Organelle-specific initiation of cell death

Abstract

In a majority of pathophysiological settings, cell death is not accidental — it is controlled by a complex molecular apparatus. Such a system operates like a computer: it receives several inputs that inform on the current state of the cell and the extracellular microenvironment, integrates them and generates an output. Thus, depending on a network of signals generated at specific subcellular sites, cells can respond to stress by attemptinwg to recover homeostasis or by activating molecular cascades that lead to cell death by apoptosis or necrosis. Here, we discuss the mechanisms whereby cellular compartments — including the nucleus, mitochondria, plasma membrane, endoplasmic reticulum, Golgi apparatus, lysosomes, cytoskeleton and cytosol — sense homeostatic perturbations and translate them into a cell-death-initiating signal.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: General organization of organelle-specific responses to stress.
Figure 2: Major pathways of cell death initiation by the nucleus.
Figure 3: Major pathways of cell death initiation by the plasma membrane.
Figure 4: Major pathways of cell death initiation by lysosomes.

References

  1. 1

    Galluzzi, L. et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 19, 107–120 (2012).

  2. 2

    Kroemer, G. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16, 3–11 (2009).

  3. 3

    Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H. & Vandenabeele, P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat. Rev. Mol. Cell Biol. 15, 135–147 (2014).

  4. 4

    Elgendy, M., Sheridan, C., Brumatti, G. & Martin, S. J. Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol. Cell 42, 23–35 (2011).

  5. 5

    Kroemer, G., Galluzzi, L. & Brenner, C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99–163 (2007).

  6. 6

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

  7. 7

    Bouwman, P. & Jonkers, J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat. Rev. Cancer 12, 587–598 (2012).

  8. 8

    Vitale, I., Galluzzi, L., Castedo, M. & Kroemer, G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat. Rev. Mol. Cell Biol. 12, 385–392 (2011).

  9. 9

    Bieging, K. T. & Attardi, L. D. Deconstructing p53 transcriptional networks in tumor suppression. Trends Cell Biol. 22, 97–106 (2012).

  10. 10

    Chipuk, J. E. et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 1010–1014 (2004).

  11. 11

    Mihara, M. et al. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11, 577–590 (2003).

  12. 12

    Vaseva, A. V. et al. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149, 1536–1548 (2012).

  13. 13

    Cook, P. J. et al. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 458, 591–596 (2009).

  14. 14

    Chung, Y. M. et al. FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage. Nat. Commun. 3, 1000 (2012).

  15. 15

    Tibbetts, R. S. et al. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 13, 152–157 (1999).

  16. 16

    Sidi, S. et al. Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3. Cell 133, 864–877 (2008).

  17. 17

    Tinel, A. & Tschopp, J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304, 843–846 (2004).

  18. 18

    Lassus, P., Opitz-Araya, X. & Lazebnik, Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 297, 1352–1354 (2002).

  19. 19

    Manzl, C. et al. Caspase-2 activation in the absence of PIDDosome formation. J. Cell Biol. 185, 291–303 (2009).

  20. 20

    Tinel, A. et al. Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-κB pathway. EMBO J. 26, 197–208 (2007).

  21. 21

    Ando, K. et al. PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling. Mol. Cell 47, 681–693 (2012).

  22. 22

    Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H. & Poirier, G. G. PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer 10, 293–301 (2010).

  23. 23

    Kepp, O., Galluzzi, L., Lipinski, M., Yuan, J. & Kroemer, G. Cell death assays for drug discovery. Nat. Rev. Drug Discov. 10, 221–237 (2011).

  24. 24

    Schutze, S., Tchikov, V. & Schneider-Brachert, W. Regulation of TNFR1 and CD95 signalling by receptor compartmentalization. Nat. Rev. Mol. Cell Biol. 9, 655–662 (2008).

  25. 25

    Mehlen, P. & Bredesen, D. E. Dependence receptors: from basic research to drug development. Sci. Signal. 4, mr2 (2011).

  26. 26

    Jost, P. J. et al. XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460, 1035–1039 (2009).

  27. 27

    Yin, X. M. et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400, 886–891 (1999).

