Adaptive capacity to dietary Vitamin B12 levels is maintained by a gene‐diet interaction that ensures optimal life span

Nair, Tripti; Chakraborty, Rahul; Singh, Praveen; Rahman, Sabnam Sahin; Bhaskar, Akash Kumar; Sengupta, Shantanu; Mukhopadhyay, Arnab

doi:10.1111/acel.13518

Cited by 14 publications

(28 citation statements)

References 62 publications

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“…The lifespan and stress responses of drl-1 and flr-4 mutants are markedly different when animals are fed E. coli HT115 bacteria compared to OP50, likely due to differences in the nutritional value of the strains (Nair et al 2022). Consistent with these observations, genetic mutation of drl-1 , as well as intestinal depletion of AID::DRL-1, more severely impairs growth of animals reared on E. coli HT115 compared to OP50 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Follicle stimulating hormone signaling opposes the DRL-1/FLR-4 MAP Kinases to balance p38-mediated growth and lipid homeostasis inC. elegans

Torzone

Park

Breen

et al. 2023

Preprint

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Animals integrate developmental and nutritional signals before committing crucial resources to growth and reproduction; however, the pathways that perceive and respond to these inputs remain poorly understood. Here, we demonstrate that DRL-1 and FLR-4, which share similarity with mammalian mitogen-activated protein kinases, maintain lipid homeostasis in theC. elegansintestine. DRL-1 and FLR-4 function in a protein complex at the plasma membrane to promote development, as mutations indrl-1orflr-4confer slow growth, small body size, and impaired lipid homeostasis. To identify factors that oppose DRL-1/FLR-4, we performed a forward genetic screen for suppressors of thedrl-1mutant phenotypes and identified mutations inflr-2andfshr-1, which encode the orthologues of follicle stimulating hormone and its putative G protein-coupled receptor, respectively. In the absence of DRL-1/FLR-4, neuronal FLR-2 acts through intestinal FSHR-1 and Protein Kinase A signaling to restrict growth. Furthermore, we show that opposing signaling through DRL-1 and FLR-2 coordinates TIR-1 phase transition, which modulates downstream p38/PMK-1 activity, lipid homeostasis, and development. Finally, we identify a surprising noncanonical role for the developmental transcription factor PHA-4/FOXA in the intestine where it restricts growth in response to impaired DRL-1 signaling. Our work uncovers a complex multi-tissue signaling network that converges on p38 signaling to maintain homeostasis during development.

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Section: Resultsmentioning

confidence: 99%

Follicle stimulating hormone signaling opposes the DRL-1/FLR-4 MAP Kinases to balance p38-mediated growth and lipid homeostasis inC. elegans

Torzone

Park

Breen

et al. 2023

Preprint

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“…SAM is the universal methyl donor in the cell and regulates a vast array of cellular activities, including the synthesis of phosphatidylcholine by methylation of phosphoethanolamine ( Vance and Vance, 2004 ). Several of the SAM functions, including lipogenesis ( Walker et al, 2011 ), gene expression changes ( Giese et al, 2020 ), innate immunity ( Ding et al, 2015 ; Nair et al, 2022 ), are regulated by phosphatidylcholine. Phosphatidylcholine can also be synthesized from choline by an alternate pathway independent of SAM ( Vance and Vance, 2004 ).…”

Section: Resultsmentioning

confidence: 99%

“…The semisoft pellet of the animals was weighed (50–70 mg of worm pellet) and stored at −80°C until further processing. The samples were processed for metabolite extraction as described earlier ( Nair et al, 2022 ) with appropriate modifications. Briefly, the worm pellets were thawed from −80°C and mixed with an ice-chilled acetonitrile–methanol–water (3:5:2) mixture containing 0.1% formic acid, followed by eight cycles of sonication with 3 s on and 30 s off at an amplitude of 40%.…”

Section: Methodsmentioning

confidence: 99%

Dithiothreitol causes toxicity in C. elegans by modulating the methionine–homocysteine cycle

Gokul

Singh

2022

eLife

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The redox reagent dithiothreitol (DTT) causes stress in the endoplasmic reticulum (ER) by disrupting its oxidative protein folding environment, which results in the accumulation and misfolding of the newly synthesized proteins. DTT may potentially impact cellular physiology by ER-independent mechanisms; however, such mechanisms remain poorly characterized. Using the nematode model Caenorhabditis elegans, here we show that DTT toxicity is modulated by the bacterial diet. Specifically, the dietary component vitamin B12 alleviates DTT toxicity in a methionine synthase-dependent manner. Using a forward genetic screen, we discover that loss-of-function of R08E5.3, an S-adenosylmethionine (SAM)-dependent methyltransferase, confers DTT resistance. DTT upregulates R08E5.3 expression and modulates the activity of the methionine-homocysteine cycle. Employing genetic and biochemical studies, we establish that DTT toxicity is a result of the depletion of SAM. Finally, we show that a functional IRE-1/XBP-1 unfolded protein response pathway is required to counteract toxicity at high, but not low, DTT concentrations.

