Apoptotic Caspases Prevent the Induction of Type I Interferons by Mitochondrial DNA
Open accessAbstract
The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death.
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In the absence of active caspases, mitochondrial DNA released after mitochondrial outer membrane permeabilization triggers type I interferon responses in a cGAS-STING-dependent manner.
“In the absence of active caspases, mtDNA released following mitochondrial outer membrane permeabilization triggers type I interferon responses in a cGAS–STING-dependent manner143,144”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [143]
Experimental — accuracy not yet measuredCASP8 inhibits necroptosis; CASP3 drives PS exposure, boosts PGE2 secretion, and inhibits type I IFN signaling from mitochondrial DNA upon MOMP.
“These include: (1) the prominent ability of CASP8 to inhibit necroptosis (see above), which is generally associated with the establishment of robust inflammatory responses linked to NF-κB activation [496 925–928]; (2) the capacity of CASP3 to drive PS exposure (see above), which generally supports the phagocytic removal of dying and dead cells while delivering anti-inflammatory signals to”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [931]
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 Rongvaux et al, 2014
ABT-737 drives type I IFN secretion by cancer cells downstream of mtDNA-driven CGAS activation, especially when caspases are inhibited.
“Finally, ABT-737 (an experimental inhibitor of multiple BCL2 family members) is known for its ability to drive robust type I IFN secretion by cancer cells downstream of mtDNA-driven CGAS activation, especially in the context of caspases inhibition (Rongvaux et al., 2014; White et al., 2014).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Rongvaux et al., 2014
Nearly half of the genes whose expression was highest in astrocytes are involved with interferon signaling: BCL2, IRF3, HMGB1, TICAM1, and TRAF3.
“Nearly half of the genes whose expression was highest in astrocytes are involved with interferon signaling: BCL2 (27) , IRF3 , HMGB1 , TICAM1 , and TRAF3 (28)”
From Single cell transcriptome profiling of the human alcohol-dependent brain (2020) · cites this paper as [27]
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- Authors
- Rongvaux, A., Jackson, R., Harman, C. C. D., Li, T., West, A. P., de Zoete, M. R., Wu, Y., Yordy, B., Lakhani, S. A., Kuan, C.-Y., Taniguchi, T., Shadel, G. S., Chen, Z. J., Iwasaki, A., & Flavell, R. A.
- Affiliations
- Yale University (US)
- The University of Texas Southwestern Medical Center (US)
- Emory University (US)
- Institute of Industrial Science, The University of Tokyo (JP)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Flavell, Richard A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 7
- Pages
- 1563-1577
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4272443
- OpenAlex
- W2015879727
- Cited by
- 847
- References
- 56
- Citations by year
- 2026: 63 · 2025: 79 · 2024: 94 · 2023: 90 · 2022: 92 · 2021: 91 · 2020: 77 · 2019: 53 · 2018: 76 · 2017: 56 · 2016: 35 · 2015: 39
- FWCI
- 19.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense (W81XWH-11-1-0745)
- Ministry of Education, Culture, Sports, Science and Technology (PF-13-035-01-DMC)
- National Institute of Allergy and Infectious Diseases (AI082030)
- National Institutes of Health (R01-AI093967)
- United Mitochondrial Disease Foundation
- American Cancer Society
- Blavatnik Family Foundation (M157176)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- caspases, type I interferon, mitochondrial DNA, cGAS-STING pathway, outer membrane permeabilization, Bax, Bak, apoptosis, antiviral immunity, mitochondrial cell death, inflammation
- MeSH terms
- Animals, DNA, Mitochondrial, Inflammation, Interferon Type I, Virus Diseases, Signal Transduction, Apoptosis, Mice, Knockout, Caspases, Mice
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