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(The FASEB Journal. 2005;19:1783-1788.)
© 2005 FASEB

"Simple but not simpler": toward a unified picture of energy requirements in cell death

Alberto Chiarugi1

Department of Pharmacology, University of Florence, Florence, Italy

1 Correspondence: Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy. E-mail: alberto.chiarugi{at}unifi.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 ENERGY-DEPENDENT STEPS IN...
 ENERGY-INDEPENDENT PATHWAYS IN...
 NECROSIS: NOT JUST A...
 CONCLUDING REMARKS
 REFERENCES
 
In 1996, Wang and his group empirically disclosed a key role of (deoxy)-ATP in functioning of the apoptotic machinery. After almost a decade, and despite the emerged intricacy of the death pathways, ATP is still considered a key determinant of apoptosis with no apparent active roles in necrosis. Yet recent findings indicate that apoptosis proceeds even without energy and that necrosis can be regulated by ATP-dependent processes. This review strictly focuses on current knowledge on the role of energy in execution of different death programs. A thorough understanding of energy requirements in cell death can help to overcome obsolete dogmas in cell biology, paving the way to a more integrated, albeit not simpler, view of the molecular mechanisms contributing to cell dismantling.—Chiarugi, A. "Simple but not simpler": toward a unified picture of energy requirements in cell death.


Key Words: necrosis • ATP • apoptosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
ENERGY-DEPENDENT STEPS IN...
 ENERGY-INDEPENDENT PATHWAYS IN...
 NECROSIS: NOT JUST A...
 CONCLUDING REMARKS
 REFERENCES
 
DURING THE LAST DECADE, the taxonomy of cell death has been substantially modified, and the concept that cells simply die by apoptosis or necrosis (1) now appears oversimplified. In fact, the identification of oncosis, aponecrosis, and autophagic death (2 3 4 5) led to a more complex and integrated scenario of cell demise, shedding doubts on the functional opposition between necrosis and apoptosis. Findings by different research groups converge to identify a continuum of different forms of cell death that share common molecular pathways and are comprised between the two extremes of necrosis and apoptosis (6) . A widely accepted dogma in cell biology is that an adequate energy availability is a prerequisite for the cell to activate the apoptotic program. Inevitably, the universality of this tenet has recently been challenged.

An update on the role of energy requirements in cell death will be provided here, with particular emphasis on the molecular mechanisms through which different bioenergetic states activate selective cell death subroutines. As shown in Fig. 1 , besides the classic ATP-dependent apoptosis, an energy-independent apoptotic apparatus along with its molecular mediators has been identified. Recent discoveries suggest that necrosis in not invariantly a passive cellular collapse, being certain necrotic programs driven by energy-dependent mechanisms. These concepts will be delineated below and are summarized in Fig. 1 , where a classification of cell death based on energy requirements is proposed. Of course, energy production as well as metabolism of ADP, AMP, and its breakdown products (IMP, adenosine and inosine) also represent key regulatory steps in commitment to a particular type of cell death. Intentionally, however, this review strictly focuses on energy requirements rather than production or availability during cell death.



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  		Figure 1. Classification of cell death based on energy requirements. Apoptosis and necrosis are two extremes of a continuum of apoptotic- and necrotic-like modes of cell death. Both energy-dependent and -independent cell death can be apoptotic or necrotic. The underlying mechanisms or specific triggers are shown. AIF, apoptosis-inducing factor; Endo G, endonuclease G; PMCA, plasma membrane Ca2+ pump; NCX, Na+/Ca2+ exchanger; PARP-1, poly(ADP-ribose) polymerase-1; RIP, receptor interacting protein. See text for further details.


