VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease

TLDR

Mitochondrial stress releases mtDNA into the cytosol, triggering a type I interferon response, yet the role of mitochondrial outer membrane permeabilization in live cells remains poorly understood. The study proposes that inhibiting VDAC oligomerization could serve as a therapeutic strategy for diseases driven by mtDNA release. Oxidatively stressed mitochondria release short mtDNA fragments through pores formed by VDAC oligomers, with VDAC1 N‑terminal residues promoting oligomerization; the inhibitor VBIT‑4 blocks this process, lowering mtDNA release, IFN signaling, neutrophil extracellular traps, and disease severity in a lupus mouse model.

Abstract

Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type Ι interferon (IFN) response. Mitochondrial outer membrane permeabilization, which is required for mtDNA release, has been extensively studied in apoptotic cells, but little is known about its role in live cells. We found that oxidatively stressed mitochondria release short mtDNA fragments via pores formed by the voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane. Furthermore, the positively charged residues in the N-terminal domain of VDAC1 interact with mtDNA, promoting VDAC1 oligomerization. The VDAC oligomerization inhibitor VBIT-4 decreases mtDNA release, IFN signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. Thus, inhibiting VDAC oligomerization is a potential therapeutic approach for diseases associated with mtDNA release.