Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 2,450

The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.

Mitochondria as multifaceted regulators of cell death

Open access
Bock, Florian J., Tait, Stephen W. G.·2020·Nature Reviews Molecular Cell Biology
DOI 10.1038/s41580-019-0173-8
Open this paper in CoChat — free account

Abstract

Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit. Mitochondria are key executioners of apoptosis. However, it has recently become clear that beyond driving apoptosis, mitochondria also contribute to pro-inflammatory signalling and other types of regulated cell death. These functions are relevant to disease and could be targeted in the treatment of, for example, degenerative disorders, infection and cancer.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41580-019-0173-8

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

1 retracted

Show all 41 references

Research works printed but not linked: 121

  1. Mehta, M. M., Weinberg, S. E. & Chandel, N. S. Mitochondrial control of immunity: beyond ATP. Nat. Rev. Immunol. 17, 608–620 (2017). · DOI · Paper page
  2. Filippi, M. D. & Ghaffari, S. Mitochondria in the maintenance of hematopoietic stem cells: new perspectives and opportunities. Blood 133, 1943–1952 (2019). · DOI · Paper page
  3. Merino, D. et al. BH3-mimetic drugs: blazing the trail for new cancer medicines. Cancer Cell 34, 879–891 (2018). · DOI · Paper page
  4. Roberts, A. W. et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 311–322 (2016). · DOI · Paper page
  5. Tuzlak, S., Kaufmann, T. & Villunger, A. Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis. Genes Dev. 30, 2133–2151 (2016). · DOI
  6. Boatright, K. M. et al. A unified model for apical caspase activation. Mol. Cell 11, 529–541 (2003). · DOI · Paper page
  7. Dorstyn, L., Akey, C. W. & Kumar, S. New insights into apoptosome structure and function. Cell Death Differ. 25, 1194–1208 (2018). · DOI · Paper page
  8. McCarthy, N. J., Whyte, M. K., Gilbert, C. S. & Evan, G. I. Inhibition of Ced-3/ICE-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl-2 homologue Bak. J. Cell Biol. 136, 215–227 (1997). · DOI · Paper page
  9. Xiang, J., Chao, D. T. & Korsmeyer, S. J. BAX-induced cell death may not require interleukin 1β-converting enzyme-like proteases. Proc. Natl Acad. Sci. USA 93, 14559–14563 (1996). · DOI · Paper page
  10. Amarante-Mendes, G. P. et al. Anti-apoptotic oncogenes prevent caspase-dependent and independent commitment for cell death. Cell Death Differ. 5, 298–306 (1998). · DOI · Paper page
  11. Cecconi, F., Alvarez-Bolado, G., Meyer, B. I., Roth, K. A. & Gruss, P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94, 727–737 (1998). · DOI · Paper page
  12. Yoshida, H. et al. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94, 739–750 (1998). · DOI · Paper page
  13. Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325–337 (1998). · DOI · Paper page
  14. Ke, F. F. S. et al. Embryogenesis and adult life in the absence of intrinsic apoptosis effectors BAX, BAK, and BOK. Cell 173, 1217–1230 e1217 (2018). This study affirms an important role for mitochondrial apoptosis in embryonic development but, surprisingly, shows that some apoptosis-deficient mice can survive to adulthood. · DOI · Paper page
  15. Lakhani, S. A. et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311, 847–851 (2006). · DOI · Paper page
  16. Goldstein, J. C., Waterhouse, N. J., Juin, P., Evan, G. I. & Green, D. R. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat. Cell Biol. 2, 156–162 (2000). · DOI · Paper page
  17. Lartigue, L. et al. Caspase-independent mitochondrial cell death results from loss of respiration, not cytotoxic protein release. Mol. Biol. Cell 20, 4871–4884 (2009). · DOI
  18. Wei, M. C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001). · DOI · Paper page
  19. Sarosiek, K. A. et al. BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response. Mol. Cell 51, 751–765 (2013). · DOI · Paper page
  20. Lopez, J. et al. Mito-priming as a method to engineer Bcl-2 addiction. Nat. Commun. 7, 10538 (2016). · DOI
