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Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production
Open accessAbstract
Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production by cells undergoing Bak/Bax-mediated apoptosis. Bak and Bax trigger the release of mitochondrial DNA. This is recognized by the cGAS/STING-dependent DNA sensing pathway, which initiates IFN production. Activated caspases attenuate this response. Pharmacological caspase inhibition or genetic deletion of caspase-9, Apaf-1, or caspase-3/7 causes dying cells to secrete IFN-β. In vivo, this precipitates an elevation in IFN-β levels and consequent hematopoietic stem cell dysfunction, which is corrected by loss of Bak and Bax. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent.
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“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 [144]
Experimental — accuracy not yet measuredIn the citing paper
“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 [932]
In the citing paper
“MtDNA has been reported to activate immunity through two distinct pathways, namely Toll-like receptor 9 (TLR9; Zhang et al, 2010;Oka et al, 2012;Liu et al, 2015), and cGAS activation (White et al, 2014;West et al, 2015).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as White et al, 2014
In the citing paper
“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 White et al, 2014
In the citing paper
“Interestingly, these events were attenuated by caloric restriction (White et al., 2014), an intervention which has been shown to extend lifespan in a plethora of organisms and decrease the burden of senescent cells (Fontana et al., 2018; Mercken et al., 2012).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as White et al., 2014
In the citing paper
“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 White et al., 2014
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Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829
Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., & Wang, X. (1997) · Cell · doi:10.1016/s0092-8674(00)80434-1 · Cited by 7,289
limma: Linear Models for Microarray Data
Smyth, G. K. (2005) · Statistics for Biology and Health · doi:10.1007/0-387-29362-0_23 · Cited by 5,796
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
Sun, L., Wu, J., Du, F., Chen, X., & Chen, Z. J. (2013) · Science · doi:10.1126/science.1232458 · Cited by 4,996 · cited 1×
“Recent evidence indicates that cGAS is activated via a direct interaction with cytosolic DNA (Civril et al., 2013; Sun et al., 2013).”
The BCL-2 protein family: opposing activities that mediate cell death
Youle, R. J., & Strasser, A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2308 · Cited by 4,806 · cited 1×
“Apoptosis comprises two convergent pathways: the intrinsic and extrinsic (Youle and Strasser, 2008).”
Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., Roth, K. A., MacGregor, G. R., Thompson, C. B., & Korsmeyer, S. J. (2001) · Science · doi:10.1126/science.1059108 · Cited by 3,988 · cited 1×
“, they can survive and generate viable progeny) (Lindsten et al., 2000; Wei et al., 2001).”
Bioinformatics and Computational Biology Solutions Using R and Bioconductor
Gentleman, R. C., Carey, V. J., Huber, W. K., Irizarry, R. A., & Dudoit, S. (2005) · Statistics in the health sciences · doi:10.1007/0-387-29362-0 · Cited by 3,470
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Oltersdorf, T., Elmore, S. W., Shoemaker, A. R., Armstrong, R. C., Augeri, D. J., Belli, B., Bruncko, M., Deckwerth, T. L., Dinges, J., Hajduk, P. J., et al. (2005) · Nature · doi:10.1038/nature03579 · Cited by 3,407 · cited 1×
“To test this, we treated WT murine splenocytes with the proapoptotic BH3 mimetic drug ABT-737, which targets the prosurvival proteins Bcl-xL and Bcl-2 (Oltersdorf et al., 2005).”
A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD
Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., & Nagata, S. (1998) · Nature · doi:10.1038/34112 · Cited by 3,239 · cited 1×
“Unlike genomic damage, which is triggered by cleavage of iCAD, the inhibitor of caspase-activated DNase (CAD) (Enari et al., 1998), and PS exposure, which is facilitated by cleavage of Xkr8 (Suzuki et al.”
