Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex.
Adenosine Triphosphate
/ metabolism
Animals
Cell Proliferation
Female
Glycolysis
HEK293 Cells
HeLa Cells
Humans
Mice, Inbred BALB C
Mice, Nude
Mitochondria
/ enzymology
Oxidative Phosphorylation
Oxygen Consumption
Pyruvate Dehydrogenase Complex
/ metabolism
STAT5 Transcription Factor
/ genetics
Tumor Burden
Tumor Hypoxia
Tumor Microenvironment
Tumor Suppressor Proteins
/ genetics
Uterine Cervical Neoplasms
/ enzymology
Warburg Effect, Oncologic
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
19 06 2021
19 06 2021
Historique:
received:
30
10
2020
accepted:
07
06
2021
revised:
31
05
2021
entrez:
20
6
2021
pubmed:
21
6
2021
medline:
21
9
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34148062
doi: 10.1038/s41419-021-03908-0
pii: 10.1038/s41419-021-03908-0
pmc: PMC8214628
doi:
Substances chimiques
Pyruvate Dehydrogenase Complex
0
STAT5 Transcription Factor
0
STAT5A protein, human
0
Tumor Suppressor Proteins
0
Adenosine Triphosphate
8L70Q75FXE
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
634Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81672558, 81972396, 91957125
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81722021, 81771627, 31521003
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 31671483, 31871432
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 31330023, 3182100, 291753207, 31930062
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