# Mitochondrial DNA release via VDAC1 in keratinocytes: a key driver of innate immunity and vitiligo pathogenesis

## TL;DR

This study reveals how oxidative stress in skin cells triggers an immune response linked to vitiligo, a skin disorder, through the release of mitochondrial DNA.

## Contribution

The study identifies VDAC1-mediated mitochondrial DNA release as a novel mechanism connecting oxidative stress to immune activation in vitiligo.

## Key findings

- Hydrogen peroxide induces mitochondrial membrane remodeling and VDAC1 oligomerization for mtDNA release.
- Released mtDNA activates cGAS–STING and NLRP3 pathways, leading to inflammation and pyroptosis.
- VDAC1 inhibition with VBIT-4 reduces mtDNA release and alleviates vitiligo symptoms in a mouse model.

## Abstract

Vitiligo is an autoimmune depigmenting disorder in which oxidative stress is considered a critical trigger of innate immune activation. Although keratinocytes are increasingly recognized as key contributors to disease progression, the mechanism by which they sense and propagate oxidative stress signals has remained unclear. Here, we identify mitochondrial DNA (mtDNA) release as a pivotal event linking oxidative stress to immune activation in keratinocytes. We demonstrate that hydrogen peroxide induces a sequential mitochondrial membrane remodeling process, in which mitochondrial permeability transition pore opening precedes oligomerization of the outer membrane channel protein VDAC1, enabling selective mtDNA release under non-apoptotic conditions. Escaped mtDNA acts as a danger signal that concurrently activates the cGAS–STING axis and the NLRP3 inflammasome, driving type I and type II interferon production, chemokine release, and pyroptosis. Importantly, genetic silencing or pharmacological inhibition of VDAC1 with VBIT-4 effectively blocked mtDNA release, suppressed downstream inflammatory cascades, and alleviated depigmentation and CD8⁺ T cell infiltration in a murine vitiligo model. These findings uncover a previously unrecognized mechanism by which keratinocytes transform oxidative stress into autoimmune signaling and highlight VDAC1-dependent mtDNA release as a promising therapeutic target to intercept vitiligo at an early stage.