miR-20a-5p targeting mfn2-mediated mitochondria-lipid droplet contacts regulated differential changes in hepatic lipid metabolism induced by two Mn sources in yellow catfish

Abstract

Understanding the hazards of different forms of metal elements provided innovative insights into their toxicity and environmental risk assessment. To date, few studies had been conducted to investigate the differential effects and mechanisms of MnO₂ NPs and MnSO₄, two widely distributed environmental pollutants, on hepatic toxicity and lipid metabolism since lipid metabolism-relevant parameters were broadly used as biomarkers for risk assessment of hazardous contaminants. Thus, using yellow catfish Pelteobagrus fulvidraco, an ecologically and economically important freshwater fish as the model, the present study investigated the differential effects and mechanisms of MnO₂ NPs and MnSO₄ influencing hepatic lipid metabolism. Compared to MnSO₄, MnO₂ NPs increased hepatic Mn content, induced lipotoxicity, up-regulated the mRNA expression of lipogenic genes, increased peridroplet mitochondrial (PDM) contents, intensified the contact between mitochondria and lipid droplets (LDs), and downregulated miR-20a-5p abundance. Importantly, miR-20a-5p targeted mfn2, which mediated the contact between mitochondria and LDs and influenced changes in lipid metabolism induced by MnO₂ NPs. Mechanistically, the direct Mfn2-Plin2 binding and Mfn2 GTPase activity promoted the MnO₂ NPs-induced interactions between mitochondria and LDs, which in turn influenced MnO₂ NPs-induced changes in hepatic lipid metabolism. For the first time, our findings indicated the significant differences between the changes in body metabolism induced by nanoparticles and inorganic elements, which helped to illuminate different mechanisms governing the responses of aquatic vertebrates to hazardous metal pollutants (MnO₂ NPs and MnSO₄).

Keywords: Lipid metabolism; Metal pollutants; Mitochondria-lipid droplets interaction; Mitochondrial dynamics; Risk assessment.