Review

Cell Death and Differentiation (2015) 22, 58–73; doi:10.1038/cdd.2014.137; published online 19 September 2014

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
Open

L Galluzzi1,2,3,126, J M Bravo-San Pedro1,2,4, I Vitale5, S A Aaronson6, J M Abrams7, D Adam8, E S Alnemri9, L Altucci10, D Andrews11, M Annicchiarico-Petruzzelli12, E H Baehrecke13, N G Bazan14, M J Bertrand15,16, K Bianchi17,18, M V Blagosklonny19, K Blomgren20, C Borner21, D E Bredesen22,23, C Brenner24,25,26, M Campanella27, E Candi28, F Cecconi29,30,31, F K Chan32, N S Chandel33, E H Cheng34, J E Chipuk6, J A Cidlowski35, A Ciechanover36, T M Dawson37,38, V L Dawson37,38, V De Laurenzi39, R De Maria5, K-M Debatin40, N Di Daniele41, V M Dixit42, B D Dynlacht43, W S El-Deiry44, G M Fimia45,46, R A Flavell47, S Fulda48, C Garrido49,50, M-L Gougeon51, D R Green52, H Gronemeyer53, G Hajnoczky54, J M Hardwick55, M O Hengartner56, H Ichijo57, B Joseph58, P J Jost59, T Kaufmann60, O Kepp2,4,61, D J Klionsky62, R A Knight63,64, S Kumar65,66, J J Lemasters67, B Levine68,69, A Linkermann70, S A Lipton71,72,73,74, R A Lockshin75, C López-Otín76, E Lugli77, F Madeo78, W Malorni79,80, J-C Marine81,82, S J Martin83, J-C Martinou84, J P Medema85, P Meier86, S Melino87, N Mizushima88, U Moll89, C Muñoz-Pinedo90, G Nuñez91, A Oberst92, T Panaretakis58, J M Penninger93, M E Peter94, M Piacentini30,46, P Pinton95, J H Prehn96, H Puthalakath97, G A Rabinovich98, K S Ravichandran99, R Rizzuto100, C M Rodrigues101, D C Rubinsztein102, T Rudel103, Y Shi104, H-U Simon105, B R Stockwell69,106, G Szabadkai100,107, S W Tait108,109, H L Tang55, N Tavernarakis110,111, Y Tsujimoto112, T Vanden Berghe15,16, P Vandenabeele15,16,113, A Villunger114, E F Wagner115, H Walczak116, E White117, W G Wood118,119, J Yuan120, Z Zakeri121,122, B Zhivotovsky123,124, G Melino28,64 and G Kroemer2,3,4,61,125

