Impact Factor 6.684 | CiteScore 2.7
More on impact ›

MINI REVIEW article

Front. Cell Dev. Biol., 21 January 2021 | https://doi.org/10.3389/fcell.2020.630771

The Role of Mitochondria in Pyroptosis

Qian Li1, Nengxian Shi2, Chen Cai2, Mingming Zhang3, Jing He2, Ying Tan2* and Weijun Fu2*
  • 1Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 2Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 3Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, China

Pyroptosis is a recently discovered aspartic aspart-specific cysteine protease (Caspase-1/4/5/11) dependent mode of gene-regulated cell death cell death, which is represented by the rupture of cell membrane perforations and the production of proinflammatory mediaters like interleukin-18(IL-18) and interleukin-1β (IL-1β). Mitochondria also play an important role in apoptotic cell death. When it comes to apoptosis of mitochondrion, mitochondrial outer membrane permeabilization (MOMP) is commonly known to cause cell death. As a downstream pathological process of apoptotic signaling, MOMP participates in the leakage of cytochrome-c from mitochondrion to the cytosol and subsequently activate caspase proteases. Hence, targeting MOMP for the sake of manipulating cell death presents potential therapeutic effects among various types of diseases, such as autoimmune disorders, neurodegenerative diseases, and cancer. In this review, we highlights the roles and significance of mitochondria in pyroptosis to provide unexplored strategies that target the mitochondria to regulate cell death for clinical benefits.

Introduction

Mitochondria are the major sites of cellular energy production through oxidative phosphorylation (Jusic and Devaux, 2020). In addition to Adenosine Triphosphate (ATP) production, mitochondria are involved in various cellular processes, such as autoinflammatory response, cell differentiation, and immune regulation (West et al., 2011; Kasahara and Scorrano, 2014; Gurung et al., 2015; Weinberg et al., 2015). The effect of mitochondria in the types of cell death has attracted wide attention recently, but the mechanisms still seem obscure. Regulating cell death is a double-edged sword (Wang et al., 2020a). Excessive cell death will lead to many neurodegenerative diseases, such as Alzheimer disease and Parkinson disease. Inhibition of cell death is beneficial to the development of autoimmunity and cancer. Thereby, there's a lot of interest in targeting mitochondria to regulate cell death in diseases (Wang et al., 2020b). Apoptosis is a major type of cell death regulation, although the role of mitochondria on this type is not complete, but the effect of MOMP on apoptosis has got some progress (Tait and Green, 2010). MOMP occurs under the drive of some certain apoptosis-related protein molecules, such as BCL-2-associated X (BAX) and BCL-2 antagonist killer (BAK), which sequentially causes a series of cascades leading to cell death (Kale et al., 2018; Kalkavan and Green, 2018). However, other non-apoptotic signals can also cause MOMP, like pyroptosis signaling. Inflammasome mediated caspase-dependent cleaved fragment of gasdermin (GSDM) family can also be located to mitochondria to cause MOMP (Lee et al., 2019; Hu et al., 2020). In addition, this process also involves the opening of potassium efflux channels and the feedback to promote the formation of the inflammasome. It can be seen that mitochondria are involved in different types of cell death, although the specific roles and mechanisms are still poorly established.

Herein, we discuss the effect of mitochondria on pyroptosis, and highlight a new perspective on the interaction between mitochondrial apoptosis and pyroptosis. Combined with recent studies related to MOMP, we further discussed the interaction between MOMP in mitochondrial pyroptosis and apoptosis, and emphasized that targeting mitochondria may as a promising strategy to change the occurrence and development of diseases by regulating cell death.

Types and Processes of Pyroptosis

Pyroptosis is a newly defined type of pro-inflammatory cell death in recent decades, which was originally considered as an inflammatory process before cell necrosis or apoptosis, but now it has been recognized as a cell death mode characterized by membrane perforation rupture and intracellular extravasation of inflammatory mediators (Zychlinsky et al., 1992; Fink and Cookson, 2005; Yuan et al., 2016). Currently, pyroptosis can be divided into three types according to different initiate activation modes, namely classical pyroptosis pathway, non-classical pyroptosis pathway, and apoptosis protein Caspase-3 mediated pyroptosis pathway (Kayagaki et al., 2015; Jorgensen et al., 2017; Wang et al., 2017). Although these three types have their own characteristics, they are related to each other. In addition, they share a common endpoint event which is to process IL-18 and IL-1β, activate the perforating protein GSDMD and eventually cause the cell membrane to break and release IL-18 and IL-1β (Ding et al., 2016; Kovacs and Miao, 2017).

