MnO₂ nanoparticles trigger hepatic lipotoxicity and mitophagy via mtROS-dependent Hsf1^Ser326 phosphorylation

Manganese (Mn) is an essential element for maintaining normal metabolism in vertebrates. Mn dioxide nanoparticles (MnO₂ NPs), a novel Mn source, have shown great potentials in biological and biomedical applications due to their distinct physical and chemical properties. However, little is known about potential adverse effects on animal or cellular metabolism. Here, we investigated whether and how dietary MnO₂ NPs affect hepatic lipid metabolism in vertebrates. We found that, excessive MnO₂ NPs intake increased hepatic and mitochondrial Mn content, promoted hepatic lipotoxic disease and lipogenesis, and inhibited hepatic lipolysis and fatty acid β-oxidation. Moreover, excessive MnO₂ NPs intake induced hepatic mitochondrial oxidative stress, damaged mitochondrial function, disrupted mitochondrial dynamics and activated mitophagy. Importantly, we uncovered that mtROS-activated phosphorylation of heat shock factor 1 (Hsf1) at Ser326 residue mediated MnO₂ NPs-induced hepatic lipotoxic disease and mitophagy. Mechanistically, MnO₂ NPs-induced lipotoxicity and mitophagy were via mtROS-induced phosphorylation and nucleus translocation of Hsf1 and its DNA binding capacity to plin2/dgat1 and bnip3 promoters, respectively. Overall, our findings uncover novel mechanisms by which mtROS-mediated mitochondrial dysfunction and phosphorylation of Hsf1^S326 contribute to MnO₂ NPs-induced hepatic lipotoxicity and mitophagy, which provide new insights into the effects of metal oxides nanoparticles on hepatotoxicity in vertebrates.