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Intracellular ATP Levels Determine Cell Death Fate by Apoptosis or Necrosis¹

Department of Medical Genetics, Biomedical Research Center, Osaka University Medical School, 2-2 Yamadaoka, Suita 565, Japan

Although apoptosis and necrosis are morphologically distinct manifestations of cell death, apoptosis and some necroses share common features in the death signaling pathway involving functional steps of death-driving interleukin 1ß-converting enzyme family proteases and anti-cell death protein Bcl-2. One evident physiological difference in cells undergoing apoptosis versus necrosis is in intracellular levels of ATP. In this study, we specifically addressed the question of whether apoptosis depends on intracellular ATP levels, since longer incubation under ATP-depleting conditions results in necrotic cell death. Incubation of cells in glucose-free medium with an inhibitor of mitochondrial F₀F₁-ATPases reduces intracellular ATP levels and completely blocks Fas/Apo-1-stimulated apoptosis. ATP supplied through glycolysis or oxidative phosphorylation restores the apoptotic cell death pathway. ATP depletion also leads to a block in Fas-induced activation of CPP32/Yama(-like) proteases, and when ATP is depleted after the activation of the proteases, subsequent apoptosis is significantly blocked. Thus, ATP-dependent steps exist both upstream and downstream of CPP32/Yama(-like) protease activation in apoptotic signal transduction. Treatment with the calcium ionophore induces apoptosis under ATP-supplying conditions but induces necrotic cell death under ATP-depleting conditions, indicating that ATP levels are a determinant of manifestation of cell death.

¹ This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas and for Center of Excellence Research from the Ministry of Education, Science and Culture, Japan.

² To whom requests for reprints should be addressed. Phone: 81-6-879-3360; Fax: 81-6-879-3369; E-mail: tsujimot@gene.med.osaka-u.ac.jp.

Received 1/13/97. Accepted 3/12/97.

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				S. Yang, H. Lin, and A. M. Diehl Fatty liver vulnerability to endotoxin-induced damage despite NF-{kappa}B induction and inhibited caspase 3 activation Am J Physiol Gastrointest Liver Physiol, August 1, 2001; 281(2): G382 - G392. [Abstract] [Full Text] [PDF]

				F. Ma, C. Zhang, K. V. S. Prasad, G. J. Freeman, and S. F. Schlossman Molecular cloning of Porimin, a novel cell surface receptor mediating oncotic cell death PNAS, July 24, 2001; (2001) 171322898. [Abstract] [Full Text] [PDF]

				M. Poppe, C. Reimertz, H. Du{beta}mann, A. J. Krohn, C. M. Luetjens, D. Bockelmann, A.-L. Nieminen, D. Kogel, and J. H. M. Prehn Dissipation of Potassium and Proton Gradients Inhibits Mitochondrial Hyperpolarization and Cytochrome c Release during Neural Apoptosis J. Neurosci., July 1, 2001; 21(13): 4551 - 4563. [Abstract] [Full Text] [PDF]

				L. Foghsgaard, D. Wissing, D. Mauch, U. Lademann, L. Bastholm, M. Boes, F. Elling, M. Leist, and M. Jaattela Cathepsin B Acts as a Dominant Execution Protease in Tumor Cell Apoptosis Induced by Tumor Necrosis Factor J. Cell Biol., May 28, 2001; 153(5): 999 - 1010. [Abstract] [Full Text] [PDF]

				N. J. Waterhouse, J. C. Goldstein, O. von Ahsen, M. Schuler, D. D. Newmeyer, and D. R. Green Cytochrome C Maintains Mitochondrial Transmembrane Potential and Atp Generation after Outer Mitochondrial Membrane Permeabilization during the Apoptotic Process J. Cell Biol., April 16, 2001; 153(2): 319 - 328. [Abstract] [Full Text] [PDF]

				A. Hartmann, J.-D. Troadec, S. Hunot, K. Kikly, B. A. Faucheux, A. Mouatt-Prigent, M. Ruberg, Y. Agid, and E. C. Hirsch Caspase-8 Is an Effector in Apoptotic Death of Dopaminergic Neurons in Parkinson's Disease, But Pathway Inhibition Results in Neuronal Necrosis J. Neurosci., April 1, 2001; 21(7): 2247 - 2255. [Abstract] [Full Text] [PDF]

				N. Sasaki, T. Sato, E. Marban, and B. O'Rourke ATP consumption by uncoupled mitochondria activates sarcolemmal KATP channels in cardiac myocytes Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1882 - H1888. [Abstract] [Full Text] [PDF]

				J. Yang, R. Gross, S. Basinger, and S. Wu Apoptotic cell death of cultured salamander photoreceptors induced by cccp: CsA-insensitive mitochondrial permeability transition J. Cell Sci., January 5, 2001; 114(9): 1655 - 1664. [Abstract] [PDF]