   ENERGY-DEPENDENT STEPS IN APOPTOSIS
TOP
 ABSTRACT
 INTRODUCTION
 ENERGY-DEPENDENT STEPS IN...
ENERGY-INDEPENDENT PATHWAYS IN...
 NECROSIS: NOT JUST A...
 CONCLUDING REMARKS
 REFERENCES
 
In their 1997 review, Kerr and colleagues hypothesized that cellular bioenergetics participates in determining the specific death program a given cell undergoes (7) . Subsequently, based on findings in cultured neuronal cells, Ankarcrona and associates postulated that under conditions of energy depletion the "default" apoptotic program cannot be executed and necrosis occurs (8) . Shortly thereafter, this hypothesis was confirmed with the identification of ATP as a key component of the apoptosome [the complex formed by apoptotic protease-activating factor (Apaf)-1, cytochrome c, and procaspase-9]. Specifically, Wang and his group showed that a prerequisite for purified cytochrome c and Apaf-1 to proteolytically activate procaspase-9 is the addition of deoxy-ATP (dATP) or ATP at micromolar or millimolar concentrations, respectively (9 , 10) . Considering that these are physiological intracellular concentrations of the two nucleotides (11) , these findings first indicated that both ATP and dATP are key regulators of the apoptotic machinery (Fig. 2 ). Further work demonstrated that the concentration of ATP necessary to activate the apoptosome in vitro changes according to the cell type and death stimulus (12 13 14 15) . The underlying molecular mechanisms however remained to be established.



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  		Figure 2. ATP-dependent steps of the extrinsic and intrinsic apoptotic pathways. The extrinsic apoptotic pathway is triggered by death receptor activation, which causes assembly of death-inducing signaling complex (DISC) and ensuing processing of procaspase-8. The latter activates executioner caspases -2, -3, and -7, which in turn activate caspase-9 and the caspase-activated DNase (CAD) by inactivating its constitutive inhibitor (ICAD). Caspase-8 can prompt the intrinsic apoptotic pathway through Bid cleavage. Executioner caspases also process other substrates causally involved in apoptosis. Caspases and other apoptotic mediators including CAD migrate into the nucleus through ATP-dependent active transport. The intrinsic apoptotic pathway is mainly activated by migration of the BH3-only proteins BAX and BAK onto mitochondria. This causes release of proapoptotic factors such as cytochrome c (Cyt c) and apoptosis-inducing factor (AIF). Depending on the cell type, each of these two factors can promote release of the other. Endonuclease G (Endo G) is a mitochondrial nuclease released during apoptosis but of unclear relevance to cell death (see text). Cytochrome c, together with apoptosis activating factor (Apaf)-1, procaspase-9 (PC-9), and ATP/deoxy-ATP [(d)ATP] form the apoptosome, which facilitates caspase-9 autoprocessing and ensuing activation of the caspase cascade. See ref 23 for information on the oligomeric state of procaspase-9 on the apoptosome. AIF and endonuclease G are mediators of the ATP-independent intrinsic apoptotic pathway (dotted lines). The role of ATP in activation of protein kinases involved in apoptosis is shown (see text for further details).

Several studies suggested that ATP binding to Apaf-1 and subsequent hydrolysis are required for procaspase-9 activation (10 , 16 , 17) . The functional significance of Apaf-1/ATP interaction was also supported by evidence that mutations in the nucleotide binding P-loop of Apaf-1 impair activation of the caspase cascade (17 18 19 20) . However, the finding that Apaf-1 lacking the WD40 repeats at the C terminus (Apaf-530) is insensitive to mutations at the P-loop and capable of activating procaspase-9 in a dATP-independent manner (10) suggested that the role of ATP in caspase processing by Apaf-1 is more complex. Later on, the elegant study by Hu and co-workers provided compelling evidence that energy released by (d)ATP prompts conformational change and oligomerization of Apaf-1, and procaspase-9 activation within 30 s (21) . Yet, although it was known that Apaf-1 bears the key elements of ATPases (i.e., the P-loop and the Walker B motif), the question as to whether Apaf-1 is a bona fide ATPase waited to be answered. Eventually, very recent unambiguous results have provided evidence that Apaf-1 transforms ATP into ADP. Riedl and colleagues report that addition of (d)ATP to a mixture containing purified WD40(1-591)-deleted Apaf-1 and procaspase-9 leads to caspase activation and ADP production. The authors demonstrate that a molecule of ADP is constitutively buried inside Apaf-1 and adjoins four different domains of the protein to fold it into an inactive state. The caspase recruitment domain (CARD) of Apaf-1 blocks the narrow channel separating the nucleotide from the solvent. On this basis, Riedl et al. propose that energy released from ATP hydrolysis is used to break the weak interactions among the four domains of Apaf-1 (22) . This in turn should induce a conformational change of Apaf-1 allowing its oligomerization into an heptameric structure (23) . Although the information provided by Riedl and associates significantly furthers our understanding of the role of ATP in Apaf-1 functioning, it remains to be established how ATP reaches the Apaf-1 nucleotide binding pocket and, importantly, through which mechanisms the heptameric apoptosome dissolves into ADP-containing monomeric Apaf-1. Another important issue waiting to be fully addressed is whether the synthesis of dATP can regulate the apoptotic process. The main limiting step in dATP formation is the activity of ribonucleotide reductase, the enzyme responsible for the neo-synthesis of the DNA precursors deoxyribonucleotides. Intriguingly, the recent finding that dAMP-dibuthylester increases intracellular contents of dADP and prompts apoptosis in HL-60 cells (24) suggests that dATP contents and/or compartmentalization are strictly regulated by the cell.

