While molybdenum (Mo) is essential for biological processes, overexposure can result in liver failure. Cadmium (Cd) is widely present in the environment, which interferes with the normal metabolic processes within cells. Mitochondria are the main target organ of heavy metal toxicity, and the coping mechanism of mitochondria under Mo and Cd co-exposure is still worthy of further study. This study aimed to decipher the mitochondrial quality control response in sheep hepatocytes under Mo and Cd co-exposure. Using an In vitro model, we found that Mo/Cd induced mitochondrial ultrastructural damage, dysfunction (elevated reactive oxygen species (ROS), reduced mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP)), and disrupted dynamics by promoting fission proteins dynamin-related protein 1 (Drp1) and fission 1 (Fis1) while suppressing fusion proteins optic atrophy 1 (OPA1) and mitofusin 2 (Mfn2), thereby triggering excessive mitophagy. Interestingly, inhibiting mitophagy with cyclosporin A (CsA) exacerbated the injury, whereas targeting the mitochondrial porin Voltage-dependent anion channel 1(VDAC1) with VBIT-4 (a small-molecule VDAC1 inhibitor) attenuated both mitophagy and dysfunction. VBIT-4 restored membrane potential, rebalanced dynamics, and improved energy production, indicating that VDAC1-mediated mitophagy acts as a pivotal adaptive mechanism. Our findings propose VDAC1 inhibition as a promising strategy to alleviate Mo/Cd-induced hepatotoxicity by restoring mitochondrial homeostasis.

To Cite This Article: Bai H, Liu L, Xing C, Gao F, Jiang Z, Wang Y, Xiong Z, Dai X, Yang F and Cao H, 2026. Voltage-dependent anion channel 1(VDAC1)-mediated mitophagy: A potential therapeutic target for mitochondrial damage induced by molybdenum and cadmium co-exposure in sheep hepatocytes. Pak Vet J, 46(4): 961-971. http://dx.doi.org/10.29261/pakvetj/2026.090