Pyroptosis targeting via mitochondria: An educated guess to innovate COVID-19 therapies

Aarti Singh, Daniela Strobbe, Michelangelo Campanella, Aarti Singh, Daniela Strobbe, Michelangelo Campanella

Abstract

Pyroptosis is a specialized form of inflammatory cell death which aids the defensive response against invading pathogens. Its normally tight regulation is lost during infection by the severe acute respiratory coronavirus 2 (SARS-CoV-2), and thus, uncontrolled pyroptosis disrupts the immune system and the integrity of organs defining the critical conditions in patients with high viral load. Molecular pathways engaged downstream of the formation and stabilization of the inflammasome, which are necessary to execute the process, have been uncovered and drugs are available for their regulation. However, the pharmacology of the upstream events, which are critical to sense and interpret the initial damage by the pathogen, is far from being elucidated. This limits our capacity to identify early markers and targets to ameliorate SARS-CoV-2 linked pyroptosis. Here, we focus attention on the mitochondria and pathways leading to their dysfunction, in order to elucidate the early steps of inflammasome formation and devise tools to predict and counter pathological states induced by SARS-CoV-2. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc.

Keywords: SARS-CoV-2; mitochondria and pharmacology; pyroptosis.

Conflict of interest statement

The authors declare no conflicts of interest.

© 2021 The British Pharmacological Society.

Figures

FIGURE 1
FIGURE 1
Activation of the NLRP3 inflammasome by SARS‐CoV‐2 via mitochondrial dysfunction. The three SARS‐CoV proteins (E, ORF3a and ORF8b) induce the activation of inflammasome (4). E protein (yellow) induces Ca2+ efflux through ERGIC/Golgi membranes to the cytosol (6). This induces influx into the mitochondria to generate mtROS (8). ORF3a (blue) induces K+ efflux to the extracellular space (7) and promotes inflammasome assembly (4) through TRAF3‐mediated ubiquitination of ASC (7; 10). On the other hand, TRAF3–ORF3a interaction is required for NF‐κβ activation, resulting in transcription of the pro–IL‐1β/IL‐18 and NLRP3 genes. ORF8b (violet) can interact directly with NLRP3 stimulating its activation (5). Consequent to inflammasome activation (4), gasdermin D (GSDMD) pores are formed on the plasma (2) and mitochondrial (3) membranes, causing IL‐1β/IL‐18 secretion (1), the cellular swelling associated with pyroptosis (1) and the induction of mitochondrial apoptotic pathway via Bax‐dependent release of cytochrome C into the cytosol. Additionally, activation of Bax can trigger NLRP3 activation via apoptotic caspases (dotted line) in a K+ efflux‐dependent manner (7). Thus, SARS‐CoV‐2 triggers NLRP3 inflammasome assembly and activation by damaging the mitochondria and inducing the production of mtROS (8) and the loss of mitochondrial membrane potential (ΔΨm) to release damaged mitochondrial DNA (mtDNA) in the cytosol through the mitochondrial pore transition (mPT). Therefore, mitophagy (11) stands as an important regulator of NLRP3 which is tethered on the mitochondria for activation in a mtROS‐dependent manner (black box)