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Zhang, K., Huang, Q., Li, X., Zhao, Z., Hong, C., Sun, Z., Deng, B., Li, C., Zhang, J., & Wang, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1352479 · Cited by 49
Senolytic therapeutics: An emerging treatment modality for osteoarthritis
Ansari, M. M., Ghosh, M., Lee, D., & Son, Y. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102275 · Cited by 49
Li, W., Nie, S., Yao, Y.-F., Liu, X., Shao, D.-Y., Gong, D., Cui, S. W., Phillips, G. O., He, M., & Xie, M. (2015) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5b03462 · Cited by 48
RNA Granules in the Mitochondria and Their Organization under Mitochondrial Stresses
Xavier, V. J., & Martinou, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179502 · Cited by 46
“For example, during late events of apoptosis [63], following downregulation of TFAM and clustering of nucleoids [66], it is the mtDNA that promotes the interferon response through activation of cytosolic DNA sensors such as Cyclic GMP/AMP Synthase–Stimulator Of Interferon Genes (cGAS-STING) [67,68].”
BackgroundRegulation and function of the cGAS-MITA/STING axis in health and disease
Zhang, Z.-D., & Zhong, B. (2022) · Cell Insight · doi:10.1016/j.cellin.2021.100001 · Cited by 44
“cGAS-MITA pathway via proteolytic cleavage of cGAS (White et al., 2014).”
BackgroundLi, M., Dai, X., Zhao, Y., Li, X., Zhao, Y., & Li, J. (2022) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c08351 · Cited by 47
Popgeorgiev, N., Gil, C., Berthenet, K., Bertolin, G., & Ichim, G. (2023) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2023.07.003 · Cited by 48
Xu, H., Wedn, A. M., Wang, J., Gu, Y., Liu, H., Zhang, J., Lin, Z., Zhou, R., Pang, X., & Cui, Y. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107063 · Cited by 49
Activation of cGAS-dependent antiviral responses by DNA intercalating agents
Pépin, G., Nejad, C., Thomas, B. J., Ferrand, J., McArthur, K., Bardin, P. G., Williams, B. R. G., & Gantier, M. P. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw878 · Cited by 50
Self-citationNew Insights on Platelets and Platelet-Derived Microparticles in Systemic Lupus Erythematosus
Scherlinger, M., Sisirak, V., Richez, C., Lazaro, E., Duffau, P., & Blanco, P. (2017) · Current Rheumatology Reports · doi:10.1007/s11926-017-0678-0 · Cited by 46
Role of Post-Translational Modifications of cGAS in Innate Immunity
Wu, Y., & Li, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217842 · Cited by 47
“However, the activated caspase cascade responsible for facilitating cell death also prevents dying cells from triggering a host immune response [47].”
BackgroundInfluentialThe Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing
Su, Y., Wang, P., & Weng, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052668 · Cited by 45
“In addition, mitochondrial apoptotic signaling causes the release of mtDNA and triggers the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) to drive interferon responses [89].”
BackgroundZampino, M., Brennan, N. A., Kuo, P.-L., Spencer, R. G., Fishbein, K. W., Simonsick, E. M., & Ferrucci, L. (2020) · GeroScience · doi:10.1007/s11357-020-00208-x · Cited by 43
“…activates the adaptor protein stimulator of interferon genes (STING) with consequent stimulation of the transcription factor interferon regulatory factor 3 (IRF3) and expression of innate immune response genes, including type I interferon (IFN) cytokines (Dhanwani et al. 2018; White et al. 2014).”
Medicinal chemistry perspective on cGAS-STING signaling pathway with small molecule inhibitors
Tian, X., Xu, F., Zhu, Q., Feng, Z., Dai, W., Zhou, Y.-L., You, Q., & Xu, X. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114791 · Cited by 44
Temporal landscape of mitochondrial proteostasis governed by the UPR mt
Uoselis, L., Lindblom, R. S. J., Lam, W. K., Küng, C. J., Skulsuppaisarn, M., Khuu, G., Nguyen, T. N., Rudler, D. L., Filipovska, A., Schittenhelm, R. B., et al. (2023) · Science Advances · doi:10.1126/sciadv.adh8228 · Cited by 47
Silke, J., & Vince, J. E. (2016) · Current topics in microbiology and immunology · doi:10.1007/82_2016_507 · Cited by 46
Non-lethal outcomes of engaging regulated cell death pathways in cancer
Kalkavan, H., Rühl, S., Shaw, J. J. P., & Green, D. R. (2023) · Nature Cancer · doi:10.1038/s43018-023-00571-6 · Cited by 48
Temozolomide-based sonodynamic therapy induces immunogenic cell death in glioma
Zhou, Y., Jiao, J., Yang, R., Wen, B., Wu, Q., Xu, L., Tong, X., & Yan, H. (2023) · Clinical Immunology · doi:10.1016/j.clim.2023.109772 · Cited by 43
DNA-sensing pathways in health, autoinflammatory and autoimmune diseases
Dong, M., & Fitzgerald, K. A. (2024) · Nature Immunology · doi:10.1038/s41590-024-01966-y · Cited by 46
“106,107), ensuring that the apoptosis process is non-inflammatory.”
