The hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans

Mehul Vora, Stephanie M. Pyonteck, Tatiana Popovitchenko, Tarmie L. Matlack, Aparna Prashar, Nanci S. Kane, John Favate, Premal Shah and Christopher Rongo ()
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Mehul Vora: Rutgers The State University of New Jersey
Stephanie M. Pyonteck: Rutgers The State University of New Jersey
Tatiana Popovitchenko: Rutgers The State University of New Jersey
Tarmie L. Matlack: Rutgers The State University of New Jersey
Aparna Prashar: Rutgers The State University of New Jersey
Nanci S. Kane: Rutgers The State University of New Jersey
John Favate: Rutgers The State University of New Jersey
Premal Shah: Rutgers The State University of New Jersey
Christopher Rongo: Rutgers The State University of New Jersey

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33849-x

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