References

    1. Alexander, S. P. H. , Fabbro, D. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. , Armstrong, J. F. , Faccenda, E. , Harding, S. D. , Pawson, A. J. , Sharman, J. L. , Southan, C. , Davies, J. A. , & CGTP Collaborators . (2019a). The Concise Guide to PHARMACOLOGY 2019/20: Catalytic receptors. British Journal of Pharmacology, 176, S247–S296. 10.1111/bph.14751
    1. Alexander, S. P. H. , Fabbro, D. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. , Armstrong, J. F. , Faccenda, E. , Harding, S. D. , Pawson, A. J. , Sharman, J. L. , Southan, C. , Davies, J. A. , & CGTP Collaborators . (2019b). The Concise Guide to PHARMACOLOGY 2019/20: Enzymes. British Journal of Pharmacology, 176, S297–S396. 10.1111/bph.14752
    1. Chen, I. Y. , Moriyama, M. , Chang, M. F. , & Ichinohe, T. (2019). Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Frontiers in Microbiology, 10, 50. 10.3389/fmicb.2019.00050
    1. Cheng, S. B. , Nakashima, A. , Huber, W. J. , Davis, S. , Banerjee, S. , Huang, Z. , Saito, S. , Sadovsky, Y. , & Sharma, S. (2019). Pyroptosis is a critical inflammatory pathway in the placenta from early onset preeclampsia and in human trophoblasts exposed to hypoxia and endoplasmic reticulum stressors. Cell Death & Disease, 10(12), 927–942. 10.1038/s41419-019-2162-4
    1. Cookson, B. T. , & Brennan, M. A. (2001). Pro‐inflammatory programmed cell death. Trends in Microbiology, 9(3), 113–114. 10.1016/s0966-842x(00)01936-3
    1. Courjon, J. , Dufies, O. , Robert, A. , Bailly, L. , Torre, C. , Chirio, D. , & Boyer, L. (2021). Heterogeneous NLRP3 inflammasome signature in circulating myeloid cells as a biomarker of COVID‐19 severity. Blood Advances, 5(5), 1523–1534. 10.1182/bloodadvances.2020003918
    1. Ferreira, A. C. , Soares, V. C. , de Azevedo‐Quintanilha, I. G. , Dias, S. D. S. G. , Fintelman‐Rodrigues, N. , Sacramento, C. Q. , & Souza, T. M. L. (2021). SARS‐CoV‐2 engages inflammasome and pyroptosis in human primary monocytes. Cell Death Discovery, 7(1), 43–55. 10.1038/s41420-021-00428-w
    1. Fritsch, M. , Günther, S. D. , Schwarzer, R. , Albert, M. C. , Schorn, F. , Werthenbach, J. P. , Schiffmann, L. M. , Stair, N. , Stocks, H. , Seeger, J. M. , Lamkanfi, M. , Krönke, M. , Pasparakis, M. , & Kashkar, H. (2019). Caspase‐8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature, 575(7784), 683–687. 10.1038/s41586-019-1770-6
    1. Guan, K. , Wei, C. , Zheng, Z. , Song, T. , Wu, F. , Zhang, Y. , & Zhong, H. (2015). MAVS promotes inflammasome activation by targeting ASC for K63‐linked ubiquitination via the E3 ligase TRAF3. Journal of Immunology, 194(10), 4880–4890. 10.4049/jimmunol.1402851
    1. He, L. , Ding, Y. , Zhang, Q. , Che, X. , He, Y. , Shen, H. , & Jiang, S. (2006). Expression of elevated levels of pro‐inflammatory cytokines in SARS‐CoV‐infected ACE2+ cells in SARS patients: Relation to the acute lung injury and pathogenesis of SARS. The Journal of Pathology, 210(3), 288–297. 10.1002/path.2067
    1. Hoffmann, M. , Kleine‐Weber, H. , Schroeder, S. , Krüger, N. , Herrler, T. , Erichsen, S. , & Pöhlmann, S. (2020). SARS‐CoV‐2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), 271–280.e278. 10.1016/j.cell.2020.02.052
    1. Hojyo, S. , Uchida, M. , Tanaka, K. , Hasebe, R. , Tanaka, Y. , Murakami, M. , & Hirano, T. (2020). How COVID‐19 induces cytokine storm with high mortality. Inflammation and Regeneration, 40(1), 37–44. 10.1186/s41232-020-00146-3
