VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease-Reference-Cited by-同舟云学术

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

Published:2019-12-20 Issue:6472 Volume:366 Page:1531-1536
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Kim Jeonghan¹^ORCID,Gupta Rajeev²^ORCID,Blanco Luz P.³,Yang Shutong¹,Shteinfer-Kuzmine Anna²,Wang Kening⁴^ORCID,Zhu Jun⁵⁶,Yoon Hee Eun¹,Wang Xinghao³^ORCID,Kerkhofs Martijn⁷^ORCID,Kang Hyeog¹^ORCID,Brown Alexandra L.¹^ORCID,Park Sung-Jun¹^ORCID,Xu Xihui¹,Zandee van Rilland Eddy¹^ORCID,Kim Myung K.¹,Cohen Jeffrey I.⁴^ORCID,Kaplan Mariana J.³^ORCID,Shoshan-Barmatz Varda²^ORCID,Chung Jay H.¹^ORCID

Affiliation:

1. Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USA.

2. Department of Life Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.

3. Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20982, USA.

4. Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.

5. Systems Biology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.

6. Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, and Leuven Kanker Instituut, KU Leuven, 3000 Leuven, Belgium.

7. Mokobio Biotechnology R&D Center, Rockville, MD 20850, USA.

Abstract

VDACs are MOM's ruin Mitochondrial DNA (mtDNA) is normally kept within the mitochondria. It can be released into the cytosol in response to stress and thus encounter cytosolic DNA sensors, triggering type I interferon responses. During apoptosis, mtDNA release is mediated by macropores in the mitochondrial outer membrane (MOM) created by oligomerization of the proteins BAX and BAK. Kim et al. found that during oxidative stress, mtDNA escapes instead through macropores formed by oligomerization of voltage-dependent anion channels (VDACs) (see the Perspective by Crow). In a mouse model of lupus, an inhibitor of VDAC oligomerization diminished mtDNA release and downstream signaling events. This treatment reduced lupus-like symptoms in the model, suggesting a potential therapeutic route for conditions mediated by mtDNA release. Science , this issue p. 1531 ; see also p. 1445

Funder

National Institutes of Health

Korea Health Industry Development Institute

Korea Research Institute of Bioscience and Biotechnology

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference36 articles.

1. Mitochondrial DNA in innate immune responses and inflammatory pathology

2. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis

3. Apoptotic Caspases Prevent the Induction of Type I Interferons by Mitochondrial DNA