BackgroundEukaryotic cells have evolved various response mechanisms to counteract the deleterious consequences of oxidative stress. Among these processes, metabolic alterations seem to play an important role.ResultsWe recently discovered that yeast cells with reduced activity of the key glycolytic enzyme triosephosphate isomerase exhibit an increased resistance to the thiol-oxidizing reagent diamide. Here we show that this phenotype is conserved in Caenorhabditis elegans and that the underlying mechanism is based on a redirection of the metabolic flux from glycolysis to the pentose phosphate pathway, altering the redox equilibrium of the cytoplasmic NADP(H) pool. Remarkably, another key glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is known to be inactivated in response to various oxidant treatments, and we show that this provokes a similar redirection of the metabolic flux.ConclusionThe naturally occurring inactivation of GAPDH functions as a metabolic switch for rerouting the carbohydrate flux to counteract oxidative stress. As a consequence, altering the homoeostasis of cytoplasmic metabolites is a fundamental mechanism for balancing the redox state of eukaryotic cells under stress conditions.
During C. elegans development, animals must choose between reproductive growth or dauer diapause in response to sensory cues. Insulin/IGF-I and TGF-beta signaling converge on the orphan nuclear receptor daf-12 to mediate this choice. Here we show that daf-9 acts downstream of these inputs but upstream of daf-12. daf-9 and daf-12 mutants have similar larval defects and modulate insulin/IGF-I and gonadal signals that regulate adult life span. daf-9 encodes a cytochrome P450 related to vertebrate steroidogenic hydroxylases, suggesting that it could metabolize a DAF-12 ligand. Sterols may be the daf-9 substrate and daf-12 ligand because cholesterol deprivation phenocopies mutant defects. Sensory neurons, hypodermis, and somatic gonadal cells expressing daf-9 identify potential endocrine tissues. Evidently, lipophilic hormones influence nematode metabolism, diapause, and life span.
Broad aspects of Caenorhabditis elegans life history, including larval developmental timing, arrest at the dauer diapause, and longevity, are regulated by the nuclear receptor DAF-12. Endogenous DAF-12 ligands are 3-keto bile acid-like steroids, called dafachronic acids, which rescue larval defects of hormone-deficient mutants, such as daf-9/cytochrome P450 and daf-36/Rieske oxygenase, and activate DAF-12. Here we examined the effect of dafachronic acid on pathways controlling lifespan. Dafachronic acid supplementation shortened the lifespan of long-lived daf-9 mutants and abolished their stress resistance, indicating that the ligand is ''proaging'' in response to signals from the dauer pathways. However, the ligand extended the lifespan of germ-line ablated daf-9 and daf-36 mutants, showing that it is ''antiaging'' in the germ-line longevity pathway. Thus, dafachronic acid regulates C. elegans lifespan according to signaling state. These studies provide key evidence that bile acid-like steroids modulate aging in animals.aging ͉ DAF-12 ͉ hormone ͉ dafachronic acid ͉ germ-line longevity E ndocrine systems coordinate many facets of animal metabolism, reproduction, and homeostasis, ensuring the proper response to changes in physiology or environment. More recently, hormones have also been shown to govern metazoan aging. Notably, a mild reduction of insulin/IGF1 signaling increases stress resistance and longevity in diverse species across taxa (1). These studies also imply that other hormones impact lifespan. Nuclear hormone receptors are transcription factors that respond to lipophilic hormones such as steroids, fatty acids, and retinoids to regulate gene expression, and are well poised to coordinate global life history traits. Indeed, genetic studies in worms and flies have implicated such molecules in lifespan regulation, but how they do so is not well understood (2-7).DAF-12 is one such nuclear receptor in Caenorhabditis elegans. Homologous to vertebrate vitamin D and LXR receptors (8), DAF-12 controls the choice between reproductive growth and arrest at a long-lived, alternate third larval stage, the dauer diapause, formed under harsh environmental conditions (9). It also specifies third larval temporal fates in the heterochronic pathway (10), a circuit that regulates developmental timing. Finally, DAF-12 and related components modulate organismal lifespan in at least two contexts (2-6): (i) in response to inputs for dauer diapause and (ii) in response to signals from the germ line. Recently, the endogenous ligands of DAF-12 have been discovered to be 3-keto bile acid-like steroids, called ⌬ 4 -and ⌬ 7 -dafachronic acids (11) and related metabolites (12), enabling a direct test of whether these ligands modulate nematode longevity and stress resistance. Here, we specifically examined ⌬ 4 -dafachronic acid. ResultsIn the dauer pathways, environmental cues (temperature, dauer pheromone, food, and cholesterol) are integrated by insulin/ IGF1 and TGF- signaling, which then converge on daf-9/ cytochrome P450 (CYP450...
C. elegans diapause, gonadal outgrowth, and life span are regulated by a lipophilic hormone, which serves as a ligand to the nuclear hormone receptor DAF-12. A key step in hormone production is catalyzed by the CYP450 DAF-9, but the extent of the biosynthetic pathway is unknown. Here, we identify a conserved Rieske-like oxygenase, DAF-36, as a component in hormone metabolism. Mutants display larval developmental and adult aging phenotypes, as well as patterns of epistasis similar to that of daf-9. Larval phenotypes are potently reversed by crude lipid extracts, 7-dehydrocholesterol, and a recently identified DAF-12 sterol ligand, suggesting that DAF-36 works early in the hormone biosynthetic pathway. DAF-36 is expressed primarily within the intestine, a major organ of metabolic and endocrine control, distinct from DAF-9. These results imply that C. elegans hormone production has multiple steps and is distributed, and that it may provide one way that tissues register their current physiological state during organismal commitments.
growth, off in dauer, hypodermal daf-9 expression is strictly daf-12 dependent, suggesting feedback regulation. Expressing daf-9 constitutively in hypodermis rescues dauer phenotypes of daf-9, as well as insulin/IGF receptor and TGFβ mutants, revealing that daf-9 is an important downstream point of control within the dauer circuits. This study illuminates how endocrine networks integrate environmental cues and transduce them into adaptive life history choices.
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