# The transsulfuration pathway suppresses the embryonic lethal phenotype of glutathione reductase mutants in Caenorhabditis elegans

## TL;DR

This study shows that a specific metabolic pathway can overcome the lethal effects of a gene mutation in C. elegans embryos.

## Contribution

The study identifies the transsulfuration pathway as a suppressor of glutathione reductase mutant lethality in C. elegans.

## Key findings

- Impairing the NMD pathway suppresses the embryonic lethality of gsr-1 mutants.
- The transsulfuration pathway, via cth-1 and cth-2, is essential for this suppression.
- The thioredoxin system is not required for this compensatory mechanism.

## Abstract

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.