Regulation Mechanisms of Pyroptosis

The negative feedback regulation mechanism of pyroptosis itself will timely prevent the occurrence of it and inflammation (Frank and Vince, 2019). When caspase-1 is activated by different pathways, on the one hand, it continues to cleave its downstream signaling molecules including caspase-4/5/11, thus promoting the activation of GSDMD and the maturation and release of inflammatory factors. On the other hand, caspase-3/7 will also be non-specific activated when the pyroptosis occurs, and this kind of molecules will inactivate GSDMD by competitively cleaving it, playing a negative regulatory role to maintain the homeostasis (Takahama et al., 2018). Interestingly, when GSDMD was inactivated, cells switched from pyroptosis to apoptosis. In addition, TNF-αand some chemotherapy drugs can transform apoptosis to pyroptosis by cleaving GSDME. It can be seen that there is antagonism and conversion between pyroptosis and apoptosis through some unknown signaling pathways (Wang et al., 2017). In addition, some initial links of pyroptosis have the same trigger point as autophagy signaling pathway (Stocks et al., 2018). Many studies have shown that autophagy can negatively regulate pyroptosis (Schroder and Tschopp, 2010; Kim et al., 2015; Pu et al., 2017), and the mechanism may be that autophagy reduces the activation of inflammatory bodies by removing certain stimuli.

Mechanisms of Mitochondrial Apoptosis

There are two kinds of apoptotic signals, death receptor pathway and mitochondrial pathway. The former occurs when the ligands outside the cell membrane bind to the receptors on the cell membrane, activating apoptosis executioner caspases (Caspase-3/7) through a series of cascade reactions, and finally leading to the activation of apoptosis (Boatright et al., 2003; Julien and Wells, 2017). The latter is derived from mitochondria. When cells are subjected to various pathological changes, such as the loss of certain growth factors and structural damage to genetic materials, the permeability of mitochondrial outer membrane increases and some soluble proteins in mitochondrial intermembrane space are released into the cytoplasm. Apoptotic signals will be then activated and cause cell death. As one of the main components of the electron transport chain, cytochrome-c is also a common soluble protein in mitochondria, which can be identified by apoptotic peptidase activating factor 1 (APAF1) to promote the formation of apoptotic bodies (Dorstyn et al., 2018). Subsequently, the initiator caspase 9 will be recognized and activated by the apoptosome. The next step is to cleave and activate apoptosis executioner caspases (Caspase-3/7), which is the common step between the two main apoptotic signaling pathways (Poreba et al., 2019). In addition, MOMP can induce cell apoptosis and death in a non-caspase-mediated way, which is related to the regulation of the B cell lymphoma 2 (BCL-2) protein family (Wei et al., 2001). The activation of BAK and BAX, some kinds of pro-apoptotic effectors, is essential for MOMP induced mitochondrial apoptosis (Lindsten et al., 2000; Ke et al., 2018). But only their specific interactions promote apoptosis, so BAK and BAX are also regarded as superfluous in some inappropriate conditions. For example, during the process of mitochondrial apoptosis, the mitochondrial membrane pore protein voltage-dependent anion-selective channel 2 (VDAC2) can associate with both two proteins, BAX is necessary for this process while BAK is not (Naghdi et al., 2015; Lauterwasser et al., 2016; Chin et al., 2018). Normally, BAK and BAX localize to the mitochondria and cytoplasm in an inactive form, respectively (Edlich et al., 2011; Schellenberg et al., 2013; Todt et al., 2015). During apoptosis, BAX moves toward the mitochondria and gets accumulation (Letai et al., 2002). Then BAK and BAX are activated by combining their hydrophobic bases with a subclass of BCL-2 homology regions (BH3)-only proteins (Leshchiner et al., 2013; Moldoveanu et al., 2013). After being activated, BAK and BAX can oligomerize each other, which is necessary for MOMP (Dewson et al., 2009, 2012; Bleicken et al., 2010; Subburaj et al., 2015).