    1. Hu, J. J. , Liu, X. , Xia, S. , Zhang, Z. , Zhang, Y. , Zhao, J. , Ruan, J. , Luo, X. , Lou, X. , Bai, Y. , Wang, J. , Hollingsworth, L. R. , Magupalli, V. G. , Zhao, L. , Luo, H. R. , Kim, J. , Lieberman, J. , & Wu, H. (2020). FDA‐approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nature Immunology, 21, 736–745. 10.1038/s41590-020-0669-6
    1. Ichinohe, T. , Yamazaki, T. , Koshiba, T. , & Yanagi, Y. (2013). Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection. Proceedings of the National Academy of Sciences of the United States of America, 110(44), 17963–17968. 10.1073/pnas.1312571110
    1. Iyer, S. S. , He, Q. , Janczy, J. R. , Elliott, E. I. , Zhong, Z. , Olivier, A. K. , & Sutterwala, F. S. (2013). Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity, 39(2), 311–323. 10.1016/j.immuni.2013.08.001
    1. Kim, Y. I. , Kim, S. G. , Kim, S. M. , Kim, E. H. , Park, S. J. , Yu, K. M. , & Choi, Y. K. (2020). Infection and rapid transmission of SARS‐CoV‐2 in ferrets. Cell Host & Microbe, 27(5), 704–709.e702. 10.1016/j.chom.2020.03.023
    1. Klok, F. A. , Kruip, M. J. H. A. , van der Meer, N. J. M. , Arbous, M. S. , Gommers, D. A. M. P. J. , Kant, K. M. , Kaptein, F. H. J. , van Paassen, J. , Stals, M. A. M. , Huisman, M. V. , & Endeman, H. (2020). Incidence of thrombotic complications in critically ill ICU patients with COVID‐19. Thrombosis Research, 191, 145–147. 10.1016/j.thromres.2020.04.013
    1. Lau, S. K. P. , Lau, C. C. Y. , Chan, K. H. , Li, C. P. Y. , Chen, H. , Jin, D. Y. , & Yuen, K. Y. (2013). Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: Implications for pathogenesis and treatment. The Journal of General Virology, 94(Pt 12), 2679–2690. 10.1099/vir.0.055533-0
    1. Li, S. , Zhang, Y. , Guan, Z. , Li, H. , Ye, M. , Chen, X. , Shen, J. , Zhou, Y. , Shi, Z. L. , Zhou, P. , & Peng, K. (2020). SARS‐CoV‐2 triggers inflammatory responses and cell death through caspase‐8 activation. Signal Transduction and Targeted Therapy, 5, 235–245. 10.1038/s41392-020-00334-0
    1. Lin, Q. , Li, S. , Jiang, N. , Shao, X. , Zhang, M. , Jin, H. , & Ni, Z. (2019). PINK1‐parkin pathway of mitophagy protects against contrast‐induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biology, 26, 101254. 10.1016/j.redox.2019.101254
    1. Long, B. , Brady, W. J. , Koyfman, A. , & Gottlieb, M. (2020). Cardiovascular complications in COVID‐19. The American Journal of Emergency Medicine, 38(7), 1504–1507. 10.1016/j.ajem.2020.04.048
    1. Murakami, T. , Ockinger, J. , Yu, J. , Byles, V. , McColl, A. , Hofer, A. M. , & Horng, T. (2012). Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proceedings of the National Academy of Sciences of the United States of America, 109(28), 11282–11287. 10.1073/pnas.1117765109
    1. Nakahira, K. , Haspel, J. A. , Rathinam, V. A. , Lee, S. J. , Dolinay, T. , Lam, H. C. , & Choi, A. M. (2011). Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature Immunology, 12(3), 222–230. 10.1038/ni.1980
    1. Nieto‐Torres, J. L. , Verdiá‐Báguena, C. , Jimenez‐Guardeño, J. M. , Regla‐Nava, J. A. , Castaño‐Rodriguez, C. , Fernandez‐Delgado, R. , & Enjuanes, L. (2015). Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology, 485, 330–339. 10.1016/j.virol.2015.08.010
    1. Patel, S. , Saxena, B. , & Mehta, P. (2021). Recent updates in the clinical trials of therapeutic monoclonal antibodies targeting cytokine storm for the management of COVID‐19. Heliyon, 7(2), e06158. 10.1016/j.heliyon.2021.e06158
