MitomiR-1736-3p regulates copper-induced mitochondrial pathway apoptosis by inhibiting AATF in chicken hepatocytes

Abstract

Copper (Cu) is a toxic heavy metal pollutant. The hepatic toxicity of Cu has attracted widespread attention from researchers. However, its underlying mechanism remains elusive. Mitochondrial microRNAs (mitomiRs) are considered important factors in regulating mitochondrial and cellular functions, and their roles have been implicated in the mechanisms of metal toxicity. Therefore, this research revealed the changes in the mitomiRs expression profile of chicken liver after Cu exposure. It was ultimately determined that mitomiR-1736-3p can be involved in Cu-induced chicken liver damage by targeting AATF. In particular, our investigations have uncovered that exposure to Cu can trigger heightened levels of apoptosis in the hepatic tissue of chickens and primary chicken embryo hepatocytes (CEHs). It is noteworthy that we found upregulation of miR-1736-3p expression can exacerbate Cu-induced cell apoptosis, while inhibition of miR-1736-3p can effectively reduce apoptosis occurrence. Subsequently, we found that Cu-induced cell apoptosis could be restored by overexpressing AATF, while silencing AATF exacerbated the level of apoptosis. Fascinatingly, this change in apoptotic level is directly influenced by AATF on Bax and Bak1, rather than on p53 and Bcl-2. Overall, these findings suggest that the mitomiR-1736-3p/AATF axis mediates the mitochondrial pathway of cell apoptosis potentially involved in Cu-induced chicken liver toxicity.