There are some other effectors can also induce MOMP. For instance, BOK, a BAX/BAK-like BCL-2 protein, has been discovered can initiate MOMP and then commit cells to die without the regulation of BCL-2 proteins (Einsele-Scholz et al., 2016; Llambi et al., 2016; Fernández-Marrero et al., 2017). The proapoptotic characteristics of BOK could be explained by the instability of its own hydrophobic subunit (Zheng et al., 2018). In addition, some non-BCL-2 family proteins, such as GSDMD and GSDME, can also promote MOMP. Cleavaged by specific caspase, the amino-terminal of GSDMD and GSDME can not only locate to the cell membrane to cause plasma membrane permeabilization but also to the mitochondria to induce MOMP (Rogers et al., 2017, 2019; Wang et al., 2017). However, this direct way of MOMP mediated by gasdermin protein family needs further study. Indeed, there are some other types of cell death that are closely related to mitochondria. Mitochondria is the main source of intracellular reactive oxygen species, which can activate some receptor protein kinases and further form necrosome causing necroptosis (Schenk and Fulda, 2015; Zhang et al., 2017). Furthermore, reactive oxygen species can cooperate with iron ions to promote the catalytic reaction of lipid peroxides leading to ferroptosis (Dixon et al., 2012; Wang et al., 2016). Cell necrosis and ferroptosis are different types of cell death from apoptosis, and although some of the mechanisms are still unknown, this is sufficient to demonstrate the important role of mitochondria in the regulation of cell death.

Interactions Between Pyroptosis and Mitochondrial Apoptosis

Pyroptosis is a newly discovered pro-inflammatory model of cell death initiated by the different inflammation-associated caspases. The inflammasome complex is assembled and activated under the stimulation of intra- and extracellular pathological signals, leading to the activation of inflammatory caspases. On the one hand, the activated caspase cleaves the precursor of inflammatory factors (IL-1β and IL-18) to promote its maturation; on the other hand, it also activates and cleaves GSDMD, leading to cell membrane pore formation and finally to lysis, cell content release and pyroptosis (Kayagaki et al., 2015; Shi et al., 2015; Broz and Dixit, 2016). As discussed earlier, the amino-terminal cleavage fragment of GSDMD can locate the mitochondria to cause MOMP, promoting the activation of caspase-3 (Rogers et al., 2019). Interestingly, caspase-3 is a executioner caspase during the activation of apoptosis. Furthermore, mitochondrial apoptosis can induce NLRP3 inflammasome mediated caspase-1 activity (Tsuchiya et al., 2019), which depends on caspase-3 mediated potassium channel glycoprotein activity. Potassium efflux from the cell via the channel, while this process should assist the assemblage of inflammasome. In addition, when GSDMD expression was low, the activation of caspase-1 tended to apoptosis rather than pyroptosis.

Another study has recently reported that another member of the gasdermin proteins family, GSDME, has the same function as GSDMD, and can also activate the intrinsic pathway downstream of inflammasome activation (Rogers et al., 2019). Briefly, GSDME is activated by caspase-3 to further generate the GSDME-N fragments. On the one hand, it can cause the pore-forming effect of cell membrane to mediate pyroptosis; On the other hand, it has been proved that GSDME-N can also cause changes in mitochondrial membrane permeability, further leading to the translocation of cytochrome-c from mitochondria to cytoplasm. While cytochrome-c can continue to activate apoptotic bodies and induce apoptosis, and the interaction between pyroptosis and apoptosis is just like a feedback regulation. Further researches should focus on the part of mitochondria to interfere with this feedback and thus influence the development of diseases associated with cell death patterns. Additionally, many studies in recent years have shown a complex link between mitophagy and pyroptosis. The current prevailing view is that there is a negative feedback regulation between mitophagy and pyroptosis (Yu et al., 2019; Davidson et al., 2020; Ding et al., 2020). Activation of caspase-1 caused by inflammasome would inhibit mitophagy and further enhance mitochondrial damage. In contrast, deletion of Parkin, a key regulator of mitophagy, would increase mitochondrial damage and promote pyroptosis (Yu et al., 2014). The mechanism may be related to the release of mitochondrial ROS and the disruption of membrane integrity mediated by pyroptosis. Moreover, potassium efflux and cytochrome-c also play important roles in the regulation of mitophagy and pyroptosis, but more details remain to be clarified. It can be seen that there are many crosstalks between mitochondrial apoptosis and pyroptosis, and a certain type of cell death cannot be emphasized alone, not just for mitochondrial apoptosis and pyroptosis.

