Hypoxic response regulators RHY-1 and EGL-9/PHD promote longevity through a VHL-1-independent transcriptional response

Kruempel, Joseph; Ha, Mina; Schaller, Megan L.; Fretz, Abrielle; Howington, Marshall; Sarker, Marjana; Huang, Siying; Leiser, Scott F.

doi:10.1007/s11357-020-00194-0

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…Like our RNAi analyses of the OCM genes, we observed changes in stress resistance of the wild type and FMO-2 OE following the knockdown of genes involved in the kynurenine pathway (Figures 6B, C). Similarly, we observed changes in the lifespan of the wild type, FMO-2 OE, and FMO-2 KO worms under the same conditions (Figures 6D, E), as assessed using log-rank test with a cutoff threshold of p < 0.0001 28 compared to the empty vector (EV) controls. Here, we again observed a separation between the regulation of stress resistance and lifespan under kmo-1 and tdo-2 knockdown (Figures 6B-E).…”

Section: Mammalian Fmo Metabolomics Analysis Reveals Tryptophan As a Substrate Of Fmo-2supporting

confidence: 58%

FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism

Choi

Bhat

et al. 2021

Preprint

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Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, contrary to its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO enzymes. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and critical role in promoting health and longevity through metabolic remodeling.

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Section: Mammalian Fmo Metabolomics Analysis Reveals Tryptophan As a Substrate Of Fmo-2supporting

confidence: 58%

FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism

Choi

Bhat

et al. 2021

Preprint

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“…HIF also contributes to the homeostasis of protein and iron [36,[42][43][44][45][46][47], reproduction, development and apoptosis [39,[48][49][50], and neural function and animal behaviors [41,[51][52][53][54][55][56][57][58][59][60]. Even more interestingly, HIF-1 has been shown to have roles in regulating animal lifespan [43,44,[61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77].…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analyses describe the consequences of persistent HIF-1 over-activation in Caenorhabditis elegans

Feng,

Qu,

Powell-Coffman

2024

PLoS ONE

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Metazoan animals rely on oxygen for survival, but during normal development and homeostasis, animals are often challenged by hypoxia (low oxygen). In metazoans, many of the critical hypoxia responses are mediated by the evolutionarily conserved hypoxia-inducible transcription factors (HIFs). The stability and activity of HIF complexes are strictly regulated. In the model organism C. elegans, HIF-1 stability and activity are negatively regulated by VHL-1, EGL-9, RHY-1 and SWAN-1. Importantly, C. elegans mutants carrying strong loss-of-function mutations in these genes are viable, and this provides opportunities to interrogate the molecular consequences of persistent HIF-1 over-activation. We find that the genome-wide gene expression patterns are compellingly similar in these mutants, supporting models in which RHY-1, VHL-1 and EGL-9 function in common pathway(s) to regulate HIF-1 activity. These studies illuminate the diversified biological roles played by HIF-1, including metabolism and stress response. Genes regulated by persistent HIF-1 over-activation overlap with genes responsive to pathogens, and they overlap with genes regulated by DAF-16. As crucial stress regulators, HIF-1 and DAF-16 converge on key stress-responsive genes and function synergistically to enable hypoxia survival.

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Section: Introductionmentioning

confidence: 99%

Transcriptome analyses describe the consequences of persistent HIF-1 over-activation inCaenorhabditis elegans

Feng,

2023

Preprint

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Metazoan animals rely on oxygen for survival, but during normal development and homeostasis, animals are often challenged by hypoxia (low oxygen). In metazoans, many of the critical hypoxia responses are mediated by the evolutionarily conserved hypoxia-inducible transcription factors (HIFs). The stability and activity of HIF complexes are strictly regulated. In the model organismC. elegans, HIF-1 stability and activity are negatively regulated by VHL-1, EGL-9, RHY-1 and SWAN-1. Importantly,C. elegansmutants carrying strong loss-of-function mutations in these genes are viable, and this provides opportunities to interrogate the molecular consequences of persistent HIF-1 over-activation. We find that the genome-wide gene expression patterns are compellingly similar in these mutants, supporting models in which RHY-1, SWAN-1 and EGL-9 function in common pathway(s) to regulate HIF-1 activity. These studies illuminate the diversified biological roles played by HIF-1, including metabolism, hypoxia and other stress responses, reproduction and development. Genes regulated by persistent HIF-1 over-activation overlap with genes responsive to pathogens, and they overlap with genes regulated by DAF-16. As crucial stress regulators, HIF-1 and DAF-16 converge on key stress-responsive genes and function synergistically to enable hypoxia survival.

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Hypoxic response regulators RHY-1 and EGL-9/PHD promote longevity through a VHL-1-independent transcriptional response

Cited by 5 publications

References 42 publications

FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism

FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism

Transcriptome analyses describe the consequences of persistent HIF-1 over-activation in Caenorhabditis elegans

Transcriptome analyses describe the consequences of persistent HIF-1 over-activation inCaenorhabditis elegans

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