  1. 1Gustave Roussy Cancer Center, Villejuif, France
  2. 2Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
  3. 3Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
  4. 4INSERM, U1138, Gustave Roussy, Paris, France
  5. 5Regina Elena National Cancer Institute, Rome, Italy
  6. 6Department of Oncological Sciences, The Tisch Cancer Institute, Ichan School of Medicine at Mount Sinai, New York, NY, USA
  7. 7Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA
  8. 8Institute of Immunology, Christian-Albrechts University, Kiel, Germany
  9. 9Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
  10. 10Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, Napoli, Italy
  11. 11Department of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada
  12. 12Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata – Istituto Ricovero Cura Carattere Scientifico (IDI-IRCCS), Rome, Italy
  13. 13Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA
  14. 14Neuroscience Center of Excellence, School of Medicine, New Orleans, LA, USA
  15. 15VIB Inflammation Research Center, Ghent, Belgium
  16. 16Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
  17. 17Barts Cancer Institute, Cancer Research UK Centre of Excellence, London, UK
  18. 18Queen Mary University of London, John Vane Science Centre, London, UK
  19. 19Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
  20. 20Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
  21. 21Institute of Molecular Medicine and Spemann Graduate School of Biology and Medicine, Albert-Ludwigs University, Freiburg, Germany
  22. 22Buck Institute for Research on Aging, Novato, CA, USA
  23. 23Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA
  24. 24INSERM, UMRS769, Châtenay Malabry, France
  25. 25LabEx LERMIT, Châtenay Malabry, France
  26. 26Université Paris Sud/Paris XI, Orsay, France
  27. 27Department of Comparative Biomedical Sciences and Consortium for Mitochondrial Research, University College London (UCL), London, UK
  28. 28Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
  29. 29Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, Rome, Italy
  30. 30Department of Biology, University of Rome Tor Vergata; Rome, Italy
  31. 31Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark
  32. 32Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
  33. 33Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
  34. 34Human Oncology and Pathogenesis Program and Department of Pathology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA
  35. 35Laboratory of Signal Transduction, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health (NIH), North Carolina, NC, USA
  36. 36Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion Israel Institute of Technology, Haifa, Israel
  37. 37Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering (ICE), Departments of Neurology, Pharmacology and Molecular Sciences, Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  38. 38Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA
  39. 39Department of Experimental and Clinical Sciences, Gabriele d'Annunzio University, Chieti, Italy
  40. 40Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
  41. 41Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
  42. 42Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA
  43. 43Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, NY, USA
  44. 44Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, USA
  45. 45Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy
  46. 46Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases Lazzaro Spallanzani, Istituto Ricovero Cura Carattere Scientifico (IRCCS), Rome, Italy
  47. 47Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
  48. 48Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt, Germany
  49. 49INSERM, U866, Dijon, France
  50. 50Faculty of Medicine, University of Burgundy, Dijon, France
  51. 51Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Institut Pasteur, Paris, France
  52. 52Department of Immunology, St Jude’s Children’s Research Hospital, Memphis, TN, USA
  53. 53Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
  54. 54Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
  55. 55W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, MD, USA
  56. 56Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
  57. 57Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
  58. 58Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institute, Stockholm, Sweden
  59. 59Medical Department for Hematology, Technical University of Munich, Munich, Germany
  60. 60Institute of Pharmacology, Medical Faculty, University of Bern, Bern, Switzerland
  61. 61Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Villejuif, France
  62. 62Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
  63. 63Medical Molecular Biology Unit, Institute of Child Health, University College London (UCL), London, UK
  64. 64Medical Research Council Toxicology Unit, Leicester, UK
  65. 65Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
  66. 66School of Medicine and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia
  67. 67Departments of Drug Discovery and Biomedical Sciences and Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
  68. 68Center for Autophagy Research, University of Texas, Southwestern Medical Center, Dallas, TX, USA
  69. 69Howard Hughes Medical Institute (HHMI), Chevy Chase, MD, USA
  70. 70Division of Nephrology and Hypertension, Christian-Albrechts University, Kiel, Germany
  71. 71The Scripps Research Institute, La Jolla, CA, USA
  72. 72Sanford-Burnham Center for Neuroscience, Aging, and Stem Cell Research, La Jolla, CA, USA
  73. 73Salk Institute for Biological Studies, La Jolla, CA, USA
  74. 74University of California, San Diego (UCSD), San Diego, CA, USA
  75. 75Department of Biological Sciences, St. John’s University, Queens, NY, USA
  76. 76Department of Biochemistry and Molecular Biology, Faculty of Medecine, Instituto Universitario de Oncología (IUOPA), University of Oviedo, Oviedo, Spain
  77. 77Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy
  78. 78Institute of Molecular Biosciences, University of Graz, Graz, Austria
  79. 79Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanita (ISS), Roma, Italy
  80. 80San Raffaele Institute, Sulmona, Italy
  81. 81Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, Leuven, Belgium
  82. 82Laboratory for Molecular Cancer Biology, Center of Human Genetics, Leuven, Belgium
  83. 83Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland
  84. 84Department of Cell Biology, University of Geneva, Geneva, Switzerland
  85. 85Laboratory for Experiments Oncology and Radiobiology (LEXOR), Academic Medical Center (AMC), Amsterdam, The Netherlands
  86. 86Institute of Cancer Research, The Breakthrough Toby Robins Breast Cancer Research Centre, London, UK
  87. 87Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy
  88. 88Graduate School and Faculty of Medicine, University of Tokyo, Tokyo, Japan
  89. 89Department of Pathology, Stony Brook University, Stony Brook, NY, USA
  90. 90Cell Death Regulation Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
  91. 91Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
  92. 92Department of Immunology, University of Washington, Seattle, WA, USA
  93. 93Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
  94. 94Department of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
  95. 95Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara, Italy
  96. 96Department of Physiology and Medical Physics, Royal College of Surgeons, Dublin, Ireland
  97. 97Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University, Melbourne, Australia
  98. 98Laboratory of Immunopathology, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
  99. 99Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA
  100. 100Department Biomedical Sciences, University of Padova, Padova, Italy
  101. 101Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
  102. 102Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK
  103. 103Department of Microbiology, University of Würzburg; Würzburg, Germany
  104. 104Soochow Institute for Translational Medicine, Soochow University, Suzhou, China
  105. 105Institute of Pharmacology, University of Bern, Bern, Switzerland
  106. 106Departments of Biological Sciences and Chemistry, Columbia University, New York, NY, USA
  107. 107Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, University College London (UCL), London, UK
  108. 108Cancer Research UK Beatson Institute, Glasgow, UK
  109. 109Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
  110. 110Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece
  111. 111Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
  112. 112Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
  113. 113Methusalem Program, Ghent University, Ghent, Belgium
  114. 114Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria
  115. 115Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  116. 116Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London (UCL), London, UK
  117. 117Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
  118. 118Department of Pharmacology, University of Minnesota School of Medicine, Minneapolis, MN, USA
  119. 119Geriatric Research, Education and Clinical Center, VA Medical Center, Minneapolis, MN, USA
  120. 120Department of Cell Biology, Harvard Medical School, Boston, MA, USA
  121. 121Department of Biology, Queens College, Queens, NY, USA
  122. 122Graduate Center, City University of New York (CUNY), Queens, NY, USA
  123. 123Division of Toxicology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
  124. 124Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia
  125. 125Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.