Conclusions and Perspectives

We have introduced the types and regulation mechanisms of pyroptosis briefly and discussed the significant effect of mitochondria on apoptosis in this review. In addition to the discussion of the mechanism between the well-known cell death type apoptosis and mitochondria, the MOMP-mediated apoptotic cell death in different signaling pathways was also be emphasized. According to recent findings, the association between MOMP and inflammasome-mediated pyroptosis was further highlighted, and the interplay between pyroptosis and apoptosis was also revealed. Although mitochondria are involved in a variety of regulatory cell death types, the molecular mechanisms involved are not completely exacted. Moreover, there are actually therapeutic drugs or molecules that target the mitochondria to regulate the pathological processes that involved mitochondria. Previous studie have ever reported that the permeability transition pore complex (PTPC), a multi-protein complex, is participated in the metabolism of mitochondrial stability and also in mitochondria-related intrinsic apoptotic pathways (Deniaud et al., 2006). This targeted intervention, which integrates multiple death signals, may be a promising therapeutic strategy for clinical application. Survivin, a member of the IAP5 gene family, has also been shown to act as a regulatory factor for mitochondrial apoptosis and to inhibit mitochondrial apoptosis by using adenovirus transduction technology in both animal and cell studies (Blanc-Brude et al., 2003). In addition, one homology domain of BCL-2 homology regions (BH3) Peptidomimetics can inhibit apoptosis and thus intervene in the progression of certain related diseases, although the development of targeted interventions is still limited (Nemec and Khaled, 2008). In summary, the targeted regulation of mitochondria and their related pathological processes has gradually aroused great interest. While further research and exploration are needed, this does not prevent the targeting of mitochondria as a new promising strategy to regulate cell death to achieve disease control or treatment of purposes.

Author Contributions

QL, NS, and CC contributed to writing the manuscript. MZ and JH revised the manuscript. YT and WF revised the manuscript and contributed to concept of the manuscript. All authors approved this submission.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Blanc-Brude, O. P., Mesri, M., Wall, N. R., Plescia, J., Dohi, T., and Altieri, D. C. (2003). Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clin. Cancer Res. 9, 2683–2692. Available online at: https://clincancerres.aacrjournals.org/content/9/7/2683.long

Google Scholar

Bleicken, S., Classen, M., Padmavathi, P. V., Ishikawa, T., Zeth, K., Steinhoff, H. J., et al. (2010). Molecular details of Bax activation, oligomerization, and membrane insertion. J. Biol. Chem. 285, 6636–6647. doi: 10.1074/jbc.M109.081539

PubMed Abstract | CrossRef Full Text | Google Scholar

Boatright, K. M., Renatus, M., Scott, F. L., Sperandio, S., Shin, H., Pedersen, I. M., et al. (2003). A unified model for apical caspase activation. Mol. Cell 11, 529–541. doi: 10.1016/S1097-2765(03)00051-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Broz, P., and Dixit, V. M. (2016). Inflammasomes: mechanism of assembly, regulation, and signalling. Nat. Rev. Immunol. 16, 407–420. doi: 10.1038/nri.2016.58

PubMed Abstract | CrossRef Full Text | Google Scholar

Chin, H. S., Li, M. X., Tan, I. K. L., Ninnis, R. L., Reljic, B., Scicluna, K., et al. (2018). VDAC2 enables BAX to mediate apoptosis and limit tumor development. Nat. Commun. 9:4976. doi: 10.1038/s41467-018-07309-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Davidson, S. M., Adameová, A., Barile, L., and Cabrera-Fuentes, H. A. (2020). Mitochondrial and mitochondrial-independent pathways of myocardial cell death during ischaemia and reperfusion injury. J. Cell. Mol. Med. 24, 3795–3806. doi: 10.1111/jcmm.15127