  28. 28

    Chen, L. et al. CD95 promotes tumour growth. Nature 465, 492–496 (2010).

  29. 29

    Bouwmeester, T. et al. A physical and functional map of the human TNF-α/NF-κB signal transduction pathway. Nat. Cell Biol. 6, 97–105 (2004).

  30. 30

    Wang, L., Du, F. & Wang, X. TNF-αinduces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).

  31. 31

    Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55–65 (2014).

  32. 32

    Guenebeaud, C. et al. The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. Mol. Cell 40, 863–876 (2010).

  33. 33

    Mille, F. et al. The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. Nat. Cell Biol. 11, 739–746 (2009).

  34. 34

    Delloye-Bourgeois, C. et al. Sonic Hedgehog promotes tumor cell survival by inhibiting CDON pro-apoptotic activity. PLoS Biol. 11, e1001623 (2013).

  35. 35

    Notomi, S. et al. Dynamic increase in extracellular ATP accelerates photoreceptor cell apoptosis via ligation of P2RX7 in subretinal hemorrhage. PLoS ONE 8, e53338 (2013).

  36. 36

    Agopyan, N., Head, J., Yu, S. & Simon, S. A. TRPV1 receptors mediate particulate matter-induced apoptosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L563–572 (2004).

  37. 37

    Pal, S., Hartnett, K. A., Nerbonne, J. M., Levitan, E. S. & Aizenman, E. Mediation of neuronal apoptosis by Kv2.1-encoded potassium channels. J. Neurosci. 23, 4798–4802 (2003).

  38. 38

    Staton, T. L. et al. Dampening of death pathways by schnurri-2 is essential for T-cell development. Nature 472, 105–109 (2011).

  39. 39

    Ahr, B., Robert-Hebmann, V., Devaux, C. & Biard-Piechaczyk, M. Apoptosis of uninfected cells induced by HIV envelope glycoproteins. Retrovirology 1, 12 (2004).

  40. 40

    Into, T. et al. Stimulation of human Toll-like receptor (TLR) 2 and TLR6 with membrane lipoproteins of Mycoplasma fermentans induces apoptotic cell death after NF-kappa B activation. Cell. Microbiol. 6, 187–199 (2004).

  41. 41

    Voisin, T., El Firar, A., Rouyer-Fessard, C., Gratio, V. & Laburthe, M. A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism. FASEB J. 22, 1993–2002 (2008).

  42. 42

    Lappano, R. & Maggiolini, M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat. Rev. Drug Discov. 10, 47–60 (2011).

  43. 43

    Tait, S. W. et al. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep. 5, 878–885 (2013).

  44. 44

    Galluzzi, L., Kepp, O. & Kroemer, G. Mitochondria: master regulators of danger signalling. Nat. Rev. Mol. Cell Biol. 13, 780–788 (2012).

  45. 45

    Weinmann, M. et al. Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner. Oncogene 23, 3757–3769 (2004).

  46. 46

    Sermeus, A. et al. Hypoxia-induced modulation of apoptosis and BCL-2 family proteins in different cancer cell types. PLoS ONE 7, e47519 (2012).

  47. 47

    Sherer, T. B. et al. Mechanism of toxicity in rotenone models of Parkinson's disease. J. Neurosci. 23, 10756–10764 (2003).

  48. 48

    Montero, J., Dutta, C., van Bodegom, D., Weinstock, D. & Letai, A. p53 regulates a non-apoptotic death induced by ROS. Cell Death Differ. 20, 1465–1474 (2013).

  49. 49

    Haynes, C. M. & Ron, D. The mitochondrial UPR - protecting organelle protein homeostasis. J. Cell Sci. 123, 3849–3855 (2010).

  50. 50

    Tabas, I. & Ron, D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat. Cell Biol. 13, 184–190 (2011).

  51. 51

    Nargund, A. M., Pellegrino, M. W., Fiorese, C. J., Baker, B. M. & Haynes, C. M. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587–590 (2012).

  52. 52

    Rowland, A. A. & Voeltz, G. K. Endoplasmic reticulum–mitochondria contacts: function of the junction. Nat. Rev. Mol. Cell Biol. 13, 607–625 (2012).

