Cited by 793Mitochondrial Function and PathologySystemic Lupus Erythematosus Researchinterferon and immune responses

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

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Kim, Jeonghan, Gupta, Rajeev, Blanco, Luz P., Yang, Shutong, Shteinfer-Kuzmine, Anna, Wang, Kening, Zhu, Jun, Yoon, Hee Eun +12 more·2019·Science

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

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  • In peripheral blood mononuclear cells, the level of VDAC oligomers and cytosolic mitochondrial DNA is higher in patients with SLE than in healthy individuals.

    “in peripheral blood mononuclear cells, the level of VDAC oligomers and cytosolic mtDNA is higher in patients with SLE than in healthy individuals”

    From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [148]

    The passage discussing Fig. 4B reports more VDAC1 oligomers in PBMCs from patients with SLE than in healthy controls. It reports elevated cytosolic mtDNA in splenocytes from lupus-prone mice, not in human PBMCs; the latter part of the claim is therefore unsupported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • Cytosolic release of mitochondrial DNA can occur in live cells through VDAC oligomer pores independently of BAX-BAK macropores and can activate the cGAS-STING pathway, as shown in Endog-deficient mouse embryo fibroblasts.

    “Cytosolic release of mtDNA can occur in live cells (as opposed to apoptotic cells) via pores formed by VDAC oligomers independent of BAX–BAK macropores and can activate the cGAS–STING pathway, as shown in mouse embryo fibroblasts deficient in Endog (a nuclear DNA-encoded mitochondrial endonuclease)148”

    From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [148]

  • Splenocytes from lupus-prone mice have more VDAC pores and cytosolic mitochondrial DNA than splenocytes from wild-type mice.

    “splenocytes from lupus-prone mice have more VDAC pores and cytosolic mtDNA than splenocytes from wild-type mice”

    From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [148]

  • Treatment with VBIT-4, a VDAC oligomerization inhibitor, can abrogate SLE-like symptoms in lupus-prone mice and is paralleled by a decrease in cytosolic mitochondrial DNA.

    “treatment with VBIT-4, a VDAC oligomerization inhibitor, can abrogate the SLE-like symptoms of lupus-prone mice, which is paralleled by a concomitant decrease in cytosolic mtDNA”

    From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [148]

  • VDAC oligomerization has been proposed to mediate mtDNA release into the cytoplasm.

    “Interestingly, a recent study has proposed a role for voltage-dependent anion channel (VDAC) oligomerization in mediating mtDNA release into the cytoplasm (Kim et al., 2019).”

    From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Kim et al., 2019

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Authors
Kim, J., Gupta, R., Blanco, L. P., Yang, S., Shteinfer-Kuzmine, A., Wang, K., Zhu, J., Yoon, H. E., Wang, X., Kerkhofs, M., Kang, H., Brown, A. L., Park, S.-J., Xu, X., Zandee van Rilland, E., Kim, M. K., Cohen, J. I., Kaplan, M. J., Shoshan-Barmatz, V., & Chung, J. H.
Affiliations
  • National Heart, Lung, and Blood Institute (US)
  • Ben-Gurion University of the Negev (IL)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (US)
  • Department of Life Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
  • National Institutes of Health (US)
  • Mokobio Biotechnology R&D Center, Rockville, MD 20850, USA.
  • Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, MD 20892, USA.
Corresponding author
Chung, Jay H.
Venue
Science
Published
2019-12-20
Volume
366
Issue
6472
Pages
1531-1536
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2996537134
Cited by
793
References
37
Citations by year
2026: 172 · 2025: 147 · 2024: 147 · 2023: 123 · 2022: 82 · 2021: 86 · 2020: 35 · 2019: 1
FWCI
16.87
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
Funders
  • National Institutes of Health
  • Korea Health Industry Development Institute (HI14C1176)
  • Korea Research Institute of Bioscience and Biotechnology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
VDAC1, mitochondrial DNA release, mitochondrial outer membrane permeabilization, mitochondrial stress, type I interferon signaling, systemic lupus erythematosus, neutrophil extracellular traps, N-terminal domain
MeSH terms
Protein Domains, Animals, Disease Models, Animal, DNA, Mitochondrial, Endodeoxyribonucleases, Humans, Interferons, Lupus Erythematosus, Systemic, Oxidative Stress, Voltage-Dependent Anion Channels, Mitochondrial Membranes, Mice, Rats, Protein Multimerization

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