  21. Lauterwasser, J. et al. The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation. Sci. Rep. 6, 32994 (2016). · DOI
  22. Naghdi, S., Varnai, P. & Hajnoczky, G. Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis. Proc. Natl Acad. Sci. USA 112, E5590–E5599 (2015). · DOI · Paper page
  23. Chin, H. S. et al. VDAC2 enables BAX to mediate apoptosis and limit tumor development. Nat. Commun. 9, 4976 (2018).
  24. Todt, F. et al. Differential retrotranslocation of mitochondrial Bax and Bak. EMBO J. 34, 67–80 (2015). · DOI · Paper page
  25. Schellenberg, B. et al. Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol. Cell 49, 959–971 (2013). · DOI · Paper page
  26. Czabotar, P. E. et al. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell 152, 519–531 (2013). · DOI · Paper page
  27. Moldoveanu, T. et al. BID-induced structural changes in BAK promote apoptosis. Nat. Struct. Mol. Biol. 20, 589–597 (2013). · DOI · Paper page
  28. Leshchiner, E. S., Braun, C. R., Bird, G. H. & Walensky, L. D. Direct activation of full-length proapoptotic BAK. Proc. Natl Acad. Sci. USA 110, E986–E995 (2013). · DOI · Paper page
  29. Brouwer, J. M. et al. Conversion of Bim-BH3 from activator to inhibitor of Bak through structure-based design. Mol. Cell 68, 659–672 e659 (2017). · DOI
  30. Gavathiotis, E., Reyna, D. E., Davis, M. L., Bird, G. H. & Walensky, L. D. BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol. Cell 40, 481–492 (2010). · DOI · Paper page
  31. Reyna, D. E. et al. Direct activation of BAX by BTSA1 overcomes apoptosis resistance in acute myeloid leukemia. Cancer Cell 32, 490–505 e410 (2017). · DOI · Paper page
  32. Dengler, M. A. et al. BAX activation: mutations near its proposed non-canonical BH3 binding site reveal allosteric changes controlling mitochondrial association. Cell Rep. 27, 359–373 e356 (2019). · DOI
  33. Dewson, G. et al. Bak activation for apoptosis involves oligomerization of dimers via their α6 helices. Mol. Cell 36, 696–703 (2009). · DOI · Paper page
  34. Dewson, G. et al. To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions. Mol. Cell 30, 369–380 (2008). · DOI · Paper page
  35. Dewson, G. et al. Bax dimerizes via a symmetric BH3:groove interface during apoptosis. Cell Death Differ. 19, 661–670 (2012). · DOI · Paper page
  36. Subburaj, Y. et al. Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species. Nat. Commun. 6, 8042 (2015). · DOI · Paper page
  37. Bleicken, S. et al. Molecular details of Bax activation, oligomerization, and membrane insertion. J. Biol. Chem. 285, 6636–6647 (2010). · DOI · Paper page
  38. Gillies, L. A. et al. Visual and functional demonstration of growing Bax-induced pores in mitochondrial outer membranes. Mol. Biol. Cell 26, 339–349 (2015). · DOI
  39. Bleicken, S., Landeta, O., Landajuela, A., Basanez, G. & Garcia-Saez, A. J. Proapoptotic Bax and Bak proteins form stable protein-permeable pores of tunable size. J. Biol. Chem. 288, 33241–33252 (2013). · DOI
  40. Zheng, J. H. et al. Intrinsic instability of BOK enables membrane permeabilization in apoptosis. Cell Rep. 23, 2083–2094 e2086 (2018). · DOI
  41. Rogers, C. et al. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 10, 1689 (2019). · DOI · Paper page
  42. Rehm, M., Dussmann, H. & Prehn, J. H. Real-time single cell analysis of Smac/DIABLO release during apoptosis. J. Cell Biol. 162, 1031–1043 (2003). · DOI
  43. Lartigue, L. et al. An intracellular wave of cytochrome c propagates and precedes Bax redistribution during apoptosis. J. Cell Sci. 121, 3515–3523 (2008). · DOI
  44. Bhola, P. D., Mattheyses, A. L. & Simon, S. M. Spatial and temporal dynamics of mitochondrial membrane permeability waves during apoptosis. Biophys. J. 97, 2222–2231 (2009). · DOI
  45. Rehm, M. et al. Dynamics of outer mitochondrial membrane permeabilization during apoptosis. Cell Death Differ. 16, 613–623 (2009). · DOI
  46. Cheng, X. & Ferrell, J. E. Jr. Apoptosis propagates through the cytoplasm as trigger waves. Science 361, 607–612 (2018). · DOI · Paper page
  47. Garcia-Perez, C. et al. Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling. Proc. Natl Acad. Sci. USA 109, 4497–4502 (2012). · DOI