PubMed Abstract | CrossRef Full Text | Google Scholar

Deniaud, A., Hoebeke, J., Briand, J. P., Muller, S., Jacotot, E., and Brenner, C. (2006). Peptido-targeting of the mitochondrial transition pore complex for therapeutic apoptosis induction. Curr. Pharm. Des. 12, 4501–4511. doi: 10.2174/138161206779010530

PubMed Abstract | CrossRef Full Text | Google Scholar

Dewson, G., Kratina, T., Czabotar, P., Day, C. L., Adams, J. M., and Kluck, R. M. (2009). Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices. Mol. Cell 36, 696–703. doi: 10.1016/j.molcel.2009.11.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Dewson, G., Ma, S., Frederick, P., Hockings, C., Tan, I., Kratina, T., et al. (2012). Bax dimerizes via a symmetric BH3:groove interface during apoptosis. Cell Death Differ. 19, 661–670. doi: 10.1038/cdd.2011.138

PubMed Abstract | CrossRef Full Text | Google Scholar

Ding, H. G., Li, Y., Li, X. S., Liu, X. Q., Wang, K. R., Wen, M. Y., et al. (2020). Hypercapnia promotes microglial pyroptosis via inhibiting mitophagy in hypoxemic adult rats. CNS Neurosci Ther. 26, 1134–1146. doi: 10.1111/cns.13435

PubMed Abstract | CrossRef Full Text | Google Scholar

Ding, J., Wang, K., Liu, W., She, Y., Sun, Q., Shi, J., et al. (2016). Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111–116. doi: 10.1038/nature18590

PubMed Abstract | CrossRef Full Text | Google Scholar

Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., et al. (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072. doi: 10.1016/j.cell.2012.03.042

PubMed Abstract | CrossRef Full Text | Google Scholar

Dorstyn, L., Akey, C. W., and Kumar, S. (2018). New insights into apoptosome structure and function. Cell Death Differ. 25, 1194–1208. doi: 10.1038/s41418-017-0025-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Edlich, F., Banerjee, S., Suzuki, M., Cleland, M. M., Arnoult, D., Wang, C., et al. (2011). Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol. Cell 145, 104–116. doi: 10.1016/j.cell.2011.02.034

PubMed Abstract | CrossRef Full Text | Google Scholar

Einsele-Scholz, S., Malmsheimer, S., Bertram, K., Stehle, D., Johänning, J., Manz, M., et al. (2016). Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak. J. Cell Sci. 129, 2213–2223. doi: 10.1242/jcs.181727

CrossRef Full Text | Google Scholar

Fernández-Marrero, Y., Bleicken, S., Das, K. K., Bachmann, D., and Kaufmann, T. (2017). The membrane activity of BOK involves formation of large, stable toroidal pores, and is promoted by cBID. FEBS J. 284, 711–724. doi: 10.1111/febs.14008

PubMed Abstract | CrossRef Full Text | Google Scholar

Fink, S. L., and Cookson, B. T. (2005). Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73, 1907–1916. doi: 10.1128/IAI.73.4.1907-1916.2005

PubMed Abstract | CrossRef Full Text | Google Scholar

Frank, D., and Vince, J. E. (2019). Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 26, 99–114. doi: 10.1038/s41418-018-0212-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Gurung, P., Lukens, J. R., and Kanneganti, T. D. (2015). Mitochondria: diversity in the regulation of the NLRP3 inflammasome. Trends Mol. Med. 21, 193–201. doi: 10.1016/j.molmed.2014.11.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Hu, L., Chen, M., and Chen, X. (2020). Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate. Cell Death Dis. 11:281. doi: 10.1038/s41419-020-2476-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Jorgensen, I., Rayamajhi, M., and Miao, E. A. (2017). Programmed cell death as a defence against infection. Nat. Rev. Immunol. 17, 151–164. doi: 10.1038/nri.2016.147

PubMed Abstract | CrossRef Full Text | Google Scholar

Julien, O., and Wells, J. A. (2017). Caspases and their substrates. Cell Death Differ. 24, 1380–1389. doi: 10.1038/cdd.2017.44