Activation of cGAS/STING pathway upon paramyxovirus infection
Iampietro, M., Dumont, C., Mathieu, C., Spanier, J., Robert, J., Charpenay, A., Dupichaud, S., Dhondt, K. P., Aurine, N., Pélissier, R., et al. (2021) · iScience · doi:10.1016/j.isci.2021.102519 · Cited by 46
Xue, Y., Jiang, X., Wang, J., Zong, Y., Yuan, Z., Miao, S., & Mao, X. (2023) · Biomarker Research · doi:10.1186/s40364-022-00433-w · Cited by 43
Killarney, S. T., Washart, R., Soderquist, R. S., Hoj, J. P., Lebhar, J., Lin, K., & Wood, K. C. (2023) · Nature Communications · doi:10.1038/s41467-023-37146-z · Cited by 44
Advances in crosstalk among innate immune pathways activated by mitochondrial DNA
Tao, G., Liao, W., Hou, J., Jiang, X., Deng, X., Chen, G., & Ding, C. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e24029 · Cited by 51
“Possible mechanisms include caspases cleaving and inactivating one or more components of the IFN-I production pathway, such as IRF3 [76], and, in addition, cystatinases mediating the degradation of mtDNA, thereby preventing its interaction with cGAS [77,78].”
BackgroundTranscriptional control of metabolism by interferon regulatory factors
Ahmad, Z., Kahloan, W., & Rosen, E. D. (2024) · Nature Reviews Endocrinology · doi:10.1038/s41574-024-00990-0 · Cited by 45
“47–49).”
Preyat, N., Rossi, M., Kers, J., Chen, L., Bertin, J., Gough, P. J., Moine, A. L., Rongvaux, A., Gool, F. V., & Léo, O. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.60 · Cited by 42
Aaes, T. L., Verschuere, H., Kaczmarek, A., Heyndrickx, L., Wiernicki, B., Delrue, I., Craene, B. D., Taminau, J., Delvaeye, T., Bertrand, M. J. M., et al. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900072 · Cited by 44
“Apoptotic caspases were also demonstrated to suppress type I IFN production (72, 73), and recently, it was”
BackgroundRegulation of the Innate Immune Response during the Human Papillomavirus Life Cycle
Moody, C. A. (2022) · Viruses · doi:10.3390/v14081797 · Cited by 47
Potential Therapeutic Value of the STING Inhibitors
Zhang, S., Zheng, R., Pan, Y., & Sun, H. (2023) · Molecules · doi:10.3390/molecules28073127 · Cited by 42
Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis
Basak, B., & Holzbaur, E. L. F. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169161 · Cited by 44
Feng, D., Tian, F., Qin, W., & Qian, X. (2015) · Chemical Science · doi:10.1039/c5sc03363b · Cited by 40
Mitochondria-Induced Immune Response as a Trigger for Neurodegeneration: A Pathogen from Within
Luna‐Sánchez, M., Bianchi, P., & Quintana, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168523 · Cited by 40
“Importantly, MOMP is also crucial for the translocation of mtDNA to the cytosol, which, in the absence of apoptotic caspase activation, is recognized by the cGAS–STING pathway and trigger type I IFN responses and expression of ISGs [59,60].”
BackgroundInfluentialXia, X., He, X., Zhao, T., Yang, J., Bi, Z., Fu, Q., Liu, J., Ao, D., Wei, Y., & Wei, X. (2023) · Cell Proliferation · doi:10.1111/cpr.13529 · Cited by 38
“48,49 Our data showed that the expression of IFN-γ was upregulated when STING was activated, which suggested that mtDNA could activate the STING pathway.”