  53. 53

    Besch, R. et al. Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. J. Clin. Invest. 119, 2399–2411 (2009).

  54. 54

    Ishibashi, O. et al. Short RNA duplexes elicit RIG-I-mediated apoptosis in a cell type- and length-dependent manner. Sci. Signal. 4, ra74 (2011).

  55. 55

    El Maadidi, S. et al. A novel mitochondrial MAVS/caspase-8 platform links RNA virus-induced innate antiviral signaling to Bax/Bak-independent apoptosis. J. Immunol. 192, 1171–1183 (2014).

  56. 56

    Lei, Y. et al. MAVS-mediated apoptosis and its inhibition by viral proteins. PLoS ONE 4, e5466 (2009).

  57. 57

    Brandizzi, F. & Barlowe, C. Organization of the ER-Golgi interface for membrane traffic control. Nat. Rev. Mol. Cell Biol. 14, 382–392 (2013).

  58. 58

    Lane, J. D. et al. Caspase-mediated cleavage of the stacking protein GRASP65 is required for Golgi fragmentation during apoptosis. J. Cell Biol. 156, 495–509 (2002).

  59. 59

    Lafont, E. et al. Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL-triggered cell death. Cell Death Differ. 17, 642–654 (2010).

  60. 60

    How, P. C. & Shields, D. Tethering function of the caspase cleavage fragment of Golgi protein p115 promotes apoptosis via a p53-dependent pathway. J. Biol. Chem. 286, 8565–8576 (2011).

  61. 61

    Kepp, O. et al. Crosstalk between ER stress and immunogenic cell death. Cytokine Growth Factor Rev. 24, 311–318 (2013).

  62. 62

    Yamaguchi, H. & Wang, H. G. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem. 279, 45495–45502 (2004).

  63. 63

    Giorgi, C. et al. PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330, 1247–1251 (2010).

  64. 64

    Puthalakath, H. et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129, 1337–1349 (2007).

  65. 65

    Morishima, N., Nakanishi, K. & Nakano, A. Activating transcription factor-6 (ATF6) mediates apoptosis with reduction of myeloid cell leukemia sequence 1 (Mcl-1) protein via induction of WW domain binding protein 1. J. Biol. Chem. 286, 35227–35235 (2011).

  66. 66

    Nakagawa, T. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98–103 (2000).

  67. 67

    Nishitoh, H. et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 16, 1345–1355 (2002).

  68. 68

    Upton, J. P. et al. IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 338, 818–822 (2012).

  69. 69

    Sandow, J. J. et al. ER stress does not cause upregulation and activation of caspase-2 to initiate apoptosis. Cell Death Differ. 21, 475–480 (2013).

  70. 70

    Hetz, C. et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1α. Science 312, 572–576 (2006).

  71. 71

    Lisbona, F. et al. BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1α. Mol. Cell 33, 679–691 (2009).

  72. 72

    Boyce, M. et al. A selective inhibitor of eIF2α dephosphorylation protects cells from ER stress. Science 307, 935–939 (2005).

  73. 73

    Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481–490 (2013).

  74. 74

    Novoa, I., Zeng, H., Harding, H. P. & Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. J. Cell Biol. 153, 1011–1022 (2001).

  75. 75

    Burikhanov, R. et al. The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 138, 377–388 (2009).

  76. 76

    Austgen, K., Johnson, E. T., Park, T. J., Curran, T. & Oakes, S. A. The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress. Nat. Cell Biol. 14, 87–92 (2012).

  77. 77

    Kang, M. J., Chung, J. & Ryoo, H. D. CDK5 and MEKK1 mediate pro-apoptotic signalling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model. Nat. Cell Biol. 14, 409–415 (2012).

  78. 78

    Scorrano, L. et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300, 135–139 (2003).

  79. 79

    Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

  80. 80

    Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

  81. 81

    Petrasek, J. et al. STING–IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc. Natl Acad. Sci. USA 110, 16544–16549 (2013).

  82. 82

    Namba, T. et al. CDIP1–BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under endoplasmic reticulum stress. Cell Rep. 5, 331–339 (2013).