Of note, staurosporine-dependent apoptosis of Jurkat T lymphocytes is inhibited when cells are cultured in a glucose-free medium and in the presence of oligomycin (an inhibitor of the mitochondrial F1Fo ATP synthase) (25) . This finding confirms the key role of ATP in execution of the intrinsic apoptotic pathway in intact cells (26) (Fig. 2) .

The extrinsic apoptotic pathway bypasses apoptosome activation by activating plasma membrane death receptors such as FAS or TNFR-1 (TNF{alpha} receptor-1). However, evidence that FAS-dependent apoptosis is impaired by ATP depletion (27) hints that ATP-dependent steps also regulate the extrinsic apoptotic pathway (Fig. 2) . It is likely that at least one of these steps is the ATP-driven intranuclear transport of cytoplasmic factors. Indeed, inhibitors of active nuclear import such as wheat germ agglutinin, p10 protein, anti-PTAC58 antibodies and the RAN-GTP{gamma}S complex block FAS-induced nuclear apoptosis (28) . Apoptosis of isolated nuclei exposed to cytoplasmic extracts from FAS-exposed Jurkat T cells requires addition of millimolar concentrations of ATP (29) . The finding that wheat germ agglutinin prevents apoptotic nuclear changes when coinjected with active caspase-3 (28) suggests that caspases themselves use the active nuclear import to translocate into the nucleus. This concept is strengthened by evidence for an ATP-dependent step downstream to caspase-3 activation (27) . Overall, data indicate that ATP regulates apoptosis at least at two main sites: one is the apoptosome-dependent caspase-9 activation, and the other is the nuclear import of apoptogenic mediators (Figs. 1 , 2) . Additional ATP-driven death effectors might be protein kinases, well known regulators of the apoptotic demise (30 31 32 33) .

Work by Nicotera and his group first showed that lack of energy impairs execution of the apoptotic program but does not prevent cell death. Indeed, classic apoptotic hallmarks such as nuclear condensation, DNA degradation and lamin cleavage do not occur in staurosporine-exposed cells when ATP is lacking, but cells eventually die by necrosis (34) . Cellular availability of ATP, therefore, appears a key determinant of the apoptosis-necrosis switch (14) . It is worth noting, however, that apoptosis switches into necrosis only if inhibition of ATP production occurs within 90 min after exposure to the apoptotic stimulus (34) . Similarly, in cells exposed to staurosporine and undergoing necrosis because of ATP depletion apoptosis can be rescued only if ATP production is restored within 120 min after the challenge (34) . It seems therefore that apoptosis needs ATP only early during execution of the death program. At later time points, commitment to apoptosis is irreversible, and ATP depletion cannot switch this cell death mode into necrosis anymore.

