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

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 obs...

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Bibliographic Details
Published in:	Cell death & disease 2021-06, Vol.12 (7), p.634-12, Article 634
Main Authors:	Zhang, Liang, Zhang, Jianong, Liu, Yan, Zhang, Pingzhao, Nie, Ji, Zhao, Rui, Shi, Qin, Sun, Huiru, Jiao, Dongyue, Chen, Yingji, Zhao, Xiaying, Huang, Yan, Li, Yao, Zhao, Jian-Yuan, Xu, Wei, Zhao, Shi-Min, Wang, Chenji
Format:	Article
Language:	eng
Subjects:	Adenosine Triphosphate - metabolism Animals Cell Proliferation Dehydrogenases Energy metabolism Female Glycolysis HEK293 Cells HeLa Cells Humans Hypoxia Metabolic pathways Metabolism Mice Mice, Inbred BALB C Mice, Nude Mitochondria Mitochondria - enzymology Mitochondria - genetics Mitochondria - pathology Oxidative Phosphorylation Oxygen Consumption Phosphorylation Pyruvate dehydrogenase (lipoamide) Pyruvate Dehydrogenase Complex - metabolism Pyruvic acid STAT5 Transcription Factor - genetics STAT5 Transcription Factor - metabolism Transcription factors Tricarboxylic acid cycle Tumor Burden Tumor Hypoxia Tumor Microenvironment Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Uterine Cervical Neoplasms - enzymology Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - pathology Warburg Effect, Oncologic
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Summary:	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.
ISSN:	2041-4889 2041-4889