TY - JOUR
T1 - VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease
AU - Kim, Jeonghan
AU - Gupta, Rajeev
AU - Blanco, Luz P.
AU - Yang, Shutong
AU - Shteinfer-Kuzmine, Anna
AU - Wang, Kening
AU - Zhu, Jun
AU - Yoon, Hee Eun
AU - Wang, Xinghao
AU - Kerkhofs, Martijn
AU - Kang, Hyeog
AU - Brown, Alexandra L.
AU - Park, Sung Jun
AU - Xu, Xihui
AU - van Rilland, Eddy Zandee
AU - Kim, Myung K.
AU - Cohen, Jeffrey I.
AU - Kaplan, Mariana J.
AU - Shoshan-Barmatz, Varda
AU - Chung, Jay H.
N1 - Funding Information:
We thank the NHLBI core facilities, including DNA Sequencing and Genomics core, Bioinformatics and Computational Biology core, Flow Cytometry core, Light Microscopy core, Pathology core, and Biochemistry core. We thank the NIH Fellows Editorial Board for manuscript preparation. Funding: Supported 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
Publisher Copyright:
© 2019 American Association for the Advancement of Science. All rights reserved.
PY - 2019/12/20
Y1 - 2019/12/20
N2 - Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type I 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.
AB - Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type I 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.
UR - http://www.scopus.com/inward/record.url?scp=85077120584&partnerID=8YFLogxK
U2 - 10.1126/science.aav4011
DO - 10.1126/science.aav4011
M3 - Article
AN - SCOPUS:85077120584
VL - 366
SP - 1531
EP - 1536
JO - Science
JF - Science
SN - 0036-8075
IS - 6472
ER -