The Modulatory Role of sti-1 in Methylmercury-Induced Toxicity in Caenorhabditis elegans

Abstract

Human exposure to the neurotoxin methylmercury (MeHg) poses a significant health risk to the development of the nervous system. The mechanisms of MeHg-induced neurotoxicity are associated with the disruption of cellular homeostasis, and include oxidative stress, loss of calcium homeostasis, and impaired protein quality control. The stress inducible protein 1 (STI-1) is involved in the regulation of protein quality control by acting as a protein cochaperone to maintain optimal protein unfolding and refolding. Here, we utilized the Caenorhabditis elegans (C. elegans) model of MeHg toxicity to characterize the role of the sti-1 gene in MeHg-induced toxicity. We showed that lifespan and developmental milestone timings were significantly altered in sti-1 knockout (KO) animals with MeHg exposure. However, knocking down sti-1 by RNAi did not result in an analogous effect for lifespan, but did still sensitize to delays in developmental milestone progression by acute MeHg, suggesting that insufficiency of sti-1 does not recapitulate all phenotypes of the null mutation. Furthermore, inhibition of ATP levels by MeHg exposure was modulated by sti-1. Considering that the skn-1/gst-4 pathway is highly involved in metal's toxicity, such pathway was also explored in our model. We showed that sti-1 mutant worms exhibited impaired capacity to upregulate the antioxidant genes skn-1/gst-4, highlighting a central role of sti-1 in modulating antioxidant response. Lastly, we showed that loss-of-function mutation in the rrf-3 gene, which encodes a putative RNA-directed RNA polymerase, has significant effect in altering MeHg-induced toxicity by potentiating the animal's detoxification system. Altogether, our novel data show an indispensable role of protein quality control in the defense against MeHg toxicity.

Keywords: Caenorhabditis elegans; Metal toxicity; Methylmercury; Protein quality control; Stress inducible protein 1.