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

Tao Ke, Abel Santamaria, Marcelo Farina, João B.T. Rocha, Aaron B. Bowman, Michael Aschner

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)837-846
Number of pages10
JournalNeurotoxicity Research
Volume40
Issue number3
DOIs
StatePublished - Jun 2022

Keywords

  • Caenorhabditis elegans
  • Metal toxicity
  • Methylmercury
  • Protein quality control
  • Stress inducible protein 1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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