  83. 83

    De Maria, R. et al. Requirement for GD3 ganglioside in CD95- and ceramide-induced apoptosis. Science 277, 1652–1655 (1997).

  84. 84

    Cheng, J. P. et al. Caspase cleavage of the Golgi stacking factor GRASP65 is required for Fas/CD95-mediated apoptosis. Cell Death Dis. 1, e82 (2010).

  85. 85

    Bennett, M. et al. Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 282, 290–293 (1998).

  86. 86

    Dumitru, R. et al. Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis. Mol. Cell 46, 573–583 (2012).

  87. 87

    Tu, S. et al. In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Nat. Cell Biol. 8, 72–77 (2006).

  88. 88

    Tsai, F. M., Shyu, R. Y. & Jiang, S. Y. RIG1 suppresses Ras activation and induces cellular apoptosis at the Golgi apparatus. Cell. Signal. 19, 989–999 (2007).

  89. 89

    Nogueira, E. et al. SOK1 translocates from the Golgi to the nucleus upon chemical anoxia and induces apoptotic cell death. J. Biol. Chem. 283, 16248–16258 (2008).

  90. 90

    Zhou, J. et al. Serine 58 of 14-3-3zeta is a molecular switch regulating ASK1 and oxidant stress-induced cell death. Mol. Cell. Biol. 29, 4167–4176 (2009).

  91. 91

    Aits, S. & Jaattela, M. Lysosomal cell death at a glance. J. Cell Sci. 126, 1905–1912 (2013).

  92. 92

    Groth-Pedersen, L., Ostenfeld, M. S., Hoyer-Hansen, M., Nylandsted, J. & Jaattela, M. Vincristine induces dramatic lysosomal changes and sensitizes cancer cells to lysosome-destabilizing siramesine. Cancer Res. 67, 2217–2225 (2007).

  93. 93

    Zou, J. et al. Poly IC triggers a cathepsin D- and IPS-1-dependent pathway to enhance cytokine production and mediate dendritic cell necroptosis. Immunity 38, 717–728 (2013).

  94. 94

    Hwang, J. J., Lee, S. J., Kim, T. Y., Cho, J. H. & Koh, J. Y. Zinc and 4-hydroxy-2-nonenal mediate lysosomal membrane permeabilization induced by H2O2 in cultured hippocampal neurons. J. Neurosci. 28, 3114–3122 (2008).

  95. 95

    Crighton, D. et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121–134 (2006).

  96. 96

    Li, J. H. & Pober, J. S. The cathepsin B death pathway contributes to TNF plus IFN-γ-mediated human endothelial injury. J. Immunol. 175, 1858–1866 (2005).

  97. 97

    Broker, L. E. et al. Cathepsin B mediates caspase-independent cell death induced by microtubule stabilizing agents in non-small cell lung cancer cells. Cancer Res. 64, 27–30 (2004).

  98. 98

    Huang, W. C. et al. Glycogen synthase kinase-3β mediates endoplasmic reticulum stress-induced lysosomal apoptosis in leukemia. J. Pharmacol. Exp. Ther. 329, 524–531 (2009).

  99. 99

    Arnandis, T. et al. Calpains mediate epithelial-cell death during mammary gland involution: mitochondria and lysosomal destabilization. Cell Death Differ. 19, 1536–1548 (2012).

  100. 100

    Gyrd-Hansen, M. et al. Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. Mol. Cell. Biol. 26, 7880–7891 (2006).

  101. 101

    Boya, P. et al. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J. Exp. Med. 197, 1323–1334 (2003).

  102. 102

    Wille, A. et al. Cathepsin L is involved in cathepsin D processing and regulation of apoptosis in A549 human lung epithelial cells. Biol. Chem. 385, 665–670 (2004).

  103. 103

    Heinrich, M. et al. Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ. 11, 550–563 (2004).

  104. 104

    Droga-Mazovec, G. et al. Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues. J. Biol. Chem. 283, 19140–19150 (2008).

  105. 105

    Chaitanya, G. V., Steven, A. J. & Babu, P. P. PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun. Signal. 8, 31 (2010).

