Condition-dependent role of VDAC1 oligomerization in doxorubicin-induced mitochondrial iron dysregulation

Doxorubicin (DOX)-induced cardiotoxicity is closely associated with mitochondrial iron overload and oxidative stress. Although voltage-dependent anion channel 1 (VDAC1) oligomerization is generally considered a pro-apoptotic event, its role in iron-driven mitochondrial stress remains unclear. We herein investigated the effects of pharmacological and genetic regulation of VDAC1 oligomerization in models of DOX-induced cardiotoxicity. DOX increased mitochondrial Fe²⁺ accumulation, reactive oxygen species (ROS) production, and mitochondrial respiratory impairment, accompanied by augmented VDAC1 oligomerization. Pharmacological inhibition of VDAC1 oligomerization using VBIT-4 unexpectedly exacerbated mitochondrial iron accumulation, oxidative stress, and respiratory dysfunction. In contrast, the ubiquitination-resistant VDAC1 mutant (K53R/K274R) significantly attenuated mitochondrial Fe²⁺ accumulation, ROS production, and mitochondrial respiratory impairment despite exhibiting increased oligomerization. These findings indicate that oligomer abundance alone does not determine mitochondrial dysfunction, demonstrating the importance of the qualitative state of VDAC1 remodeling under iron-driven oxidative stress. Our study suggests a condition-dependent role of VDAC1 oligomerization in DOX cardiotoxicity and highlights outer mitochondrial membrane remodeling as a potential therapeutic target.