Inflammation and mitophagy are mitochondrial checkpoints to aging
Guilbaud, E., Sarosiek, K. A., & Galluzzi, L. (2024) · Nature Communications · doi:10.1038/s41467-024-47840-1 · Cited by 42
Chen, F., Xu, K., Han, Y., Ding, J., Ren, J., Wang, Y., Ma, Z., & Cao, F. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1503087 · Cited by 43
Marcatti, M., Saada, J. I., Okereke, I. C., Wade, C. E., Bossmann, S. H., Motamedi, M., & Szczęsny, B. (2021) · Cells · doi:10.3390/cells10040819 · Cited by 39
“The presence of particular mtDNA in cytoplasm has been well documented in various pathological conditions, including infection [38,39], neurodegeneration [40], and cancer [41], to name just few.”
BackgroundUnraveling the Underlying Interaction Mechanism Between Dabie bandavirus and Innate Immune Response
Zhou, C., & Yu, X.-J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.676861 · Cited by 39
Häcker, G. A., & Haimovici, A. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01058-0 · Cited by 42
“Release of mtDNA into the cytosol has been discovered upon stress caused by aberrant DNA-packaging [75] and during (fullblown) apoptosis [8, 9].”
BackgroundWang, Y., Karki, R., Mall, R., Sharma, B. R., Kalathur, R., Lee, S., Kancharana, B., So, M., Combs, K. L., & Kanneganti, T. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111434 · Cited by 40
“These findings are consistent with the reported function of the CASP9-CASP3 axis in suppressing cGAS-STING-driven type I IFN production (Rongvaux et al., 2014; White et al., 2014).”
Mitochondrial Dysfunction-Associated Mechanisms in the Development of Chronic Liver Diseases
Arumugam, M. K., Gopal, T., Kandy, R. R. K., Boopathy, L. K., Perumal, S. K., Ganesan, M., Rasineni, K., Donohue, T. M., Osna, N. A., & Kharbanda, K. K. (2023) · Biology · doi:10.3390/biology12101311 · Cited by 40
“[124].”
BackgroundChacon, J. A., Schutsky, K., & Powell, D. J. (2016) · Vaccines · doi:10.3390/vaccines4040043 · Cited by 39
“In this way, STING/cGAS in DCs is activated by DNA originating from dying cancer cells and critical for high levels of type-I IFN-1 generated during anti-tumor immune response and optimal cross-priming of T cells [59,123,124].”
BackgroundThe Role of Mitochondrial DNA in the Development of Ischemia Reperfusion Injury
Hu, Q., Zhou, Q., Wu, J., Wu, X., & Ren, J. (2018) · Shock · doi:10.1097/shk.0000000000001190 · Cited by 39
mtDNA in the Pathogenesis of Cardiovascular Diseases
Wang, L., Zhang, Q., Yuan, K., & Yuan, J. (2021) · Disease Markers · doi:10.1155/2021/7157109 · Cited by 40
“mtDNA also activates cGAS-STING to initiate the production of type 1 interferon (IFNS), which triggers an inflammatory response [36].”
BackgroundWu, X., Chen, Y.-J., Liu, C.-A., Gong, J.-H., & Xu, X. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/8123157 · Cited by 40
“STING can activate TBK1 and IRF3, resulting in enhanced expression of type I IFNs and proin fl ammatory cytokines [46 – 48] and apoptosis [49, 50].”
Guo, W., Chen, Z., Li, Z., Huang, H., Ren, Y., Zhao, B., Li, G., & Hu, Y. (2022) · Chemical Engineering Journal · doi:10.1016/j.cej.2022.136428 · Cited by 38
mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases
Shang, D., Huang, M., Wang, B., Yan, X., Wu, Z., & Zhang, X. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220810114644 · Cited by 44
“The subsequent phosphorylation of IRF-3 by TRAF family member-associated NF-κB activator (TANK)-binding kinase 1 triggers the expression of IFN-I and IFN-III and causes inflammation [97, 98].”