  106. 106

    Cuvillier, O. et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381, 800–803 (1996).

  107. 107

    Conus, S., Pop, C., Snipas, S. J., Salvesen, G. S. & Simon, H. U. Cathepsin D primes caspase-8 activation by multiple intra-chain proteolysis. J. Biol. Chem. 287, 21142–21151 (2012).

  108. 108

    Kurz, T., Gustafsson, B. & Brunk, U. T. Intralysosomal iron chelation protects against oxidative stress-induced cellular damage. FEBS J. 273, 3106–3117 (2006).

  109. 109

    Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

  110. 110

    Syntichaki, P., Xu, K., Driscoll, M. & Tavernarakis, N. Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans. Nature 419, 939–944 (2002).

  111. 111

    Wen, Y. D. et al. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy 4, 762–769 (2008).

  112. 112

    Yamashima, T. et al. Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates. Hippocampus 13, 791–800 (2003).

  113. 113

    Sahara, S. & Yamashima, T. Calpain-mediated Hsp70.1 cleavage in hippocampal CA1 neuronal death. Biochem. Biophys. Res. Commun. 393, 806–811 (2010).

  114. 114

    Luke, C. J. et al. An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury. Cell 130, 1108–1119 (2007).

  115. 115

    Kirkegaard, T. et al. Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. Nature 463, 549–553 (2010).

  116. 116

    Fehrenbacher, N. et al. Sensitization to the lysosomal cell death pathway by oncogene-induced down-regulation of lysosome-associated membrane proteins 1 and 2. Cancer Res. 68, 6623–6633 (2008).

  117. 117

    Appelqvist, H. et al. Attenuation of the lysosomal death pathway by lysosomal cholesterol accumulation. Am. J. Pathol. 178, 629–639 (2011).

  118. 118

    Zhao, M., Eaton, J. W. & Brunk, U. T. Protection against oxidant-mediated lysosomal rupture: a new anti-apoptotic activity of Bcl-2? FEBS Lett. 485, 104–108 (2000).

  119. 119

    Galluzzi, L., Blomgren, K. & Kroemer, G. Mitochondrial membrane permeabilization in neuronal injury. Nat. Rev. Neurosci. 10, 481–494 (2009).

  120. 120

    Kreuzaler, P. A. et al. Stat3 controls lysosomal-mediated cell death in vivo. Nat. Cell Biol. 13, 303–309 (2011).

  121. 121

    Fischer, U., Janicke, R. U. & Schulze-Osthoff, K. Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ. 10, 76–100 (2003).

  122. 122

    Rudel, T. & Bokoch, G. M. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science 276, 1571–1574 (1997).

  123. 123

    Vilas, G. L. et al. Posttranslational myristoylation of caspase-activated p21-activated protein kinase 2 (PAK2) potentiates late apoptotic events. Proc. Natl Acad. Sci. USA 103, 6542–6547 (2006).

  124. 124

    Moriceau, S. et al. Coronin-1 is associated with neutrophil survival and is cleaved during apoptosis: potential implication in neutrophils from cystic fibrosis patients. J. Immunol. 182, 7254–7263 (2009).

  125. 125

    Rovini, A., Savry, A., Braguer, D. & Carre, M. Microtubule-targeted agents: when mitochondria become essential to chemotherapy. Biochim. Biophys. Acta 1807, 679–688 (2011).

  126. 126

    Puthalakath, H., Huang, D. C., O'Reilly, L. A., King, S. M. & Strasser, A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell 3, 287–296 (1999).

  127. 127

    Puthalakath, H. et al. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293, 1829–1832 (2001).

  128. 128

    Li, R., Moudgil, T., Ross, H. J. & Hu, H. M. Apoptosis of non-small-cell lung cancer cell lines after paclitaxel treatment involves the BH3-only proapoptotic protein Bim. Cell Death Differ. 12, 292–303 (2005).

  129. 129

    Schmelzle, T. et al. Functional role and oncogene-regulated expression of the BH3-only factor Bmf in mammary epithelial anoikis and morphogenesis. Proc. Natl Acad. Sci. USA 104, 3787–3792 (2007).

