期刊
SCIENCE
卷 366, 期 6472, 页码 1531-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aav4011
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资金
- National Heart Lung and Blood Institute
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of Allergy and Infectious Diseases
- National Institute for Biotechnology in the Negev
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health and Welfare, Republic of Korea [HI14C1176]
- KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006119] Funding Source: NIH RePORTER
- Korea Health Promotion Institute [HI14C1176000015] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type I interferon (IFN) response. Mitochondrial outer membrane permeabilization, which isrequired for mtDNA release, has been extensively studied inapoptotic cells, but little isknown 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 inthe 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.
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