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

Science. 2019 Dec 20;366(6472):1531-1536. doi: 10.1126/science.aav4011. Epub 2019 Dec 19.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Mitochondrial / metabolism*
  • Disease Models, Animal
  • Endodeoxyribonucleases / genetics
  • Humans
  • Interferons / metabolism
  • Lupus Erythematosus, Systemic / drug therapy
  • Lupus Erythematosus, Systemic / metabolism*
  • Mice
  • Mitochondrial Membranes / metabolism*
  • Oxidative Stress
  • Protein Domains
  • Protein Multimerization* / drug effects
  • Rats
  • Voltage-Dependent Anion Channels / antagonists & inhibitors
  • Voltage-Dependent Anion Channels / genetics
  • Voltage-Dependent Anion Channels / metabolism*


  • DNA, Mitochondrial
  • Voltage-Dependent Anion Channels
  • Interferons
  • Endodeoxyribonucleases
  • endonuclease G