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

Winter, A. D., Tjahjono, E., Beltrán, L. L., Johnstone, I. L., Bulleid, N. J. and Page, A. P. (2022) Dietary-derived vitamin B12 protects Caenorhabditis elegans from thiol-reducing agents. BMC Biology, 20, 228. (doi: 10.1186/s12915-022-01415-y) (PMID:36209095) (PMCID:PMC9548181)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Page, Professor Tony and Bulleid, Professor Neil and Johnstone, Professor Iain and Winter, Dr Alan
Authors: Winter, A. D., Tjahjono, E., Beltrán, L. L., Johnstone, I. L., Bulleid, N. J., and Page, A. P.
College/School:College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:BMC Biology
Publisher:BioMed Central
ISSN (Online):1741-7007
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in BMC Biology 20: 228
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190589Shedding light on oxidative stress: Identifying factors modulating the redox balance in the endoplasmic reticulum of Caenorhabditis elegans.Antony PageBiotechnology and Biological Sciences Research Council (BBSRC)BB/K006983/1Institute of Biodiversity, Animal Health and Comparative Medicine