  48. Munoz-Pinedo, C. et al. Different mitochondrial intermembrane space proteins are released during apoptosis in a manner that is coordinately initiated but can vary in duration. Proc. Natl Acad. Sci. USA 103, 11573–11578 (2006). · DOI · Paper page
  49. Scorrano, L. et al. A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev. Cell 2, 55–67 (2002). · DOI · Paper page
  50. Yamaguchi, R. et al. Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol. Cell 31, 557–569 (2008). · DOI · Paper page
  51. van der Laan, M., Horvath, S. E. & Pfanner, N. Mitochondrial contact site and cristae organizing system. Curr. Opin. Cell Biol. 41, 33–42 (2016). · DOI · Paper page
  52. Prudent, J. et al. MAPL SUMOylation of Drp1 stabilizes an ER/mitochondrial platform required for cell death. Mol. Cell 59, 941–955 (2015). · DOI · Paper page
  53. Pernas, L. & Scorrano, L. Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu. Rev. Physiol. 78, 505–531 (2016). · DOI · Paper page
  54. Parone, P. A. et al. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol. Cell Biol 26, 7397–7408 (2006). · DOI · Paper page
  55. Estaquier, J. & Arnoult, D. Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis. Cell Death Differ. 14, 1086–1094 (2007). · DOI · Paper page
  56. Korwitz, A. et al. Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria. J. Cell Biol. 212, 157–166 (2016). · DOI
  57. Sun, M. G. et al. Correlated three-dimensional light and electron microscopy reveals transformation of mitochondria during apoptosis. Nat. Cell Biol. 9, 1057–1065 (2007). · DOI · Paper page
  58. Colell, A. et al. GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell 129, 983–997 (2007). · DOI · Paper page
  59. Tait, S. W. et al. Resistance to caspase-independent cell death requires persistence of intact mitochondria. Dev. Cell 18, 802–813 (2010). · DOI · Paper page
  60. Deshmukh, M. & Johnson, E. M. Jr. Evidence of a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c. Neuron 21, 695–705 (1998). · DOI · Paper page
  61. Martinou, I. et al. The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event. J. Cell Biol. 144, 883–889 (1999). · DOI · Paper page
  62. Gama, V. et al. The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells. Sci. Signal 7, ra67 (2014). · DOI
  63. Malladi, S., Challa-Malladi, M., Fearnhead, H. O. & Bratton, S. B. The Apaf-1*procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer. EMBO J. 28, 1916–1925 (2009). · DOI
  64. Kavanagh, E., Rodhe, J., Burguillos, M. A., Venero, J. L. & Joseph, B. Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia. Cell Death Dis. 5, e1565 (2014). · DOI
  65. Gonzalvez, F. et al. TRAF2 sets a threshold for extrinsic apoptosis by tagging caspase-8 with a ubiquitin shutoff timer. Mol. Cell 48, 888–899 (2012). · DOI · Paper page
  66. Weber, G. F. & Menko, A. S. The canonical intrinsic mitochondrial death pathway has a non-apoptotic role in signaling lens cell differentiation. J. Biol. Chem. 280, 22135–22145 (2005). · DOI
  67. Liu, X. et al. Caspase-3 promotes genetic instability and carcinogenesis. Mol. Cell 58, 284–296 (2015). · DOI · Paper page
  68. Lovric, M. M. & Hawkins, C. J. TRAIL treatment provokes mutations in surviving cells. Oncogene 29, 5048–5060 (2010). · DOI
  69. Miles, M. A. & Hawkins, C. J. Executioner caspases and CAD are essential for mutagenesis induced by TRAIL or vincristine. Cell Death Dis. 8, e3062 (2017). · DOI
  70. Cartwright, I. M., Liu, X., Zhou, M., Li, F. & Li, C. Y. Essential roles of caspase-3 in facilitating Myc-induced genetic instability and carcinogenesis. eLife 6, e26371 (2017). · DOI
  71. Gong, Y. N., Crawford, J. C., Heckmann, B. L. & Green, D. R. To the edge of cell death and back. FEBS J. 286, 430–440 (2019). · DOI
  72. McArthur, K. & Kile, B. T. Apoptotic caspases: multiple or mistaken identities? Trends Cell Biol. 28, 475–493 (2018). · DOI · Paper page
  73. Jiang, X. et al. A small molecule that protects the integrity of the electron transfer chain blocks the mitochondrial apoptotic pathway. Mol. Cell 63, 229–239 (2016). · DOI
  74. Martin, S. J., Henry, C. M. & Cullen, S. P. A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol. Cell 46, 387–397 (2012). · DOI · Paper page