Correspondence: L Galluzzi or G Kroemer, Equipe 11 - ‘Apoptose, cancer et immunité’, Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine, 75006 Paris, France. Tel: +33 1 4427 7661 or +33 1 4427 7667; Fax: +33 1 4427 7674; E-mail: deadoc@vodafone.it or kroemer@orange.fr

126Share senior co-authorship.

Received 23 July 2014; Accepted 30 July 2014
Advance online publication 19 September 2014

Edited by A Stephanou

Top

Abstract

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Abbreviations:

ACD, accidental cell death; APAF1, apoptotic peptidase-activating factor 1; BAX, BCL2-associated X protein; BAK1, BCL2-antagonist/killer 1; BCL2, B-cell CLL/lymphoma 2; BID, BH3-interacting domain death agonist; BIRC, baculoviral IAP repeat containing; CASP3, caspase-3; CASP8, caspase-8; CASP9, caspase-9; CYPD, cyclophilin D; DAMP, damage-associated molecular pattern; FADD, Fas (TNFRSF6)-associated via death domain; GPX4, glutathione peroxidase 4; MLKL, mixed lineage kinase domain-like; MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition; NCCD, Nomenclature Committee on Cell Death; Nec-1, necrostatin 1; PARP1, poly(ADP-ribose) polymerase 1; PCD, programmed cell death; PPIF, peptidylprolyl isomerase F; PTPC, permeability transition pore complex; Q-VD-OPh, (3S)-5-(2,6-difluorophenoxy)-3-[[(2S)-3-methyl-1-oxo-2-[(2-quinolinylcarbonyl)amino]butyl]amino]-4-oxo-pentanoic acid hydrate; RCD, regulated cell death; RIPK1, receptor-interacting protein kinase 1; RIPK3, receptor-interacting protein kinase 3; SMAC, second mitochondria-derived activator of caspases; TAK1, TGFβ-activated kinase 1; TLR, Toll-like receptor; TNFR1, tumor necrosis factor receptor 1; XIAP, X-linked inhibitor of apoptosis; Z-VAD-fmk, N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethylketone