Mitochondrial DNA stress primes the antiviral innate immune response
Open accessAbstract
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.
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Detection of mitochondrial motives by innate and adaptive immunity might elicit potent pro-inflammatory responses.
“Given the bacterial features of mitochondria, the detection of mitochondrial motives by cells of the innate and adaptive immunity might elicit potent pro-inflammatory responses147,276,277.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [147]
The paper’s Abstract reports that cytosolic mitochondrial DNA engages an innate immune sensor and potentiates type I interferon responses. It does not establish detection by adaptive immune cells or a broad, potent pro-inflammatory response; the demonstrated response is specifically antiviral innate signaling. The indexed passages provide no page number. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIntrinsic self-dsDNA released into the cytosol from nucleus or mitochondrion due to cellular or mitochondrial stress can bind to cGAS and activate the cGAS-STING pathway.
“Besides the exogenous dsDNA released by virus or bacterial, intrinsic self-dsDNA released into the cytosol from nucleus or mitochondrion due to cellular or mitochondrial stress can also bind to cGAS and activate cGAS-STING pathway.400,401”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [401]
The paper’s main text reports that mtDNA stress allows mitochondrial DNA to escape into the cytosol, where cGAS senses it and triggers STING-dependent signaling. Extended Data Figure 8 also depicts this pathway. These passages support the mitochondrial part of the claim, but do not establish the claimed release of nuclear DNA under cellular stress. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMitochondrial DNA or mitochondrial RNA released into the cytosol through BAX-BAK macropores can activate cytosolic nucleic acid sensors independently of cell death, leading to type I interferon production.
“mtDNA or mtRNA released into the cytosol via BAX–BAK macropores can activate nucleic acid sensors in the cytosol145 independently of cell death130,146,147, ultimately leading to the production of type I interferon”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [147]
mtDNA stress from TFAM haploinsufficiency can cause robust cGAS-STING activation.
“This finding contrasts with previous work showing that mtDNA stress, induced by the haploinsufficiency of the mitochondrial transcription factor A (TFAM), can lead to robust cGAS–STING activation147”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [147]
Cytosolic mtDNA activates cGAS and promotes STING-IRF3-dependent signaling.
“Thus, cytosolic mtDNA activates the DNA sensor cGAS and promotes STING-IRF3-dependent signaling (Rongvaux et al, 2014;White et al, 2014;West et al, 2015).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as West et al, 2015
The pattern of mtDNA changes suggests existence of mtDNA stress similar to that detected upon TFAM repression.
“This pattern of changes suggests the existence of mitochondrial DNA stress similar to what detected upon TFAM repression (West et al, 2015).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as West et al, 2015
Anti-viral priming and resistance in TFAM-deficient fibroblasts can be ablated by ddC, which inhibits mtDNA replication and reduces mtDNA stress, suggesting cytosolic mtDNA potentiates anti-viral innate immunity.
“Anti-viral priming and resistance to viral infection could be ablated by treating TFAM-deficient fibroblasts with dideoxycytidine (ddC), which inhibits mtDNA replication and reduces mtDNA stress in these cells, suggesting that cytosolic mtDNA potentiates anti-viral innate immunity (West et al., 2015).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as West et al., 2015
TFAM-deficient fibroblasts, which have increased cytosolic mtDNA, display elongated and hyperfused mitochondria.
“TFAM-deficient fibroblasts, which have increased cytosolic mtDNA, display elongated and hyperfused mitochondria (West et al., 2015).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as West et al., 2015
TFAM-deficient cells show heightened type I interferon and ISG expression upon HSV-1 infection and are more resistant to infection than wild-type cells.
“Consistent with a role for mtDNA in priming the anti-viral immune response, TFAM-deficient cells display heightened expression of type I interferon and ISG upon infection with Herpes Simplex Virus 1 (HSV-1) and are more resistant to infection compared to wild type cells (West et al., 2015).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as West et al., 2015
Reduced TFAM expression causes aberrant mtDNA packaging, organization, and distribution, leading to mtDNA release into the cytosol.
“For example, reduced TFAM expression, which results in aberrant mtDNA packaging, organization and distribution, leads to release of mtDNA into the cytosol (West et al., 2015).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as West et al., 2015
Increased mitochondrial fission by Mfn1 knockdown in TFAM-depleted cells is associated with reduced ISG expression, suggesting mitochondrial network disruptions influence mtDNA-induced interferon gene expression.
“Consistent with this, the authors showed that increased mitochondria fission, due to knock down of mitofusin 1 (Mfn1) in TFAM-depleted cells, was associated with reduced expression of interferon-stimulated gene (ISGs), suggesting that disruptions in the mitochondria network also influence mtDNA-induced expression of interferon genes (West et al., 2015).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as West et al., 2015
In TFAM-depleted cells, cytosolic mtDNA is associated with increased ISG expression in a cGAS-STING-IRF3-dependent manner.
“For example, in TFAM-depleted cells, the presence of mtDNA in the cytosol was associated with increased expression of interferon-stimulated genes (ISGs) in a cGAS-STING-IRF3-dependent manner (West et al., 2015) (Fig. 3).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as West et al., 2015
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- Authors
- West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., Kaech, S. M., Smiley, J. R., Means, R. E., Iwasaki, A., & Shadel, G. S.
- Affiliations
- Yale University (US)
- University of Alberta (CA)
- Washington University in St. Louis (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shadel, Gerald S.
- ORCID
- Venue
- Nature
- Published
- 2015-02-02
- Volume
- 520
- Issue
- 7548
- Pages
- 553-557
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4409480
- OpenAlex
- W2035232303
- Cited by
- 1,975
- References
- 50
- Citations by year
- 2026: 307 · 2025: 211 · 2024: 216 · 2023: 224 · 2022: 199 · 2021: 216 · 2020: 161 · 2019: 130 · 2018: 108 · 2017: 94 · 2016: 70 · 2015: 36
- FWCI
- 50.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000142)
- Canadian Institutes of Health Research (MOP37995)
- National Institute on Aging (R01AG047632, F31AG039163)
- National Institute of Allergy and Infectious Diseases (R01AI054359, T32AI055403, R01AI081884)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK091042)
- National Institute of Environmental Health Sciences (P01ES011163)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- antiviral innate immunity, type I interferon, herpesvirus infection, interferon-stimulated genes, virus resistance, mitochondrial nucleoids
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Cell Line, DNA-Binding Proteins, DNA, Mitochondrial, Female, Gene Expression Regulation, High Mobility Group Proteins, Humans, Immunity, Innate, Interferon Type I, Membrane Proteins, Nucleotidyltransferases, Stress, Physiological, Herpesvirus 1, Human, Interferon Regulatory Factor-3, Mice
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