Sun, Y., Aliyari, S. R., Parvatiyar, K., Wang, L., Zhen, A., Sun, W. Y., Han, X. B., Zhang, A., Kato, E., Shi, H., et al. (2025) · Cell Death and Differentiation · doi:10.1038/s41418-025-01457-z · Cited by 38
IRE-1α promotes viral infection by conferring resistance to apoptosis
Fink, S., Jayewickreme, T., Molony, R. D., Iwawaki, T., Landis, C. S., Lindenbach, B., & Iwasaki, A. (2017) · Science Signaling · doi:10.1126/scisignal.aai7814 · Cited by 39
Regulation of cGAS activity by RNA‐modulated phase separation
Chen, S., Miao, R., Lv, Y., Zhu, D., & Xiang, Y. (2022) · EMBO Reports · doi:10.15252/embr.202051800 · Cited by 37
“…2008; Jin et al , 2008; Zhong et al , 2008; Sun et al , 2009; Gao et al , 2013; Zhang et al , 2013). cGAS binds dsDNA in a sequence-independent manner (Rongvaux et al , 2014; White et al , 2014; Lau et al , 2015; West et al , 2015; Mackenzie et al , 2017; Yang et al , 2017; Wang et al , 2017a).”
Strategies involving STING pathway activation for cancer immunotherapy: Mechanism and agonists
Pan, X., Zhang, W., Guo, H., Wang, L., Wu, H., Ding, L., & Yang, B. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115596 · Cited by 36
Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy
Chen, Z., Behrendt, R., Wild, L., Schlee, M., & Bode, C. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02174-2 · Cited by 44
Evidence of Aberrant Immune Response by Endogenous Double‐Stranded RNAs: Attack from Within
Kim, S., Ku, Y., Ku, J., & Kim, Y. (2019) · BioEssays · doi:10.1002/bies.201900023 · Cited by 34
Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy
Amon, L., Hatscher, L., Heger, L., Dudziak, D., & Lehmann, C. H. K. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12070663 · Cited by 37
“To tackle the unwanted inhibition of productive immune responses to such cells, the development of antagonists for STING-suppressive pathways including caspase-9 or caspase 3/7 inhibitors or by interfering with the rapid regulatory STING turnover, might circumvent immunologically silenced apoptosis and might enhance a…”
BackgroundPPP6C Negatively Regulates STING-Dependent Innate Immune Responses
Ni, G., Ma, Z., Wong, J. P., Zhang, Z., Cousins, E. M., Major, M. B., & Damania, B. (2020) · mBio · doi:10.1128/mbio.01728-20 · Cited by 36
Mitochondria: Powering the Innate Immune Response to Mycobacterium tuberculosis Infection
Patrick, K. L., & Watson, R. O. (2021) · Infection and Immunity · doi:10.1128/iai.00687-20 · Cited by 38
Apoptosis in infectious diseases as a mechanism of immune evasion and survival
Quarleri, J. F., Cevallos, C. G., & Delpino, M. V. (2021) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2021.01.001 · Cited by 39
Xia, J., Wang, L., Shen, T., Li, P., Zhu, P., Xie, S., Chen, Z., Zhou, F., Zhang, J., Ling, J., et al. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.11.019 · Cited by 36
Mechanisms of Photosensitivity in Autoimmunity
Estadt, S. N., Maz, M. P., Musai, J., & Kahlenberg, J. M. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2021.05.007 · Cited by 37
Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies
Zhang, J., Yu, S., Peng, Q., Wang, P., & Fang, L. (2024) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2023.0440 · Cited by 38
“Mitochondria are a recognized source of reactive oxygen species, and radiation-induced oxidative stress can lead to the leakage of mtDNA into the cytoplasm and activation of the cGAS-STING pathway 85 .”
BackgroundMitochondrial DNA leakage triggers inflammation in age-related cardiovascular diseases
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Mishra, Y., Kumar, A., & Kaundal, R. K. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04412-0 · Cited by 39
“Blocking caspase activity after MOMP has been shown to enhance IFN-I responses and NFκB signaling, potentially leading to increased inflammation and immunogenic cell death [31, 175, 179].”
Xiong, Y., Chen, J., Liang, W., Li, K., Huang, Y., Song, J., Zhang, B., Qiu, X., Qiu, D., Zhang, Q., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05588-8 · Cited by 35
“According to reports, the release of cytoplasmic mtDNA was increased following the administration of ABT737 (an inhibitor of Bcl2) and Z-VAD-FMK (an inhibitor of caspases) [38, 39].”