PubMed Abstract | CrossRef Full Text | Google Scholar

Jusic, A., and Devaux, Y. (2020). Mitochondrial noncoding RNA-regulatory network in cardiovascular disease. Basic Res. Cardiol. 115:23. doi: 10.1007/s00395-020-0783-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Kale, J., Osterlund, E. J., and Andrews, D. W. (2018). BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ. 25, 65–80. doi: 10.1038/cdd.2017.186

PubMed Abstract | CrossRef Full Text | Google Scholar

Kalkavan, H., and Green, D. R. (2018). MOMP, cell suicide as a BCL-2 family business. Cell Death Differ. 25, 46–55. doi: 10.1038/cdd.2017.179

PubMed Abstract | CrossRef Full Text | Google Scholar

Kasahara, A., and Scorrano, L. (2014). Mitochondria: from cell death executioners to regulators of cell differentiation. Trends Cell Biol. 24, 761–770. doi: 10.1016/j.tcb.2014.08.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Kayagaki, N., Stowe, I. B., Lee, B. L., O'rourke, K., Anderson, K., Warming, S., et al. (2015). Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671. doi: 10.1038/nature15541

PubMed Abstract | CrossRef Full Text | Google Scholar

Ke, F. F. S., Vanyai, H. K., Cowan, A. D., Delbridge, A. R. D., Whitehead, L., Grabow, S., et al. (2018). Embryogenesis and adult life in the absence of intrinsic apoptosis effectors BAX, BAK, and BOK. Cell 173, 1217–1230. doi: 10.1016/j.cell.2018.04.036

PubMed Abstract | CrossRef Full Text | Google Scholar

Kim, J. Y., Paton, J. C., Briles, D. E., Rhee, D. K., and Pyo, S. (2015). Streptococcus pneumoniae induces pyroptosis through the regulation of autophagy in murine microglia. Oncotarget 6, 44161–44178. doi: 10.18632/oncotarget.6592

PubMed Abstract | CrossRef Full Text | Google Scholar

Kovacs, S. B., and Miao, E. A. (2017). Gasdermins: effectors of pyroptosis. Trends Cell Biol. 27, 673–684. doi: 10.1016/j.tcb.2017.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Lauterwasser, J., Todt, F., Zerbes, R. M., Nguyen, T. N., Craigen, W., Lazarou, M., et al. (2016). The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation. Sci. Rep. 6:32994. doi: 10.1038/srep32994

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, E., Hwang, I., Park, S., Hong, S., Hwang, B., et al. (2019). MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration. Cell Death Differ. 26, 213–228. doi: 10.1038/s41418-018-0124-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Leshchiner, E. S., Braun, C. R., Bird, G. H., and Walensky, L. D. (2013). Direct activation of full-length proapoptotic BAK. Proc. Natl. Acad. Sci. U.S.A. 110, E986–E995. doi: 10.1073/pnas.1214313110

PubMed Abstract | CrossRef Full Text | Google Scholar

Letai, A., Bassik, M. C., Walensky, L. D., Sorcinelli, M. D., Weiler, S., and Korsmeyer, S. J. (2002). Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2, 183–192. doi: 10.1016/S1535-6108(02)00127-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Lindsten, T., Ross, A. J., King, A., Zong, W. X., Rathmell, J. C., Shiels, H. A., et al. (2000). The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol. Cell 6, 1389–1399. doi: 10.1016/S1097-2765(00)00136-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Llambi, F., Wang, Y. M., Victor, B., Yang, M., Schneider, D. M., Gingras, S., et al. (2016). BOK is a non-canonical BCL-2 family effector of apoptosis regulated by ER-associated degradation. Cell 165, 421–433. doi: 10.1016/j.cell.2016.02.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Moldoveanu, T., Grace, C. R., Llambi, F., Nourse, A., Fitzgerald, P., Gehring, K., et al. (2013). BID-induced structural changes in BAK promote apoptosis. Nat. Struct. Mol. Biol. 20, 589–597. doi: 10.1038/nsmb.2563

PubMed Abstract | CrossRef Full Text | Google Scholar

Naghdi, S., Várnai, P., and Hajnóczky, G. (2015). Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis. Proc. Natl. Acad. Sci. U.S.A. 112, E5590–E5599. doi: 10.1073/pnas.1510574112