				X. Lu, J. Errington, V. J. Chen, N. J. Curtin, A. V. Boddy, and D. R. Newell Cellular ATP Depletion by LY309887 as a Predictor of Growth Inhibition in Human Tumor Cell Lines Clin. Cancer Res., January 1, 2001; 6(1): 271 - 277. [Abstract] [Full Text]

				E. Katz, M. R. Deehan, S. Seatter, C. Lord, R. D. Sturrock, and M. M. Harnett B Cell Receptor-Stimulated Mitochondrial Phospholipase A2 Activation and Resultant Disruption of Mitochondrial Membrane Potential Correlate with the Induction of Apoptosis in WEHI-231 B Cells J. Immunol., January 1, 2001; 166(1): 137 - 147. [Abstract] [Full Text] [PDF]

				B. Beltran, A. Mathur, M. R. Duchen, J. D. Erusalimsky, and S. Moncada The effect of nitric oxide on cell respiration: A key to understanding its role in cell survival or death PNAS, December 19, 2000; 97(26): 14602 - 14607. [Abstract] [Full Text] [PDF]

				H. Matsumura, Y. Shimizu, Y. Ohsawa, A. Kawahara, Y. Uchiyama, and S. Nagata Necrotic Death Pathway in FAS Receptor Signaling J. Cell Biol., December 11, 2000; 151(6): 1247 - 1256. [Abstract] [Full Text] [PDF]

				D. S. Martin, J. R. Bertino, and J. A. Koutcher ATP Depletion + Pyrimidine Depletion Can Markedly Enhance Cancer Therapy: Fresh Insight for a New Approach Cancer Res., December 1, 2000; 60(24): 6776 - 6783. [Full Text]

				K. Fettucciari, E. Rosati, L. Scaringi, P. Cornacchione, G. Migliorati, R. Sabatini, I. Fetriconi, R. Rossi, and P. Marconi Group B Streptococcus Induces Apoptosis in Macrophages J. Immunol., October 1, 2000; 165(7): 3923 - 3933. [Abstract] [Full Text] [PDF]

				A. R. Pettitt, P. D. Sherrington, and J. C. Cawley Role of Poly(ADP-ribosyl)ation in the Killing of Chronic Lymphocytic Leukemia Cells by Purine Analogues Cancer Res., August 1, 2000; 60(15): 4187 - 4193. [Abstract] [Full Text]

				A. J. Williams, J. R. Dave, J. B. Phillips, Y. Lin, R. T. McCabe, and F. C. Tortella Neuroprotective Efficacy and Therapeutic Window of the High-Affinity N-Methyl-D-aspartate Antagonist Conantokin-G: In Vitro (Primary Cerebellar Neurons) and In Vivo (Rat Model of Transient Focal Brain Ischemia) Studies J. Pharmacol. Exp. Ther., July 1, 2000; 294(1): 378 - 386. [Abstract] [Full Text]

				E. Shacter, J. A. Williams, R. M. Hinson, S. Senturker, and Y.-j. Lee Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis Blood, July 1, 2000; 96(1): 307 - 313. [Abstract] [Full Text] [PDF]

				U. A. Hirt, F. Gantner, and M. Leist Phagocytosis of Nonapoptotic Cells Dying by Caspase- Independent Mechanisms J. Immunol., June 15, 2000; 164(12): 6520 - 6529. [Abstract] [Full Text] [PDF]

				P. M. Kang and S. Izumo Apoptosis and Heart Failure : A Critical Review of the Literature Circ. Res., June 9, 2000; 86(11): 1107 - 1113. [Full Text] [PDF]

				M. Latta, G. Kunstle, M. Leist, and A. Wendel Metabolic Depletion of Atp by Fructose Inversely Controls Cd95- and Tumor Necrosis Factor Receptor 1-Mediated Hepatic Apoptosis J. Exp. Med., June 5, 2000; 191(11): 1975 - 1986. [Abstract] [Full Text] [PDF]

				L. Liu, J. R. Trimarchi, and D. L. Keefe Involvement of Mitochondria in Oxidative Stress-Induced Cell Death in Mouse Zygotes Biol Reprod, June 1, 2000; 62(6): 1745 - 1753. [Abstract] [Full Text]

				E. DAUGAS, S. A. SUSIN, N. ZAMZAMI, K. F. FERRI, T. IRINOPOULOU, N. LAROCHETTE, M.-C. PRÉVOST, B. LEBER, D. ANDREWS, J. PENNINGER, et al. Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis FASEB J, April 1, 2000; 14(5): 729 - 739. [Abstract] [Full Text]