Related Experiment Video
Updated: Jun 25, 2026
Measuring Oxidative Stress Resistance of Caenorhabditis elegans in 96-well Microtiter Plates
Published on: May 9, 2015
fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans
Angela M Tuckowski1, Safa Beydoun2, Elizabeth S Kitto2
1Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States.
Abstract:
Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.
Insights
Flavin-containing monooxygenase 4 (FMO-4) in C. elegans extends lifespan and stress resistance. This longevity gene interacts with calcium homeostasis and is regulated by ATF-6, highlighting conserved roles for FMOs in aging.
Area of Science:
- Biochemistry
- Genetics
- Aging Research
Background:
- Flavin-containing monooxygenases (FMOs) are xenobiotic enzymes implicated in longevity interventions.
- FMO-2 in C. elegans is known to promote longevity and healthspan.
- The conserved role of other FMO family members in longevity is unexplored.
Purpose of the Study:
- To investigate the role of C. elegans FMO-4 in longevity and stress resistance.
- To determine if FMO-4 acts downstream of known longevity pathways like dietary restriction and mTOR inhibition.
- To elucidate the molecular mechanisms, including interactions with calcium signaling, underlying FMO-4's effects.
Main Methods:
- Overexpression of C. elegans fmo-4 in specific tissues (hypodermis).
- Transcriptomic analysis to identify downstream gene expression changes.
- Assays for lifespan, paraquat stress resistance, and sensitivity to thapsigargin.
- Genetic and small molecule modulation of intracellular calcium.
- Knockdown experiments of activating transcription factor-6 (atf-6).
Main Results:
- C. elegans fmo-4 expression extends lifespan and enhances paraquat resistance, downstream of dietary restriction and mTOR inhibition.
- Hypodermal expression of fmo-4 is sufficient for these benefits and significantly alters the transcriptome.
- Genes involved in calcium signaling are significantly modulated by fmo-4.
- FMO-4 overexpressing animals show sensitivity to thapsigargin, indicating a role in calcium homeostasis.
- FMO-4 functions downstream of atf-6, with atf-6 knockdown inducing and requiring fmo-4.
Conclusions:
- C. elegans fmo-4 is a novel longevity-promoting gene.
- FMO-4's longevity and stress resistance effects are linked to the modulation of calcium homeostasis.
- FMO-4 interacts with established longevity pathways and the ATF-6/calcium signaling axis.