PubMed Abstract | CrossRef Full Text | Google Scholar

Nemec, K. N., and Khaled, A. R. (2008). Therapeutic modulation of apoptosis: targeting the BCL-2 family at the interface of the mitochondrial membrane. Yonsei Med. J. 49, 689–697. doi: 10.3349/ymj.2008.49.5.689

PubMed Abstract | CrossRef Full Text | Google Scholar

Poreba, M., Groborz, K., Navarro, M., Snipas, S. J., Drag, M., and Salvesen, G. S. (2019). Caspase selective reagents for diagnosing apoptotic mechanisms. Cell Death Differ. 26, 229–244. doi: 10.1038/s41418-018-0110-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Pu, Q., Gan, C., Li, R., Li, Y., Tan, S., Li, X., et al. (2017). Atg7 deficiency intensifies inflammasome activation and pyroptosis in pseudomonas sepsis. J. Immunol. 198, 3205–3213. doi: 10.4049/jimmunol.1601196

PubMed Abstract | CrossRef Full Text | Google Scholar

Rogers, C., Erkes, D. A., Nardone, A., Aplin, A. E., Fernandes-Alnemri, T., and Alnemri, E. S. (2019). Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 10:1689. doi: 10.1038/s41467-019-09397-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Rogers, C., Fernandes-Alnemri, T., Mayes, L., Alnemri, D., Cingolani, G., and Alnemri, E. S. (2017). Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8:14128. doi: 10.1038/ncomms14128

PubMed Abstract | CrossRef Full Text | Google Scholar

Schellenberg, B., Wang, P., Keeble, J. A., Rodriguez-Enriquez, R., Walker, S., Owens, T. W., et al. (2013). Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol. Cell 49, 959–971. doi: 10.1016/j.molcel.2012.12.022

PubMed Abstract | CrossRef Full Text | Google Scholar

Schenk, B., and Fulda, S. (2015). Reactive oxygen species regulate Smac mimetic/TNFα-induced necroptotic signaling and cell death. Oncogene 34, 5796–5806. doi: 10.1038/onc.2015.35

PubMed Abstract | CrossRef Full Text | Google Scholar

Schroder, K., and Tschopp, J. (2010). The inflammasomes. Cell 140, 821–832. doi: 10.1016/j.cell.2010.01.040

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, J., Zhao, Y., Wang, K., Shi, X., Wang, Y., Huang, H., et al. (2015). Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665. doi: 10.1038/nature15514

PubMed Abstract | CrossRef Full Text | Google Scholar

Stocks, C. J., Schembri, M. A., Sweet, M. J., and Kapetanovic, R. (2018). For when bacterial infections persist: toll-like receptor-inducible direct antimicrobial pathways in macrophages. J. Leukoc. Biol. 103, 35–51. doi: 10.1002/JLB.4RI0917-358R

PubMed Abstract | CrossRef Full Text | Google Scholar

Subburaj, Y., Cosentino, K., Axmann, M., Pedrueza-Villalmanzo, E., Hermann, E., Bleicken, S., et al. (2015). Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species. Nat. Commun. 6:8042. doi: 10.1038/ncomms9042

PubMed Abstract | CrossRef Full Text | Google Scholar

Tait, S. W., and Green, D. R. (2010). Mitochondria and cell death: outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell Biol. 11, 621–632. doi: 10.1038/nrm2952

PubMed Abstract | CrossRef Full Text | Google Scholar

Takahama, M., Akira, S., and Saitoh, T. (2018). Autophagy limits activation of the inflammasomes. Immunol. Rev. 281, 62–73. doi: 10.1111/imr.12613

PubMed Abstract | CrossRef Full Text | Google Scholar

Todt, F., Cakir, Z., Reichenbach, F., Emschermann, F., Lauterwasser, J., Kaiser, A., et al. (2015). Differential retrotranslocation of mitochondrial Bax and Bak. Embo J. 34, 67–80. doi: 10.15252/embj.201488806

PubMed Abstract | CrossRef Full Text | Google Scholar

Tsuchiya, K., Nakajima, S., Hosojima, S., and Thi Nguyen, D. (2019). Caspase-1 initiates apoptosis in the absence of gasdermin D. Nat. Commun. 10:2091. doi: 10.1038/s41467-019-09753-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, J., Toan, S., and Zhou, H. (2020a). Mitochondrial quality control in cardiac microvascular ischemia-reperfusion injury: new insights into the mechanisms and therapeutic potentials. Pharmacol. Res. 156:104771. doi: 10.1016/j.phrs.2020.104771

