Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA

By A. Rongvaux, Ruaidhri Jackson, Christian C. D. Harman, Tuo Li, A. West, M. D. Zoete, Youtong Wu, Brian Yordy, S. Lakhani, C. Kuan and 5 more. Cell, 2014

791 citations recorded by the source corpus.

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 of a mechanism by which mitochondria and downstream pro-apoptotic 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 pro-inflammatory type of cell death.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/307e052a9ad1066a8e6cbaa26b73046be4e3ffb3

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Citations in the corpus

Mitochondrial metabolism and cancer (2017, background): “That said, the release of mtDNA upon MOMP promotes the secretion of type I interferon (IFN) by malignant cells, and this is required for the activation of optimal anticancer immune responses upon chemotherapy and radiation therapy [202-205].”
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, background): “TDP-43 Triggers mtDNA Release into the Cytoplasm In sterile settings, cGAS can respond to double-stranded DNA (dsDNA) of either mitochondrial (Rongvaux et al., 2014) or nuclear origin (Ahn et al.”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Of note, lysosome-dependent cell death does not necessarily involve MOMP and caspases, and does not necessarily manifest with an apoptotic morphotype [782].”
cGAS in action: Expanding roles in immunity and inflammation (2019, background): “Despite the release of DNA into the cytosol as a result of inner mitochondrial membrane herniations via BAK or BAX macropores, apoptotic cells restrain innate immune signaling through the action of apoptotic caspases (61, 62).”
Molecular mechanisms and physiological functions of mitophagy (2021, positive): “Disruption of mitochondria triggers inflammatory responses via the NLRP3 inflammasome and also via the cGAS-STING pathway (Rongvaux et al , 2014).”
Mitochondrial DNA in inflammation and immunity (2020, positive): “…activates cGAS in a promiscuous manner, which in vivo leads to mildly elevated IFN-b protein levels in blood, though a level sufficient to induce the expression of interferon-stimulated genes [37,38] Various mitochondrial stresses including bacterial or viral infection can lead to mtDNA release.”