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“…Major differences identified between the E. coli strains OP50-1 and HT115(DE3) are the levels of carbohydrate, fatty acids [ 11 ], and vitamin B12. The E. coli strain OP50-1 poorly expresses TonB, a transporter required for vitamin B12 uptake from the environment [ 12 ], causing this strain to be relatively deficient in vitamin B12 compared to HT115(DE3) [ 5 – 8 ]. To examine this possible link between vitamin B12 and DTT resistance, we tested the effect of different growth media.…”

Section: Resultsmentioning

confidence: 99%

“…Bacterial diet can have a profound effect on the development of C. elegans and vitamin B12 has been shown to be an essential vitamin [ 4 ]. C. elegans acquires vitamin B12 from its bacterial food source; however, the most commonly used laboratory food source, the E. coli strain OP50, is mildly deficient in vitamin B12 when compared to HT115 (used for C. elegans RNAi feeding experiments) and other bacterial species such as Comamonas [ 5 – 8 ]. Mild vitamin B12 deficiency affects the conversion of methylmalonyl coenzyme A to succinyl-CoA in the mitochondrion and impairs the breakdown of propionate and branched-chain amino acids, ultimately leading to mitochondrial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Dietary-derived vitamin B12 protects Caenorhabditis elegans from thiol-reducing agents

et al. 2022

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Background One-carbon metabolism, which includes the folate and methionine cycles, involves the transfer of methyl groups which are then utilised as a part of multiple physiological processes including redox defence. During the methionine cycle, the vitamin B12-dependent enzyme methionine synthetase converts homocysteine to methionine. The enzyme S-adenosylmethionine (SAM) synthetase then uses methionine in the production of the reactive methyl carrier SAM. SAM-binding methyltransferases then utilise SAM as a cofactor to methylate proteins, small molecules, lipids, and nucleic acids. Results We describe a novel SAM methyltransferase, RIPS-1, which was the single gene identified from forward genetic screens in Caenorhabditis elegans looking for resistance to lethal concentrations of the thiol-reducing agent dithiothreitol (DTT). As well as RIPS-1 mutation, we show that in wild-type worms, DTT toxicity can be overcome by modulating vitamin B12 levels, either by using growth media and/or bacterial food that provide higher levels of vitamin B12 or by vitamin B12 supplementation. We show that active methionine synthetase is required for vitamin B12-mediated DTT resistance in wild types but is not required for resistance resulting from RIPS-1 mutation and that susceptibility to DTT is partially suppressed by methionine supplementation. A targeted RNAi modifier screen identified the mitochondrial enzyme methylmalonyl-CoA epimerase as a strong genetic enhancer of DTT resistance in a RIPS-1 mutant. We show that RIPS-1 is expressed in the intestinal and hypodermal tissues of the nematode and that treating with DTT, β-mercaptoethanol, or hydrogen sulfide induces RIPS-1 expression. We demonstrate that RIPS-1 expression is controlled by the hypoxia-inducible factor pathway and that homologues of RIPS-1 are found in a small subset of eukaryotes and bacteria, many of which can adapt to fluctuations in environmental oxygen levels. Conclusions This work highlights the central importance of dietary vitamin B12 in normal metabolic processes in C. elegans, defines a new role for this vitamin in countering reductive stress, and identifies RIPS-1 as a novel methyltransferase in the methionine cycle.

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Adaptive capacity to dietary Vitamin B12 levels is maintained by a gene‐diet interaction that ensures optimal life span

Cited by 14 publications

References 62 publications

Follicle stimulating hormone signaling opposes the DRL-1/FLR-4 MAP Kinases to balance p38-mediated growth and lipid homeostasis inC. elegans

Follicle stimulating hormone signaling opposes the DRL-1/FLR-4 MAP Kinases to balance p38-mediated growth and lipid homeostasis inC. elegans

Dithiothreitol causes toxicity in C. elegans by modulating the methionine–homocysteine cycle

Dietary-derived vitamin B12 protects Caenorhabditis elegans from thiol-reducing agents

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