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, J., Toan, S., and Zhou, H. (2020b). New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury. Angiogenesis 23, 299–314. doi: 10.1007/s10456-020-09720-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, Y., Gao, W., Shi, X., Ding, J., Liu, W., He, H., et al. (2017). Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103. doi: 10.1038/nature22393

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, Y. Q., Chang, S. Y., Wu, Q., Gou, Y. J., Jia, L., Cui, Y. M., et al. (2016). The Protective Role of Mitochondrial Ferritin on Erastin-Induced Ferroptosis. Front. Aging Neurosci. 8:308. doi: 10.3389/fnagi.2016.00308

PubMed Abstract | CrossRef Full Text | Google Scholar

Wei, M. C., Zong, W. X., Cheng, E. H., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., et al. (2001). Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730. doi: 10.1126/science.1059108

PubMed Abstract | CrossRef Full Text | Google Scholar

Weinberg, S. E., Sena, L. A., and Chandel, N. S. (2015). Mitochondria in the regulation of innate and adaptive immunity. Immunity 42, 406–417. doi: 10.1016/j.immuni.2015.02.002

PubMed Abstract | CrossRef Full Text | Google Scholar

West, A. P., Shadel, G. S., and Ghosh, S. (2011). Mitochondria in innate immune responses. Nat. Rev. Immunol. 11, 389–402. doi: 10.1038/nri2975

PubMed Abstract | CrossRef Full Text | Google Scholar

Yu, J., Nagasu, H., Murakami, T., Hoang, H., Broderick, L., Hoffman, H. M., et al. (2014). Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc. Natl. Acad. Sci. U.S.A. 111, 15514–15519. doi: 10.1073/pnas.1414859111

PubMed Abstract | CrossRef Full Text | Google Scholar

Yu, X., Hao, M., Liu, Y., Ma, X., Lin, W., Xu, Q., et al. (2019). Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. CNS Neurosci. Ther. 864:172715. doi: 10.1016/j.ejphar.2019.172715

PubMed Abstract | CrossRef Full Text | Google Scholar

Yuan, J., Najafov, A., and Py, B. F. (2016). Roles of caspases in necrotic cell death. Cell 167, 1693–1704. doi: 10.1016/j.cell.2016.11.047

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, Y., Su, S. S., Zhao, S., Yang, Z., Zhong, C. Q., Chen, X., et al. (2017). RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat. Commun. 8:14329. doi: 10.1038/ncomms14329

PubMed Abstract | CrossRef Full Text | Google Scholar

Zheng, J. H., Grace, C. R., Guibao, C. D., Mcnamara, D. E., Llambi, F., Wang, Y. M., et al. (2018). Intrinsic instability of BOK enables membrane permeabilization in apoptosis. Cell Rep. 23, 2083–2094. doi: 10.1016/j.celrep.2018.04.060

PubMed Abstract | CrossRef Full Text | Google Scholar

Zychlinsky, A., Prevost, M. C., and Sansonetti, P. J. (1992). Shigella flexneri induces apoptosis in infected macrophages. Nature 358, 167–169. doi: 10.1038/358167a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: mitochondria, MOMP, pyroptosis, gasdermin, apoptosis

Citation: Li Q, Shi N, Cai C, Zhang M, He J, Tan Y and Fu W (2021) The Role of Mitochondria in Pyroptosis. Front. Cell Dev. Biol. 8:630771. doi: 10.3389/fcell.2020.630771

Received: 18 November 2020; Accepted: 28 December 2020;
Published: 21 January 2021.

Edited by:

Hao Zhou, People's Liberation Army General Hospital, China

Reviewed by:

Xing Chang, China Academy of Chinese Medical Sciences, China
Corey Wright, Los Medanos College, United States

Copyright © 2021 Li, Shi, Cai, Zhang, He, Tan and Fu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Ying Tan, tanying0924@163.com; Weijun Fu, weiwang@smu.edu.cn

These authors have contributed equally to this work