  75. Green, D. R. Means to an end: apoptosis and other cell death mechanisms (Cold Spring Harbor Laboratory Press, 2010).
  76. Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014). · DOI · Paper page
  77. Riley, J. S. et al. Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO J. 37, e99238 (2018). · DOI · Paper page
  78. Ader, N. R. et al. Molecular and topological reorganizations in mitochondrial architecture interplay during Bax-mediated steps of apoptosis. eLife 8, e40712 (2019). Together with Riley et al. (2018) and McArthur et al. (2018), this article describes the formation of BAX/BAK-dependent macropores on the mitochondrial outer membrane leading to inner mitochondrial membrane extrusion and mtDNA release.
  79. Giampazolias, E. et al. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Nat. Cell Biol. 19, 1116–1129 (2017). This study shows that under caspase-inhibited conditions MOMP elicits anti-tumour immunity, thereby supporting the rationale for inhibiting apoptotic caspase function in cancer. · DOI · Paper page
  80. Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131, 682–693 (2007). · DOI · Paper page
  81. Verhagen, A. M. et al. Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs. Cell Death Differ. 14, 348–357 (2007). · DOI
  82. Zhuang, M., Guan, S., Wang, H., Burlingame, A. L. & Wells, J. A. Substrates of IAP ubiquitin ligases identified with a designed orthogonal E3 ligase, the NEDDylator. Mol. Cell 49, 273–282 (2013). · DOI
  83. Chauhan, D. et al. BAX/BAK-induced apoptosis results in caspase-8-dependent IL-1β maturation in macrophages. Cell Rep. 25, 2354–2368 e2355 (2018). · DOI
  84. Vince, J. E. et al. The mitochondrial apoptotic effectors BAX/BAK activate caspase-3 and -7 to trigger NLRP3 inflammasome and caspase-8 driven IL-1β activation. Cell Rep. 25, 2339–2353 e2334 (2018). · DOI · Paper page
  85. Tenev, T. et al. The ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol. Cell 43, 432–448 (2011). · DOI · Paper page
  86. Feoktistova, M. et al. cIAPs block ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol. Cell 43, 449–463 (2011). · DOI · Paper page
  87. Chen, K. W. et al. Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly. EMBO J. 38, e101638 (2019).
  88. Dhir, A. et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 560, 238–242 (2018). · DOI · Paper page
  89. Ning, X. et al. Apoptotic caspases suppress type I interferon production via the cleavage of cGAS, MAVS, and IRF3. Mol. Cell 74, 19–31 e17 (2019). · DOI · Paper page
  90. Arandjelovic, S. & Ravichandran, K. S. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16, 907–917 (2015). · DOI · Paper page
  91. Leonard, J. R., Klocke, B. J., D’Sa, C., Flavell, R. A. & Roth, K. A. Strain-dependent neurodevelopmental abnormalities in caspase-3-deficient mice. J. Neuropathol. Exp. Neurol. 61, 673–677 (2002). · DOI
  92. Honarpour, N. et al. Adult Apaf-1-deficient mice exhibit male infertility. Dev. Biol. 218, 248–258 (2000). · DOI · Paper page
  93. Liu, X. et al. PNPT1 release from mitochondria during apoptosis triggers decay of poly(A) RNAs. Cell 174, 187–201 e112 (2018). · DOI
  94. Lindqvist, L. M. et al. Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion. Cell Death Differ. 25, 782–794 (2018). · DOI
  95. Potts, M. B., Vaughn, A. E., McDonough, H., Patterson, C. & Deshmukh, M. Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP. J. Cell Biol. 171, 925–930 (2005). · DOI
  96. Potts, P. R., Singh, S., Knezek, M., Thompson, C. B. & Deshmukh, M. Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis. J. Cell Biol. 163, 789–799 (2003). · DOI
  97. King, K. R. et al. IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat. Med. 23, 1481–1487 (2017). · DOI · Paper page
  98. Thomas, R. L. et al. Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev. 27, 1365–1377 (2013). · DOI · Paper page
  99. Messmer, M. N., Snyder, A. G. & Oberst, A. Comparing the effects of different cell death programs in tumor progression and immunotherapy. Cell Death Differ. 26, 115–129 (2019). · DOI
  100. Yatim, N., Cullen, S. & Albert, M. L. Dying cells actively regulate adaptive immune responses. Nat. Rev. Immunol. 17, 262–275 (2017). · DOI · Paper page
