The hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 10 2022
18 10 2022
Historique:
received:
12
07
2021
accepted:
05
10
2022
entrez:
18
10
2022
pubmed:
19
10
2022
medline:
21
10
2022
Statut:
epublish
Résumé
Actively dividing cells, including some cancers, rely on aerobic glycolysis rather than oxidative phosphorylation to generate energy, a phenomenon termed the Warburg effect. Constitutive activation of the Hypoxia Inducible Factor (HIF-1), a transcription factor known for mediating an adaptive response to oxygen deprivation (hypoxia), is a hallmark of the Warburg effect. HIF-1 is thought to promote glycolysis and suppress oxidative phosphorylation. Here, we instead show that HIF-1 can promote gluconeogenesis. Using a multiomics approach, we reveal the genomic, transcriptomic, and metabolomic landscapes regulated by constitutively active HIF-1 in C. elegans. We use RNA-seq and ChIP-seq under aerobic conditions to analyze mutants lacking EGL-9, a key negative regulator of HIF-1. We integrate these approaches to identify over two hundred genes directly and functionally upregulated by HIF-1, including the PEP carboxykinase PCK-1, a rate-limiting mediator of gluconeogenesis. This activation of PCK-1 by HIF-1 promotes survival in response to both oxidative and hypoxic stress. Our work identifies functional direct targets of HIF-1 in vivo, comprehensively describing the metabolome induced by HIF-1 activation in an organism.
Identifiants
pubmed: 36257965
doi: 10.1038/s41467-022-33849-x
pii: 10.1038/s41467-022-33849-x
pmc: PMC9579151
doi:
Substances chimiques
Transcription Factors
0
Oxygen
S88TT14065
Hypoxia-Inducible Factor 1, alpha Subunit
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6168Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM101972
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124976
Pays : United States
Organisme : Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
ID : R01GM101972
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
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