Oligomerization of VDAC1 promotes mtDNA release and lupus‐like disease

Abstract

Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, triggering immunostimulatory pathways such as the type‐Ι interferon response. Pores formed in the outer membrane of mitochondria (OMM) can promote mtDNA release; however, the identity of such a pore in living cells is not well characterized. Here, we provide genetic and biochemical evidence demonstrating that the oligomerization of voltage‐dependent anion channel 1 (VDAC1) in the OMM promotes mtDNA release and triggers the type‐Ι interferon response in living cells. In addition to forming OMM pores, VDAC1 interacts with mtDNA via its positively charged residues in the N‐terminal domain and increases both VDAC1 oligomerization and type‐Ι interferon response. VBIT‐4, which inhibits VDAC1 oligomerization, decreases mtDNA release, type‐Ι interferon signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. These findings suggest that VDAC1 oligomerization is a potential therapeutic target for lupus.Support or Funding InformationSupported by the Intramural Research Program of the National Heart Lung and Blood Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases and by a grant from the National Institute for Biotechnology in the Negev (V.S.‐B.) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number HI14C1176) and a grant from the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea.VDAC oligomers form mitochondrial pores to release mtDNA fragments.Figure 1