Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex

被引：24

作者：

Zhang, Liang ^{[1
]}

Zhang, Jianong ^{[1
]}

Liu, Yan ^{[2
]}

Zhang, Pingzhao ^{[3
,4
]}

Nie, Ji ^{[1
]}

Zhao, Rui ^{[1
]}

Shi, Qin ^{[1
]}

Sun, Huiru ^{[1
]}

Jiao, Dongyue ^{[1
]}

Chen, Yingji ^{[1
]}

Zhao, Xiaying ^{[1
]}

Huang, Yan ^{[1
]}

Li, Yao ^{[1
]}

Zhao, Jian-Yuan ^{[5
]}

Xu, Wei ^{[6
,7
]}

Zhao, Shi-Min ^{[1
]}

Wang, Chenji ^{[1
]}

机构：

[1] Fudan Univ, Key Lab Reprod Regulat NPFPC SIPPR, MOE Engn Res Ctr Gene Technol,Sch Life Sci, Obstet & Gynecol Hosp,State Key Lab Genet Engn,IR, Shanghai 200438, Peoples R China

[2] Fudan Univ, Inst Metab & integrat Biol IMIB, Sch Life Sci, Shanghai 200438, Peoples R China

[3] Fudan Univ, Shanghai Canc Ctr, Shanghai 200032, Peoples R China

[4] Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Dept Pathol, Shanghai 200032, Peoples R China

[5] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200438, Peoples R China

[6] Fudan Univ, Shanghai Peoples Hosp 5, Shanghai 20032, Peoples R China

[7] Fudan Univ, Inst Biomed Sci, Shanghai 20032, Peoples R China

来源：

CELL DEATH & DISEASE | 2021年 / 12卷 / 07期

基金：

国家重点研发计划; 美国国家科学基金会;

关键词：

DNA-BINDING; SERINE PHOSPHORYLATION; CANCER; E2;

D O I：

10.1038/s41419-021-03908-0

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：12

共 44 条

[1]

BEHAL RH, 1993, ANNU REV NUTR, V13, P497, DOI 10.1146/annurev.nu.13.070193.002433

[2] Stat5a serine phosphorylation -: Serine 779 is constitutively phosphorylated in the mammary gland, and serine 725 phosphorylation influences prolactin-stimulated in vitro DNA binding activity [J].