The transsulfuration pathway suppresses the embryonic lethal phenotype of glutathione reductase mutants in <i>Caenorhabditis elegans</i>
The gsr-1 gene encodes the only glutathione reductase in Caenorhabditis elegans and gsr-1 loss-of-function alleles have a fully penetrant embryonic lethal phenotype. Therefore, maintenance of glutathione redox homeostasis is essential for nematode survival. We report here that impairment of the nonsense-mediated mRNA decay (NMD) pathway suppresses the embryonic lethality of gsr-1 mutants, allowing their normal development and growth. This NMD pathway dependent suppression requires cth-1 and cth-2 that encode 2 isoforms of cystathionine-γ-lyase that catalyze the conversion of cystathionine to cysteine through the transsulfuration pathway. In contrast, the thioredoxin system that can also provide cysteine through the cystine reduction pathway appears to be dispensable for the suppression of the lethal phenotype of gsr-1 embryos when the NMD pathway is inactivated. Together, our data indicate that increasing the activity of the reverse transsulfuration pathway can compensate the detrimental effect of the gsr-1 mutation, raising the interesting question of why C. elegans has not preserved such compensatory mechanism to avoid the embryonic lethality of these mutants.
Authors
- José Antonio Mora-Lorca
- Dunja Petrovic
- Akiko Hatakeyama
- David Guerrero‐Gómez (ORCID: https://orcid.org/0000-0001-9403-6431)
- Elias S.J. Arnér (ORCID: https://orcid.org/0000-0002-4807-6114)
- Angelina Zheleva (ORCID: https://orcid.org/0000-0002-6898-6289)
- Shuichi Onami (ORCID: https://orcid.org/0000-0002-8255-1724)
- A. Ordóñez‐Luque
- Miloš R. Filipović (ORCID: https://orcid.org/0000-0003-0060-0041)
- Nigel J. O’Neil (ORCID: https://orcid.org/0000-0002-1992-6976)
- Julián Cerón (ORCID: https://orcid.org/0000-0003-4739-2243)
- Marina Valenzuela-Villatoro (ORCID: https://orcid.org/0000-0001-5601-9462)
- Peter Askjaer (ORCID: https://orcid.org/0000-0003-3192-4428)
- Antonio Miranda–Vizuete (ORCID: https://orcid.org/0000-0002-6856-5396)
- Juan Cabello (ORCID: https://orcid.org/0000-0002-3835-0116)
- Eva Gómez‐Orte (ORCID: https://orcid.org/0000-0001-6802-1746)
- Qing Cheng (ORCID: https://orcid.org/0000-0002-3170-9333)
- Cristina Ayuso (ORCID: https://orcid.org/0000-0002-7179-4309)
Institutions
- Consejo Superior de Investigaciones Científicas (ES)
- University of British Columbia (CA)
- Karolinska Institutet (SE)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Centro Andaluz de Biología del Desarrollo (ES)
- RIKEN Center for Biosystems Dynamics Research (JP)
- National Institute of Oncology (HU)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Canada's Michael Smith Genome Sciences Centre (CA)
- Instituto de Biomedicina de Sevilla (ES)
- Center for Biomedical Research of La Rioja (ES)
- Hospital Universitario Virgen del Rocío (ES)
- Universidad de Sevilla (ES)
- Junta de Andalucía (ES)
- Universidad Pablo de Olavide (ES)
Publication Details
- Journal
- G3 Genes Genomes Genetics
- Published
- 2025-05-07
- DOI
- https://doi.org/10.1093/g3journal/jkaf102
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Junta de Andalucía
- National Institutes of Health
- Agencia Estatal de Investigación