MicroRNA Expression Influences Methylmercury-Induced Lipid Accumulation and Mitochondrial Toxicity in Caenorhabditis elegans

Abstract

Metabolic effects of methylmercury (MeHg) are gaining wider attention. We have previously shown that MeHg causes lipid dysregulation in Caenorhabditis elegans (C. elegans), leading to altered gene expression, increased triglyceride levels and lipid storage, and altered feeding behaviors. Transcriptional regulators, such as transcription factors and microRNAs (miRNAs), have been shown to regulate lipid storage, serum triglycerides, and adipogenic gene expression in human and rodent models of metabolic diseases. As we recently investigated adipogenic transcription factors induced by MeHg, we were, therefore, interested in whether MeHg may also regulate miRNA sequences to cause metabolic dysfunction. Lipid dysregulation, as measured by triglyceride levels, lipid storage sites, and feeding behaviors, was assessed in wild-type (N2) worms and in transgenic worms that either were sensitive to miRNA expression or were unable to process miRNAs. Worms that were sensitive to the miRNA expression were protected from MeHg-induced lipid dysregulation. In contrast, the mutant worms that were unable to process miRNAs had exacerbated MeHg-induced lipid dysregulation. Concurrent with differential lipid homeostasis, miRNA-expression mutants had altered MeHg-induced mitochondrial toxicity as compared to N2, with the miRNA-sensitive mutants showing mitochondrial protection and the miRNA-processing mutants showing increased mitotoxicity. Taken together, our data demonstrate that the expression of miRNAs is an important determinant in MeHg toxicity and MeHg-induced metabolic dysfunction in C. elegans.

Epigenetics and Methylmercury-Induced Neurotoxicity, Evidence from Experimental Studies

“…Intriguingly, miRNAs also regulate RNAi sensitivity to endogenous and exogenous siRNAs [ 61 ]. Several studies have shown that enzymes in the siRNA biogenesis might be involved in MeHg-induced toxicity in C. elegans [ 62 , 63 , 64 ].…”

“…The mutant strain ( rrf-3 (pk1426)) is hypersensitive to RNAi and resistant to MeHgCl-induced toxicity [ 62 , 63 ]. Another independent study showed that C. elegans mutant strains, including ( rrf-1 (pk1417)) and ( rrf-3 (pk1426)), were also resistant to MeHgCl-induced toxicity [ 64 ]. Additionally, the molecular components in the early steps of siRNA genesis may also be involved in MeHg-induced toxicity.…”

“…The gene of nuclear RNAi defective-2 ( nrde-2 ) encodes one of C. elegans homologs of Argonaute, which is required for siRNA-mediated transcriptional silencing in nuclei (nuclear RNAi) [ 71 , 72 ], and heterochromatin assembly by siRNA [ 73 ]. The study on genetic mutant strains of pash-1 and nrde-2 showed that these worms were hypersensitive to MeHgCl-induced toxicity, suggesting that the endogenous RNAi pathway might be evoked against toxic effects of MeHgCl [ 64 ].…”

Expression Profiling of Adipogenic and Anti-Adipogenic MicroRNA Sequences following Methylmercury Exposure in Caenorhabditis elegans

“…Additionally, lipid dysregulation could be modified by altering the ability of the worms to produce miRNAs. Worms that expressed more miRNA than wild type were protected from MeHg toxicity and lipid dysregulation, whereas worms that could not produce functional miRNA had exacerbated toxicity and lipid dysregulation in response to MeHg [19].…”

Association between Heavy Metals, Metalloids and Metabolic Syndrome: New Insights and Approaches

“…Multiple studies have shown that miRNA expression is altered in the adipose tissue of individuals with metabolic disorders [ 241 , 242 ]. Altering the ability of C. elegans to express miRNA significantly affected the ability of MeHg to cause lipid dysregulation [ 243 ]. This suggests that MeHg may affect the expression of the miRNA sequences involved in lipid homeostasis.…”