BackgroundInnate Immune Recognition of mtDNA—An Undercover Signal?
Kanneganti, T., Kundu, M., & Green, D. R. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.019 · Cited by 35
“White et al. (White et al., 2014) and Rongvaux et al. (Rongvaux et al., 2014) concurrently published that the activation of caspases involved in the intrinsic pathway of apoptosis (caspase-3, caspase-7, and caspase-9) prevents activation of the IFN response in cells undergoing apoptosis mediated by…”
BackgroundInfluential2016: A ‘Mitochondria’ Odyssey
Cherry, C. J., Thompson, B. S., Saptarshi, N., Wu, J., & Hoh, J. J. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.03.009 · Cited by 34
The cGAS-STING Pathway in Hematopoiesis and Its Physiopathological Significance
Liao, W., Du, C., & Wang, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.573915 · Cited by 34
“However, caspase activation following BAK/BAX activation will attenuate the IFN-I response possibly through global cellular demolition (54).”
BackgroundTRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense
Wang, L., & Ning, S. (2021) · Viruses · doi:10.3390/v13020279 · Cited by 34
Caspase-Dependent Cleavage of DDX21 Suppresses Host Innate Immunity
Wu, W., Qu, Y., Yu, S., Wang, S., Yin, Y., Liu, Q., Meng, C., Liao, Y., Rehman, Z. U., Tan, L., et al. (2021) · mBio · doi:10.1128/mbio.01005-21 · Cited by 35
“(E) HeLa cells were transfected with either empty vector or Flag tagged WT and 753 truncates of DDX21 (1-125, 127-784).”
BackgroundMethodZhang, Y., Wang, W., Gong, Z., Peng, Y., Li, X., Zhang, Z., Zhang, X., You, X., & Wu, J. (2022) · Inflammation Research · doi:10.1007/s00011-022-01663-2 · Cited by 40
“Specifically, the BAX-mediated formation of pores in the mitochondrial outer membrane increases the permeability of the inner membrane, resulting in mtDNA efflux [48, 49].”
BackgroundZaid, A. K. M. A., & Ariel, A. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115204 · Cited by 35
Early host defense against virus infections
Paludan, S. R., Pradeu, T., Pichlmair, A., Wray, K. B., Mikkelsen, J. G., Olagnier, D. P., & Mogensen, T. H. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.115070 · Cited by 38
Established and emerging roles for mitochondria in neutrophils
Peng, S., Gao, J., Stojkov, D., Yousefi, S., & Simon, H. (2022) · Immunological Reviews · doi:10.1111/imr.13158 · Cited by 34
Wang, Y., Wang, J., Tao, S., Liang, Z., xie, R., Liu, N., Deng, R., Zhang, Y., Deng, D., & Jiang, G. (2023) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3733 · Cited by 36
“55,58 55–57 Extracellular mtDNA can stimulate immune cell trafficking, activate neutrophils 59,60 and vascular endothelial cells, and cause inflammation in distant tissues.”
BackgroundThe link between Mitochondria and Sarcopenia
Kamarulzaman, N. T., & Makpol, S. (2025) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-024-01062-7 · Cited by 33
“…of mtDNA into the cytoplasm, as a result of mitochondrial stress and damage, can activate the cGAS-STING inflammatory response (Akbari et al. 2019; Michael et al. 2014; Sliter et al. 2018; West et al. 2015) but the removal of damaged or stressed mitochondria by mitophagy inhibited this response…”
Mitochondrial dynamics and pore formation in regulated cell death pathways
Hohorst, L., Ros, U., & García‐Sáez, A. J. (2025) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2025.09.001 · Cited by 36
Lepelley, A., Wai, T., & Crow, Y. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.729763 · Cited by 33
“Seminal studies first described IFN induction due to mtDNA release upon abortive apoptosis in 2014 (32, 33), the process of which was detailed in real-time by high-resolution imaging in 2018 (34, 35).”
