TMEM126B deficiency reduces mitochondrial SDH oxidation by LPS, attenuating HIF-1α stabilization and IL-1β expression.
TMEM126B deficiency reduces mitochondrial SDH oxidation by LPS, attenuating HIF-1α stabilization and IL-1β expression.
复制标题
DOI：
10.1016/j.redox.2018.10.007
复制
发表时间：
2019-01
期刊：
影响因子：
11.4
通讯作者：
Brüne B
中科院分区：
文献类型：
--
作者：
Fuhrmann DC;Wittig I;Brüne B
线粒体衍生的活性氧（mtROS）在生理学和病理学中以其信号传导质量而闻名。为了阐明脂多糖（LPS）刺激后线粒体复合物I依赖性ROS信号传导，产生了敲低跨膜蛋白TMEM 126 B的THP-1巨噬细胞。TMEM敲除细胞（sh 126 B）显示复合物I的组装减少和mtROS产生减弱。在这些细胞中，我们确定了蛋白质氧化的mtROS在LPS处理后，使用BIAM开关分析耦合到液相色谱和质谱。线粒体ROS的靶点之一是琥珀酸脱氢酶（SDH）黄素蛋白亚基A（SDHA）。SDHA的氧化降低了其酶活性和SDH的药理学抑制作用，进而稳定了缺氧诱导因子（HIF）-1α，并引起随后的白细胞介素-1 β（IL-1β）的持续表达。LPS处理后，sh 126 B细胞中SDHA的氧化减弱，而atpenin A5对SDH的药理学抑制恢复了sh 126 B细胞中IL-1β的表达。总之，线粒体ROS对SDH的氧化作用与代谢改变（即琥珀酸积累与巨噬细胞中HIF-1驱动的炎症变化）有关。TMEM 126 B的敲低降低了mtROS的产生。TMEM 126 B敲低减少LPS介导的线粒体蛋白氧化。琥珀酸脱氢酶被氧化并被mtROS抑制。降低琥珀酸脱氢酶活性可稳定HIF-1α。HIF-1α的稳定性增强了IL-1β的产生。
Mitochondrial derived reactive oxygen species (mtROS) are known for their signaling qualities in both physiology and pathology. To elucidate mitochondrial complex I-dependent ROS-signaling after lipopolysaccharide (LPS)-stimulation THP-1 macrophages with a knockdown of the transmembrane protein TMEM126B were generated. TMEM knockdown cells (sh126B) showed a reduced assembly of complex I and attenuated mtROS production. In these cells we identified protein oxidization by mtROS upon LPS-treatment using the BIAM switch assay coupled to liquid chromatography and mass spectrometry. One of the identified targets of mtROS was succinate dehydrogenase (SDH) flavoprotein subunit A (SDHA). Oxidation of SDHA decreased its enzymatic activity and pharmacological inhibition of SDH in turn stabilized hypoxia inducible factor (HIF)-1α and caused the subsequent, sustained expression of interleukin-1β (IL-1β). Oxidation of SDHA in sh126B cells was attenuated, while pharmacological inhibition of SDH by atpenin A5 restored IL-1β expression in sh126B cells upon LPS-treatment. Conclusively, oxidation of SDH by mtROS links an altered metabolism, i.e. succinate accumulation to HIF-1-driven, inflammatory changes in macrophages. A knockdown of TMEM126B decreased mtROS production. TMEM126B knockdown reduced LPS-mediated mitochondrial protein oxidation. Succinate dehydrogenase is oxidized and inhibited by mtROS. Lowering succinate dehydrogenase activity stabilized HIF-1α. Stabilization of HIF-1α enhanced IL-1β production.
登录
查看更多内容
Itaconate连接琥珀酸脱氢酶与巨噬细胞代谢重塑和调节炎症的联系。
影响因子：
29
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
通讯作者：
Artyomov MN
影响因子：
--
作者：
Kaludercic N;Giorgio V
通讯作者：
Giorgio V
影响因子：
4.8
作者：
Garcia, Jerome;Han, Derick;Cadenas, Enrique
通讯作者：
Cadenas, Enrique
影响因子：
3.5
作者：
Brière, JJ;Favier, J;Rustin, P
通讯作者：
Rustin, P
影响因子：
4
作者：
Bénit, P;Slama, A;Rustin, P
通讯作者：
Rustin, P