Increased Mitochondrial Superoxide Level Is Partially Associated With Vemurafenib-Induced Renal Tubular Toxicity

Abstract

Vemurafenib (VEM) reportedly inhibits the mitochondrial respiratory chain and reduces ferrochelatase (FECH) activity, thereby causing VEM-induced renal tubular toxicity. However, the exact mechanisms underlying VEM-induced renal tubular toxicity remain unclear. In this study, we treated human renal proximal tubular epithelial cells with VEM to elucidate these mechanisms. VEM treatment for 24 h resulted in cell damage, reduced cell viability, increased lactate dehydrogenase release and elevated the production of inflammatory cytokines. Transmission electron microscopy (TEM) and fluorescence microscopy revealed accumulation and enlargement of lysosome-derived vacuoles and mitochondrial superoxide production. Although MitoTracker showed no change in the total mitochondrial volume, TEM indicated mitochondrial damage, including smaller and less visible mitochondria. Enhanced superoxide production was confirmed using mtSOX. The mitochondria-specific antioxidant XJB-5-131 partially alleviated VEM-induced superoxide production and improved cell viability, indicating the role of superoxide in VEM-induced renal tubular toxicity. The inhibition of lysosomal acidification by bafilomycin A1 did not mitigate VEM-induced cytotoxicity, suggesting potential autophagy impairment. These findings highlight that mitochondrial dysfunction and lysosomal abnormalities are significant factors in VEM-induced renal tubular toxicity, warranting further investigation into the relationship between their mechanisms, reduced FECH activity and potential renoprotective targets.