VDAC oligomer pores: A mechanism in disease triggered by mtDNA release

Abstract A recent study suggests that voltage‐dependent anion channel (VDAC) oligomer pores promote mitochondrial outer membrane permeabilization and allow mitochondrial DNA (mtDNA) to be released into the cytosol in live cells. It challenges the notion that only occurs in apoptotic cells via BAX/BAK macropores. Cytosolic mtDNA activates cyclic GMP–AMP synthase (cGAS)–stimulator of IFN gene (STING) pathway and triggers type I interferon (IFN) response thereafter, which ultimately causes systemic lupus erythematosus. Mechanistically, mtDNA can interact with three positively charged residues (Lys12, Arg15, and Lys20) at the N‐terminus of VDAC1, thereby strengthening VDAC1 oligomerization and facilitating mtDNA release. In addition, there are other pathways that can mediate mtDNA release, such as BAX/BAK macropores and virus‐derived pores. The mtDNA released into the cytosol also triggers type I IFN response via the generally accepted cGAS–STING–TANK‐binding kinase 1–IFN regulatory factor 3 axis. Collectively, VDAC oligomer pores provide us an attractive direction for us to understand mtDNA release‐related diseases.