BackgroundSrinivasan, K., Pandey, A. K., Livingston, A., & Venkatesh, S. (2021) · Molecular Biomedicine · doi:10.1186/s43556-021-00060-1 · Cited by 36
Aging and Clonal Behavior of Hematopoietic Stem Cells
Yamashita, M., & Iwama, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23041948 · Cited by 36
Mitochondrial DNA: Consensuses and Controversies
Shokolenko, I. N., & ALEXEYEV, M. F. (2022) · DNA · doi:10.3390/dna2020010 · Cited by 35
MOMP: A critical event in cell death regulation and anticancer treatment
Liu, D., Liu, Z., Yan, H., Xiong, W., Wang, D., & Zeng, Z. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189280 · Cited by 34
Okazaki, T., Higuchi, M., Takeda, K., Iwatsuki‐Horimoto, K., Kiso, M., Miyagishi, M., Yanai, H., Kato, A., Yoneyama, M., Fujita, T., et al. (2015) · Science Signaling · doi:10.1126/scisignal.aab1883 · Cited by 31
Insights Into the Role of Mitochondrial Ion Channels in Inflammatory Response
Ponnalagu, D., & Singh, H. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00258 · Cited by 32
“Phosphorylated IRF3s translocate to the nucleus and cause the activation of an IFN-1 response that triggers both innate and adaptive immunity (Rongvaux et al., 2014; White et al., 2014).”
BackgroundThe Cytosolic DNA-Sensing cGAS-STING Pathway in Liver Diseases
Wang, Z., Chen, N., Li, Z., Xu, G., Zhan, X., Tang, J., Xiao, X., & Bai, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.717610 · Cited by 32
Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA
Fermaintt, C. S., Takahashi‐Ruiz, L., Liang, H., Mooberry, S. L., & Risinger, A. L. (2021) · Molecular Pharmacology · doi:10.1124/molpharm.121.000297 · Cited by 33
“This method has been used by others to evaluate mtDNA-mediated activation of the cGAS-STING pathway (White et al., 2014; Yamazaki et al., 2020; Hu et al., 2021).”
MethodHaimovici, A., Höfer, C., Badr, M. T., Haghighi, E. B., Amer, T., Boerries, M., Bronsert, P., Glavynskyi, I., Fanfone, D., Ichim, G., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04768-y · Cited by 34
“Notably, DNA-signaling has previously been linked to mitochondrial apoptosis [22, 23] and even sub-lethal signals [28]: mitochondrial DNA can be released into the cytosol during apoptosis [29, 30], where it may be recognized by cGAS.”
BackgroundGomes, M. T., Palasiewicz, K., Gadiyar, V., Lahey, K. C., Calianese, D. C., Birge, R. B., & Ucker, D. S. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102034 · Cited by 36
“an essential role in the suppression of type I interferon production by apoptotic cells themselves (69, 70).”
BackgroundXing, Y., Peng, A., Yang, J., Cheng, Z., Yue, Y. S., Liu, F., Li, F., Liu, Y., & Liu, Q. (2024) · Advanced Science · doi:10.1002/advs.202309583 · Cited by 32
Croker, B. A., Silke, J., & Gerlic, M. (2015) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000148 · Cited by 33
“For example, HMGB1 and mitochondrial DNA are potent inducers of type I interferon, and they have the capacity to negatively regulate emergency hematopoiesis [24,25,80].”
Hu, X., Peng, X., Lu, C., Zhang, X., Gan, L., Gao, Y., Yang, S., Xu, W., Wang, J., Yin, Y., et al. (2019) · FEBS Journal · doi:10.1111/febs.15001 · Cited by 31
A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions
Wang, D., Zhao, H., Shen, Y., & Chen, Q. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.826880 · Cited by 34
“Mitochondrial DNA can also be released from dying cells, which then triggers release of proinflammatory factors and IFN-I that acts on hematopoietic stem cells and has a profound impact on cell function (90, 91).”