    1. Santa Cruz, A. , Mendes‐Frias, A. , Oliveira, A. I. , Dias, L. , Matos, A. R. , Carvalho, A. , & Silvestre, R. (2021). Interleukin‐6 is a biomarker for the development of fatal severe acute respiratory syndrome coronavirus 2 pneumonia. Frontiers in Immunology, 12, 613422. 10.3389/fimmu.2021.613422
    1. Shi, C.‐S. , Nabar, N. R. , Huang, N.‐N. , & Kehrl, J. H. (2019). SARS‐coronavirus open reading frame‐8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. Cell Death Discovery, 5(1), 101–113. 10.1038/s41420-019-0181-7
    1. Shi, J. , Zhao, Y. , Wang, K. , Shi, X. , Wang, Y. , Huang, H. , & Shao, F. (2015). Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 526(7575), 660–665. 10.1038/nature15514
    1. Singh, A. , Faccenda, D. , & Campanella, M. (2021). Pharmacological advances in mitochondrial therapy. eBioMedicine, 65, 103244. 10.1016/j.ebiom.2021.103244 Epub 2021 Feb 26. PMID: 33647769; PMCID: PMC7920826
    1. Siu, K. L. , Yuen, K. S. , Castaño‐Rodriguez, C. , Ye, Z. W. , Yeung, M. L. , Fung, S. Y. , & Jin, D. Y. (2019). Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3‐dependent ubiquitination of ASC. The FASEB Journal, 33(8), 8865–8877. 10.1096/fj.201802418R
    1. Toldo, S. , Bussani, R. , Nuzzi, V. , Bonaventura, A. , Mauro, A. G. , Cannatà, A. , & Abbate, A. (2021). Inflammasome formation in the lungs of patients with fatal COVID‐19. Inflammation Research: Official Journal of the European Histamine Research Society … [et al.], 70(1), 7–10. 10.1007/s00011-020-01413-2
    1. Torres, J. , Maheswari, U. , Parthasarathy, K. , Ng, L. , Liu, D. X. , & Gong, X. (2007). Conductance and amantadine binding of a pore formed by a lysine‐flanked transmembrane domain of SARS coronavirus envelope protein. Protein Science, 16(9), 2065–2071. 10.1110/ps.062730007
    1. Wu, C. , Lu, W. , Zhang, Y. , Zhang, G. , Shi, X. , Hisada, Y. , & Li, Z. (2019). Inflammasome activation triggers blood clotting and host death through pyroptosis. Immunity, 50(6), 1401–1411.e1404. 10.1016/j.immuni.2019.04.003
    1. Yang, Y. , Wang, H. , Kouadir, M. , Song, H. , & Shi, F. (2019). Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death & Disease, 10(2), 128–139. 10.1038/s41419-019-1413-8
    1. Yap, J. K. Y. , Moriyama, M. , & Iwasaki, A. (2020). Inflammasomes and pyroptosis as therapeutic targets for COVID‐19. The Journal of Immunologyji2000513, 205, 307–312. 10.4049/jimmunol.2000513
    1. Zhang, N.‐P. , Liu, X.‐J. , Xie, L. , Shen, X.‐Z. , & Wu, J. (2019). Impaired mitophagy triggers NLRP3 inflammasome activation during the progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis. Laboratory Investigation, 99(6), 749–763. 10.1038/s41374-018-0177-6
    1. Zheng, Z. , & Li, G. (2020). Mechanisms and therapeutic regulation of pyroptosis in inflammatory diseases and cancer. International Journal of Molecular Sciences, 21(4), 1456. 10.3390/ijms21041456
    1. Zhong, Z. , Umemura, A. , Sanchez‐Lopez, E. , Liang, S. , Shalapour, S. , Wong, J. , & Karin, M. (2016). NF‐κB restricts inflammasome activation via elimination of damaged mitochondria. Cell, 164(5), 896–910. 10.1016/j.cell.2015.12.057
    1. Zhou, J. , Chu, H. , Li, C. , Wong, B. H. , Cheng, Z. S. , Poon, V. K. , & Yuen, K. Y. (2014). Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: Implications for pathogenesis. The Journal of Infectious Diseases, 209(9), 1331–1342. 10.1093/infdis/jit504
    1. Zhou, R. , Yazdi, A. S. , Menu, P. , & Tschopp, J. (2011). A role for mitochondria in NLRP3 inflammasome activation. Nature, 469(7329), 221–225. 10.1038/nature09663

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