Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1.
Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1.
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DOI：
10.1038/nature17399
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发表时间：
2016-04-07
期刊：
影响因子：
64.8
通讯作者：
Spiegelman BM
中科院分区：
文献类型：
--
作者：
Chouchani ET;Kazak L;Jedrychowski MP;Lu GZ;Erickson BK;Szpyt J;Pierce KA;Laznik-Bogoslavski D;Vetrivelan R;Clish CB;Robinson AJ;Gygi SP;Spiegelman BM
棕色脂肪组织(BAT)可以通过热源呼吸释放化学能，这需要解偶联蛋白1(UCP1)。蝙蝠和米色脂肪的生热作用可以对抗肥胖和糖尿病，鼓励研究体内控制UCP1依赖的呼吸的因素。在这里，我们表明，急性激活的蝙蝠产热是由线粒体活性氧物种(ROS)水平的大幅增加来定义的。值得注意的是，这一过程支持体内BAT的热产生，因为线粒体ROS的药理耗尽导致冷暴露时的体温降低，并抑制UCP1依赖的全身能量消耗的增加。我们进一步证实，生热ROS改变了BAT半胱氨酸硫醇的氧化还原状态以驱动呼吸增加，而UCP1的Cys253是一个关键靶点。UCP1 Cys253在产热过程中被磺化，而该位点的突变使载体的嘌呤核苷酸抑制状态对肾上腺素能激活和解偶联不敏感。这些研究发现，BAT线粒体ROS的诱导是一种驱动UCP1依赖的产热和全身能量消耗的机制，这为开发更好的治疗策略来对抗代谢疾病开辟了道路。
Brown adipose tissue (BAT) can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from BAT and beige adipose can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Herein we show that acutely activated BAT thermogenesis is defined by a substantial increase in mitochondrial reactive oxygen species (ROS) levels. Remarkably, this process supports in vivo BAT thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole body energy expenditure. We further establish that thermogenic ROS alter BAT cysteine thiol redox status to drive increased respiration, and Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine nucleotide inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify BAT mitochondrial ROS induction as a mechanism that drives UCP1-dependent thermogenesis and whole body energy expenditure, which opens the way to develop improved therapeutic strategies for combating metabolic disorders.
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影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
--
作者：
Klomsiri, Chananat;Nelson, Kimberly J.;Bechtold, Erika;Soito, Laura;Johnson, Lynnette C.;Lowther, W. Todd;Ryu, Seong-Eon;King, S. Bruce;Furdui, Cristina M.;Poole, Leslie B.
通讯作者：
Poole, Leslie B.
影响因子：
64.5
作者：
Fedorenko A;Lishko PV;Kirichok Y
通讯作者：
Kirichok Y
影响因子：
4.8
作者：
Hurd, Thomas R.;Collins, Yvonne;James, Andrew M.
通讯作者：
James, Andrew M.
DOI：
10.1007/978-1-59745-365-3_30
发表时间：
2007-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Davidson, Sean M;Yellon, Derek;Duchen, Michael R
通讯作者：
Duchen, Michael R