Статья

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

Jeonghan KimLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USARajeev GuptaDepartment of Life Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelLuz P. BlancoSystemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20982, USAShutong YangLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USAAnna Shteinfer‐KuzmineDepartment of Life Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelKening WangMedical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USAJun ZhuLaboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, and Leuven Kanker Instituut, KU Leuven, 3000 Leuven, BelgiumHee Eun YoonLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USAXinghao WangSystemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20982, USAMartijn KerkhofsMokobio Biotechnology R&D Center, Rockville, MD 20850, USAHyeog KangLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USAAlexandra L. BrownLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USASung-Jun ParkLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USAXihui XuLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USAEddy D. Zandee van RillandLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USAMyung K. KimLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USAJeffrey I. CohenMedical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USAMariana J. KaplanSystemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20982, USAVarda Shoshan‐BarmatzDepartment of Life Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, IsraelJay H. ChungLaboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USA

2019en

ABI

Аннотация

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.

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Идентификаторы

DOI: 10.1126/science.aav4011

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar