Abstract
Mitochondria are essential for cellular energy production and play a critical role in maintaining overall cellular homeostasis. Mitochondrial dysfunction primarily affects energy-demanding tissues such as heart and skeletal muscle, as well as tissues (e.g., the liver) that are exposed to xenobiotics. In fact, mitochondrial toxicity is recognized as a major contributor to drug-induced liver injury (DILI). However, reliable methods for assessment of mitochondrial toxicity in vitro or in vivo remain lacking. Here, through a series of in vitro and in vivo experiments, we identified amiodarone as a model compound for evaluation of mitochondrial toxicity in hepatocytes and liver tissues. Among five known hepatotoxic agents tested, amiodarone consistently induced characteristic features of mitochondrial toxicity, including reduced mitochondrial membrane potential, elevated mitochondrial reactive oxygen species (ROS), and disrupted mitochondrial dynamics in both primary hepatocytes and surrogate cell lines. Because mitochondrial damage frequently triggers activation of antioxidant defense pathways, we further confirmed increased antioxidant gene expression and serum transaminase level elevation in mice administered with amiodarone. Indeed, the hepatotoxicity induced by amiodarone was significantly enhanced in Nrf2-deficient mice. Our approach, importantly, can be applied to the evaluation of drug-induced mitochondrial damage in the liver.
Supplementary information:
The online version contains supplementary material available at 10.1007/s43188-025-00310-2.
Keywords:
Amiodarone; Hepatocytes; Mitochondrial toxicity; Nrf2.