BackgroundRecent advances in the activation and regulation of the cGAS-STING pathway
Fang, R., Jiang, Q., Yu, X., Zhao, Z., & Jiang, Z. (2022) · Advances in immunology · doi:10.1016/bs.ai.2022.09.003 · Cited by 30
Mechanisms of Mitochondrial Oxidative Stress in Brain Injury: From Pathophysiology to Therapeutics
Nguyen, A., Patel, A. B., Kioutchoukova, I. P., Diaz, M. J., & Lucke-Wold, B. P. (2023) · Oxygen · doi:10.3390/oxygen3020012 · Cited by 30
“Even when cancerous cells undergo apoptosis, the physiology has been found to be immunologically silent, with reduced secretion of cytokines and inflammatory mediators involved in Type 1 IFN production [95,96].”
BackgroundYe, B., Pei, Y., Wang, L., Meng, D., Zhang, Y., Zou, S., Li, H., Liu, J., Xie, Z., Tian, C., et al. (2024) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30522 · Cited by 33
“11 12 – 14 When DNA abnormally appears in the cytoplasm, the innate immune activation pathway of the cyclic guanosine monophosphate (GMP) ‐ adenosine monophosphate (AMP) synthase (cGAS) ‐ STING (stimulator of interferon genes) DNA ‐ sensing pathway detects the presence of cytosolic is activated,…”
BackgroundConrad, M., Strasser, A., Jost, P. J., Yuan, J., Shao, F., Vandenabeele, P., & Wahida, A. (2026) · Cell · doi:10.1016/j.cell.2026.03.024 · Cited by 40
Therapeutic opportunities based on caspase modulation
Fulda, S. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.12.008 · Cited by 30
Huang, L., Chang, W., Huang, Y., Xu, X., Yang, Y., & Qiu, H. (2020) · Journal of Thoracic Disease · doi:10.21037/jtd.2020.02.49 · Cited by 29
“Moreover, markedly increased levels of circulating free mtDNA fragments have been observed in both sepsis and trauma conditions (12-16).”
BackgroundLauriano, E. R., Aragona, M., Alesci, A., Cascio, P. L., & Pergolizzi, S. (2021) · Tissue and Cell · doi:10.1016/j.tice.2021.101584 · Cited by 30
Su, Y., Tu, Y., Lin, H. L., Wang, M., Zhang, G., Yang, J., Liu, H., & Su, Z. G. (2021) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2021.111653 · Cited by 30
Innate immune recognition against SARS-CoV-2
Yamada, T., & Takaoka, A. (2023) · Inflammation and Regeneration · doi:10.1186/s41232-023-00259-5 · Cited by 33
Xu, Y., Nowsheen, S., & Deng, M. (2023) · Cancers · doi:10.3390/cancers15051619 · Cited by 31
Vaios, E., Winter, S. F., Shih, H. A., Dietrich, J., Peters, K. B., Floyd, S., Kirkpatrick, J. P., & Reitman, Z. J. (2023) · Cancers · doi:10.3390/cancers15092432 · Cited by 31
Cell-Cycle Cross Talk with Caspases and Their SubstratesPreprint
Connolly, P. F., García-Carpio, I., & Villunger, A. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a036475 · Cited by 32
Metadata
- Authors
- White, M. J., McArthur, K., Metcalf, D., Lane, R. M., Cambier, J. C., Herold, M. J., van Delft, M. F., Bedoui, S., Lessene, G., Ritchie, M. E., Huang, D. C. S., & Kile, B. T.
- Affiliations
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- National Jewish Health (US)
- Corresponding author
- White, Michael J.
- Kile, Benjamin T.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 7
- Pages
- 1549-1562
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4520319
- OpenAlex
- W2028107828
- Cited by
- 983
- References
- 68
- Citations by year
- 2026: 89 · 2025: 88 · 2024: 118 · 2023: 107 · 2022: 111 · 2021: 94 · 2020: 93 · 2019: 61 · 2018: 76 · 2017: 63 · 2016: 39 · 2015: 40
- FWCI
- 21.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R21AI099346)
- 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, apoptosis, type I interferon, STING, cGAS, mitochondrial DNA, Bak, Bax, caspase-9, Apaf-1, caspase-3, caspase-7, interferon-beta, hematopoietic stem cells
- MeSH terms
- STING Protein, Animals, Crosses, Genetic, DNA, Mitochondrial, Female, Hematopoietic Stem Cells, Interferon Type I, Male, Membrane Proteins, Mice, Inbred C57BL, Signal Transduction, Apoptosis, Caspases, Caspase 9
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