Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.
Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.
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线粒体 STAT5A 通过灭活丙酮酸脱氢酶复合物促进代谢重塑和 Warburg 效应
DOI：
10.1038/s41419-021-03908-0
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发表时间：
2021-06-19
影响因子：
9
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Zhang L;Zhang J;Liu Y;Zhang P;Nie J;Zhao R;Shi Q;Sun H;Jiao D;Chen Y;Zhao X;Huang Y;Li Y;Zhao JY;Xu W;Zhao SM;Wang C
信号转导子和激活子5a（STAT5A）是一种经典的转录因子，在肿瘤发生、发展等多种生物学过程中起着重要作用。一部分STAT5A定位于线粒体中，但线粒体STAT5A的生物学功能仍然不清楚。在这里，我们发现STAT5A与丙酮酸脱氢酶复合物（PDC）相互作用，PDC是连接两个关键代谢途径（糖酵解和三羧酸循环）的线粒体看门酶。线粒体STAT5A破坏PDC完整性，从而抑制PDC活性并重塑细胞糖酵解和氧化磷酸化。在缺氧条件下，STAT5A的线粒体易位增加。这增强了癌细胞中的瓦尔堡效应，并促进缺氧条件下的体外细胞生长和体内肿瘤生长。我们的研究结果表明STAT5A在能量代谢中具有独特的促癌作用，这与其作为转录因子的经典功能不同。
Signal transducer and activator 5a (STAT5A) is a classical transcription factor that plays pivotal roles in various biological processes, including tumor initiation and progression. A fraction of STAT5A is localized in the mitochondria, but the biological functions of mitochondrial STAT5A remain obscure. Here, we show that STAT5A interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme connecting two key metabolic pathways, glycolysis and the tricarboxylic acid cycle. Mitochondrial STAT5A disrupts PDC integrity, thereby inhibiting PDC activity and remodeling cellular glycolysis and oxidative phosphorylation. Mitochondrial translocation of STAT5A is increased under hypoxic conditions. This strengthens the Warburg effect in cancer cells and promotes in vitro cell growth under hypoxia and in vivo tumor growth. Our findings indicate distinct pro-oncogenic roles of STAT5A in energy metabolism, which is different from its classical function as a transcription factor.
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影响因子：
2.6
作者：
Holness MJ;Zariwala G;Walker CG;Sugden MC
通讯作者：
Sugden MC
DOI：
10.1016/j.bbrc.2010.10.112
发表时间：
2010-11-26
影响因子：
3.1
作者：
Chueh FY;Leong KF;Yu CL
通讯作者：
Yu CL
影响因子：
11.4
作者：
GOUILLEUX, F;WAKAO, H;GRONER, B
通讯作者：
GRONER, B
影响因子：
16
作者：
Fan, Jun;Shan, Changliang;Kang, Hee-Bum;Elf, Shannon;Xie, Jianxin;Tucker, Meghan;Gu, Ting-Lei;Aguiar, Mike;Lonning, Scott;Chen, Huaibin;Mohammadi, Moosa;Britton, Laura-Mae P.;Garcia, Benjamin A.;Aleckovic, Masa;Kang, Yibin;Kaluz, Stefan;Devi, Nara;Van Meir, Erwin G.;Hitosugi, Taro;Seo, Jae Ho;Lonial, Sagar;Gaddh, Manila;Arellano, Martha;Khoury, Hanna J.;Khuri, Fadlo R.;Boggon, Titus J.;Kang, Sumin;Chen, Jing
通讯作者：
Chen, Jing
影响因子：
64.5
作者：
Huttlin EL;Ting L;Bruckner RJ;Gebreab F;Gygi MP;Szpyt J;Tam S;Zarraga G;Colby G;Baltier K;Dong R;Guarani V;Vaites LP;Ordureau A;Rad R;Erickson BK;Wühr M;Chick J;Zhai B;Kolippakkam D;Mintseris J;Obar RA;Harris T;Artavanis-Tsakonas S;Sowa ME;De Camilli P;Paulo JA;Harper JW;Gygi SP
通讯作者：
Gygi SP