Inhibiting ribosomal RNA synthesis in C. elegans protects against reductive stress during de novo fatty acid synthesis deficiency
Abstract
Reductive stress has remained underappreciated as a significant disrupter of redox homeostasis. Recent studies have begun to link the accumulation of NADH and NADPH to the development and progression of metabolic diseases such as cancer, cardiac disease, and diabetes. In this study, we use the nematode Caenorhabditis elegans to examine the phenomenon of catastrophic reductive death caused by combined biguanide treatment and fasn-1 deficiency. This process of synergistic biguanide-induced reductive stress correlates with the activation of hypodermal stress response genes and aberrant alternations in the nucleolar morphology of hypodermal cells. Interestingly, we find that loss-of-function and RNAi-based knockdown of the catalytic RNA exosome subunit crn-3 significantly protects against reductive death. RNAi knockdown of multiple other genes involved in rRNA synthesis recapitulate this phenotype. We postulate that this reversal of reductive death can be attributed to impaired ribosomal RNA biogenesis that promotes tolerance of accumulated reducing equivalents Nicotinamide Adenine Dinucleotide Phosphate (NADPH) and Nicotinamide Adenine Dinucleotide (NADH) while also preventing the accumulation of Glutathione (GSH) by potentially activating downstream signaling pathways. Notably, we identify a downstream nuclear RNAi pathway that is activated by phenformin in a fasn-1-dependent manner and is also activated upon disruption of rRNA processing. Overall, we identify a novel mechanism by which pathologic states of reductive stress-related diseases could be ameliorated.
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BibTeX
@article{rotti2026inhibiting,
title = {{Inhibiting ribosomal RNA synthesis in C. elegans protects against reductive stress during de novo fatty acid synthesis deficiency}},
author = {Jen F Rotti and Fasih Ahsan and Nicole L Stuhr and Sinclair Emans and Alexander Soukas and Armen Yerevanian},
journal = {Genetics},
year = {2026},
month = aug,
doi = {10.1093/genetics/iyag214},
url = {https://doi.org/10.1093/genetics/iyag214},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Inhibiting ribosomal RNA synthesis in C. elegans protects against reductive stress during de novo fatty acid synthesis deficiency
AU - Jen F Rotti
AU - Fasih Ahsan
AU - Nicole L Stuhr
AU - Sinclair Emans
AU - Alexander Soukas
AU - Armen Yerevanian
PY - 2026
DA - 2026/08/11
JO - Genetics
DO - 10.1093/genetics/iyag214
UR - https://doi.org/10.1093/genetics/iyag214
AB - Reductive stress has remained underappreciated as a significant disrupter of redox homeostasis. Recent studies have begun to link the accumulation of NADH and NADPH to the development and progression of metabolic diseases such as cancer, cardiac disease, and diabetes. In this study, we use the nematode Caenorhabditis elegans to examine the phenomenon of catastrophic reductive death caused by combined biguanide treatment and fasn-1 deficiency. This process of synergistic biguanide-induced reductive stress correlates with the activation of hypodermal stress response genes and aberrant alternations in the nucleolar morphology of hypodermal cells. Interestingly, we find that loss-of-function and RNAi-based knockdown of the catalytic RNA exosome subunit crn-3 significantly protects against reductive death. RNAi knockdown of multiple other genes involved in rRNA synthesis recapitulate this phenotype. We postulate that this reversal of reductive death can be attributed to impaired ribosomal RNA biogenesis that promotes tolerance of accumulated reducing equivalents Nicotinamide Adenine Dinucleotide Phosphate (NADPH) and Nicotinamide Adenine Dinucleotide (NADH) while also preventing the accumulation of Glutathione (GSH) by potentially activating downstream signaling pathways. Notably, we identify a downstream nuclear RNAi pathway that is activated by phenformin in a fasn-1-dependent manner and is also activated upon disruption of rRNA processing. Overall, we identify a novel mechanism by which pathologic states of reductive stress-related diseases could be ameliorated.
SN - 0016-6731
SN - 1943-2631
ER -