  130. 130

    Pinto, V. I., Senini, V. W., Wang, Y., Kazembe, M. P. & McCulloch, C. A. Filamin A protects cells against force-induced apoptosis by stabilizing talin- and vinculin-containing cell adhesions. FASEB J. 28, 453–463 (2014).

  131. 131

    Raval, G. N. et al. Loss of expression of tropomyosin-1, a novel class II tumor suppressor that induces anoikis, in primary breast tumors. Oncogene 22, 6194–6203 (2003).

  132. 132

    Perez-Mancera, P. A. et al. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature 486, 266–270 (2012).

  133. 133

    Schwickart, M. et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463, 103–107 (2010).

  134. 134

    Lei, K. & Davis, R. J. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc. Natl Acad. Sci. USA 100, 2432–2437 (2003).

  135. 135

    VanBrocklin, M. W., Verhaegen, M., Soengas, M. S. & Holmen, S. L. Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res. 69, 1985–1994 (2009).

  136. 136

    Kuo, W. C., Yang, K. T., Hsieh, S. L. & Lai, M. Z. Ezrin is a negative regulator of death receptor-induced apoptosis. Oncogene 29, 1374–1383 (2010).

  137. 137

    Kirschnek, S. et al. Phagocytosis-induced apoptosis in macrophages is mediated by up-regulation and activation of the Bcl-2 homology domain 3-only protein Bim. J. Immunol. 174, 671–679 (2005).

  138. 138

    Giannakakou, P. et al. p53 is associated with cellular microtubules and is transported to the nucleus by dynein. Nat. Cell Biol. 2, 709–717 (2000).

  139. 139

    Posey, S. C. & Bierer, B. E. Actin stabilization by jasplakinolide enhances apoptosis induced by cytokine deprivation. J. Biol. Chem. 274, 4259–4265 (1999).

  140. 140

    Chua, B. T. et al. Mitochondrial translocation of cofilin is an early step in apoptosis induction. Nat. Cell Biol. 5, 1083–1089 (2003).

  141. 141

    Klamt, F. et al. Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin. Nat. Cell Biol. 11, 1241–1246 (2009).

  142. 142

    Wabnitz, G. H. et al. Mitochondrial translocation of oxidized cofilin induces caspase-independent necrotic-like programmed cell death of T cells. Cell Death Dis. 1, e58 (2010).

  143. 143

    Ferri, K. F. & Kroemer, G. Organelle-specific initiation of cell death pathways. Nat. Cell Biol. 3, E255–263 (2001).

  144. 144

    Schenck, A. et al. The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 133, 486–497 (2008).

  145. 145

    Kaiser, W. J. et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288, 31268–31279 (2013).

  146. 146

    Noack, J. et al. TLR9 agonists induced cell death in Burkitt's lymphoma cells is variable and influenced by TLR9 polymorphism. Cell Death Dis. 3, e323 (2012).

  147. 147

    Young, M. M. et al. Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J. Biol. Chem. 287, 12455–12468 (2012).

  148. 148

    Han, J. et al. A complex between Atg7 and caspase-9: a novel mechanism of cross-regulation between autophagy and apoptosis. J. Biol. Chem. 289, 6485–6497 (2013).

  149. 149

    Jin, Z. et al. Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 137, 721–735 (2009).

  150. 150

    Taylor, R. C., Cullen, S. P. & Martin, S. J. Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell Biol. 9, 231–241 (2008).

Download references

Acknowledgements

We apologise to the scientists working in this area for being unable to cite here the huge amount of top-quality literature dealing with the organelle-specific initiation of cell death. Authors are supported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; AXA Chair for Longevity Research; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).

Author information

L.G. and J.M.B-S.P contributed equally to this work. L.G. and G.K. jointly supervised this work.

Correspondence to Lorenzo Galluzzi or Guido Kroemer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Galluzzi, L., Bravo-San Pedro, J. & Kroemer, G. Organelle-specific initiation of cell death. Nat Cell Biol 16, 728–736 (2014). https://doi.org/10.1038/ncb3005

Download citation

Further reading