VDAC1 oligomerization-mediated mtDNA release under sublethal oxidative stress: A novel inflammatory mechanism in vitiligo

Abstract

Oxidative stress is a critical initiating factor in vitiligo, yet the early molecular events linking redox imbalance to melanocyte immune activation remain unclear. Here, we demonstrate that sub-lethal hydrogen peroxide (H₂O₂, 0.1 mM) exposure in human epidermal melanocytes induces a robust pro-inflammatory response independent of apoptosis or pyroptosis. This response is driven by the selective cytosolic release of mitochondrial DNA (mtDNA), which activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Mechanistically, voltage-dependent anion channel 1 (VDAC1) oligomerization cooperates with mitochondrial permeability transition pore (mPTP) opening to mediate mtDNA release. Both genetic VDAC1 knockdown and pharmacological inhibition blocked mtDNA leakage and downstream cytokine production. In H₂O₂-induced vitiligo mice, intradermal administration of the VDAC1 oligomerization inhibitor VBIT-4 restored melanin pigmentation, reduced CD8⁺ T cell infiltration, and alleviated cutaneous inflammation. These findings identify VDAC1-dependent mtDNA release as a key driver of innate immune activation in melanocytes and highlight VDAC1 as a potentially druggable therapeutic target for early intervention in vitiligo.