  101. Kim, K. W., Moretti, L. & Lu, B. M867, a novel selective inhibitor of caspase-3 enhances cell death and extends tumor growth delay in irradiated lung cancer models. PLOS ONE 3, e2275 (2008).
  102. Werthmoller, N., Frey, B., Wunderlich, R., Fietkau, R. & Gaipl, U. S. Modulation of radiochemoimmunotherapy-induced B16 melanoma cell death by the pan-caspase inhibitor zVAD-fmk induces anti-tumor immunity in a HMGB1-, nucleotide- and T-cell-dependent manner. Cell Death Dis. 6, e1761 (2015). · DOI
  103. Xu, M. et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat. Med. 22, 1101–1107 (2016). · DOI · Paper page
  104. Weinlich, R., Oberst, A., Beere, H. M. & Green, D. R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 18, 127–136 (2017). · DOI · Paper page
  105. Schenk, B. & Fulda, S. Reactive oxygen species regulate Smac mimetic/TNFα-induced necroptotic signaling and cell death. Oncogene 34, 5796–5806 (2015). · DOI · Paper page
  106. Zhang, Y. et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat. Commun. 8, 14329 (2017).
  107. Yang, Z. et al. RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis. Nat. Cell Biol. 20, 186–197 (2018). · DOI · Paper page
  108. Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016). · DOI · Paper page
  109. Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015). Together with Kayagaki et al. (2015), this article demonstrates that caspase cleavage of gasdermin D causes plasma membrane permeabilization and pyroptosis. · DOI · Paper page
  110. de Vasconcelos, N. M., Van Opdenbosch, N., Van Gorp, H., Parthoens, E. & Lamkanfi, M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ. 26, 146–161 (2019). · DOI · Paper page
  111. Tsuchiya, K. et al. Caspase-1 initiates apoptosis in the absence of gasdermin D. Nat. Commun. 10, 2091 (2019). · DOI · Paper page
  112. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012). · DOI · Paper page
  113. Gaschler, M. M. et al. Determination of the subcellular localization and mechanism of action of ferrostatins in suppressing ferroptosis. ACS Chem. Biol. 13, 1013–1020 (2018). · DOI · Paper page
  114. Wang, Y. Q. et al. The protective role of mitochondrial ferritin on erastin-induced ferroptosis. Front. Aging Neurosci. 8, 308 (2016).
  115. Fang, X. X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019). · DOI · Paper page
  116. Ding, A. X. et al. CasExpress reveals widespread and diverse patterns of cell survival of caspase-3 activation during development in vivo. eLife 5, e10936 (2016).
  117. Garner, T. P. et al. Small-molecule allosteric inhibitors of BAX. Nat. Chem. Biol. 15, 322–330 (2019). · DOI
  118. Niu, X. et al. A small-molecule inhibitor of bax and bak oligomerization prevents genotoxic cell death and promotes neuroprotection. Cell Chem. Biol. 24, 493–506 e495 (2017). Together with Garner et al. (2019), this work describes the development of small-molecule BAX/BAK inhibitors that may serve as prototypes to develop therapeutic inhibitors of mitochondrial apoptosis. · DOI
  119. Llambi, F. et al. A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol. Cell 44, 517–531 (2011). · DOI · Paper page
  120. Pecot, J. et al. Tight sequestration of BH3 proteins by BCL-xL at subcellular membranes contributes to apoptotic resistance. Cell Rep. 17, 3347–3358 (2016). · DOI
  121. Liu, Q. et al. Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2. eLife 8, e37689 (2019).

Cited by

See all 2,450

Metadata

Authors
Bock, F. J., & Tait, S. W. G.
Venue
Nature Reviews Molecular Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2019-10-21
Volume
21
Issue
2
Pages
85-100
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
DOI
10.1038/s41580-019-0173-8
OpenAlex
W2980622391
Cited by
2,450
References
41
FWCI
13.79
Type
journal article
Language
en
Open access
green
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Mitochondria as multifaceted regulators of cell death. https://app.cochat.ai/papers/10.1038/s41580-019-0173-8
The paper
Bock, F. J., & Tait, S. W. G. (2020). Mitochondria as multifaceted regulators of cell death. Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-019-0173-8

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.