Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages.
Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages.
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DOI：
10.1016/j.cell.2016.08.064
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发表时间：
2016-10-06
期刊：
影响因子：
64.5
通讯作者：
O'Neill LA
中科院分区：
文献类型：
--
作者：
Mills EL;Kelly B;Logan A;Costa ASH;Varma M;Bryant CE;Tourlomousis P;Däbritz JHM;Gottlieb E;Latorre I;Corr SC;McManus G;Ryan D;Jacobs HT;Szibor M;Xavier RJ;Braun T;Frezza C;Murphy MP;O'Neill LA
活化的巨噬细胞经历代谢重编程，从而驱动其促炎表型，但其机制基础仍不清楚。在脂多糖（LPS）刺激下，巨噬细胞从氧化磷酸化产生ATP转变为糖酵解，同时增加琥珀酸水平。我们发现，通过琥珀酸脱氢酶（SDH）增加的线粒体琥珀酸氧化和线粒体膜电位的升高共同驱动线粒体ROS的产生。RNA测序显示，这种组合诱导促炎基因表达谱，而琥珀酸氧化抑制剂丙二酸二甲酯（DMM）促进抗炎结果。通过解偶联线粒体或表达替代氧化酶（AOX），用鱼藤酮阻断ROS的产生可抑制这种炎症表型，AOX可保护小鼠免受LPS致死。因此，巨噬细胞激活后发生的代谢改变将线粒体从ATP合成转变为ROS产生，以促进促炎状态。
Activated macrophages undergo metabolic reprogramming which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here we demonstrate that upon lipopolysaccharide (LPS) stimulation macrophages shift from producing ATP by oxidative phosphorylation to glycolysis, while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial ROS production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone, by uncoupling mitochondria, or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
20.3
作者：
Everts, Bart;Amiel, Eyal;Pearce, Edward J.
通讯作者：
Pearce, Edward J.
DOI：
10.1084/jem.20151570
发表时间：
2016-01-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
O'Neill LA;Pearce EJ
通讯作者：
Pearce EJ
影响因子：
64.8
作者：
Chouchani, Edward T.;Pell, Victoria R.;Gaude, Edoardo;Aksentijevic, Dunja;Sundier, Stephanie Y.;Robb, Ellen L.;Logan, Angela;Nadtochiy, Sergiy M.;Ord, Emily N. J.;Smith, Anthony C.;Eyassu, Filmon;Shirley, Rachel;Hu, Chou-Hui;Dare, Anna J.;James, Andrew M.;Rogatti, Sebastian;Hartley, Richard C.;Eaton, Simon;Costa, Ana S. H.;Brookes, Paul S.;Davidson, Sean M.;Duchen, Michael R.;Saeb-Parsy, Kourosh;Shattock, Michael J.;Robinson, Alan J.;Work, Lorraine M.;Frezza, Christian;Krieg, Thomas;Murphy, Michael P.
通讯作者：
Murphy, Michael P.
影响因子：
12.3
作者：
Langmead B;Trapnell C;Pop M;Salzberg SL
通讯作者：
Salzberg SL