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VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease
Open accessAbstract
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 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]
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“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]
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“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]
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“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]
In the citing paper
“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
In the citing paper
“It was shown that mouse fibroblasts deficient in the mitochondrial endonuclease γ, which display increased oxidative stress, had higher levels of cytosolic mtDNA and this could be attenuated by knocking down VDAC 1 and 3 (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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“Moreover, cytoplasmic mtDNA that accumulates in response to mitochondrial endonuclease γ deficiency, has also been shown to induce expression of ISGs in mouse fibroblasts (Kim et al., 2019), suggesting that cytosolic mtDNA is a major trigger of inflammatory pathways.”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Kim et al., 2019
In the citing paper
“Furthermore, inhibiting VDAC oligomerization by using the inhibitor VBIT-4 has been shown to decrease mtDNA release and IFN signaling in a mouse model of systemic lupus erythematosus and ameliorated the disease severity (Kim et al., 2019), suggesting that inhibition of VDAC oligomerization and perhaps mPTP might represent an effective therapeutic strategy to improve diseases involving cytosolic mt”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Kim et al., 2019
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Metadata
- 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.
- ORCID
- Venue
- Science
- Published
- 2019-12-20
- Volume
- 366
- Issue
- 6472
- Pages
- 1531-1536
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC8325171
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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