specifically increased mitochondrial superoxide and hydrogen peroxide without altering mitochondrial respiration in intact cells. Under these conditions, MitoPQ impaired insulin-stimulated glucose uptake and glucose transporter 4 (GLUT4) translocation to the plasma membrane in both adipocytes and myotubes. MitoPQ recapitulated many features of insulin resistance found in other experimental models, including increased oxidants in mitochondria but not cytosol; a more profound effect on glucose transport than on other insulin-regulated processes, such as protein synthesis and lipolysis; an absence of overt defects in insulin signaling; and defective insulin- but not AMP-activated protein kinase (AMPK)-regulated GLUT4 translocation. We conclude that elevated mitochondrial oxidants rapidly impair insulin-regulated GLUT4 translocation and significantly contribute to insulin resistance and that MitoPQ is an ideal tool for studying the link between mitochondrial oxidative stress and regulated GLUT4 trafficking.