The amount of ATP necessary for the apoptotic program to keep on has not been clearly established. Given the bioenergetic differences existing among cells of different tissues, it is plausible that the quantitative aspects of ATP requirement in apoptosis vary depending on the specific experimental setting and cell type under investigation. Yet the finding that a 50% decrease of ATP contents is sufficient to impair staurosporine-induced cell death suggests that intracellular ATP must be in the millimolar range to fuel apoptosis (34) . In apparent contrast with this finding, however, the in vitro study by the Shi group shows that Apaf-1-dependent procaspase-9 activation is already maximal with ATP concentrations as low as 1µM (22) . If this finding will hold true in intact cells (which have ~1–3 mM free ATP), then it can be reasoned that inhibition of the apoptotic program because of ATP deficiency-dependent apoptosome dysfunction would be difficult to occur. Yet it has been unambiguously shown that ATP deficiency impairs execution of apoptosis (13 , 14) . On this basis, it can by hypothesized that processes showing lower affinity for ATP seem to be better candidates to regulate the apoptosis/necrosis switch. These considerations raise concerns on the pathophysiological significance of the ATP-dependent apoptosis/necrosis switch. The finding that nitric oxide (NO) transforms apoptosis into necrosis by impairing mitochondrial ATP generation (35) hints that inhibition of the energy-dependent apoptotic program may be of relevance to disorders characterized by excessive NO production.


   ENERGY-INDEPENDENT PATHWAYS IN APOPTOSIS
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 ABSTRACT
 INTRODUCTION
 ENERGY-DEPENDENT STEPS IN...
 ENERGY-INDEPENDENT PATHWAYS IN...
NECROSIS: NOT JUST A...
 CONCLUDING REMARKS
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It is widely accepted that apoptosis also occurs without caspase activation (36) . For instance, apoptosis is not abolished in C. elegans null for ced-3 (the worm homologue of caspase-3) (37) , and embryonic fibroblasts from Apaf-1 null mice undergo apoptosis even if unable to process caspase-2, -3, -6, and -7 (38) . Given that caspase activation is the main ATP-dependent step in the apoptotic program, these findings suggested that apoptosis is not invariantly energy dependent. Although the underlying molecular mechanisms are still elusive, evidence demonstrates that several mitochondrial proteins are released during caspase-independent apoptosis and actively participate in different steps of the cell death process (39) . Few studies, however, have carefully analyzed cellular energy dynamics during caspase-independent apoptosis. Specifically, studies by the Kroemer group show that ATP is dispensable for apoptosis-inducing factor (AIF)-dependent chromatin condensation (40) and large-scale DNA fragmentation (41) . Even though cell death triggered by AIF differs from classical apoptosis, biochemical and morphological analysis points to AIF as a powerful inducer of cell death showing apoptotic-like features (42 43 44) . Further substantiating the notion that AIF works in an ATP-independent manner, recent findings show a causative role of AIF in cell death triggered by poly(ADP-ribose) polymerase (PARP)-1. PARP-1 is a nuclear enzyme involved in DNA repair but causing ATP depletion and cell death when overactivated (45) . Although PARP-1-dependent cell death is mainly necrotic, and PARP-1 is a preferred caspase substrates (see below), a key role of PARP-1 in apoptosis has emerged (43 , 46 , 47) . In particular, PARP-1 hyperactivity triggers mitochondrial release of AIF and apoptosis in different cells such as fibroblasts, neurons, astrocytes, and HeLa (48 49 50 51) . However, energy dynamics in cells undergoing PARP-1-dependent apoptosis remained to be established. We very recently reported that PARP-1 hyperactivation triggers a specific apoptotic program in cells lacking ATP. Biophysical and biochemical analysis reveals that upon PARP-1 activation massive ATP depletion rapidly occurs (15–30 min), and persists when apoptotic hallmarks such as AIF release, nuclear fragmentation, and phosphatidylserine exposure take place. Of note, under these conditions caspases are not activated (51) . The slow progression of this PARP-1-dependent death process (8–12 h) (51) , is in line with the notion that caspase-independent cell demise is a long-lasting process compared with that brought about by apoptosome activation (52) . Another proapoptotic protein released from mitochondria during apoptosis is endonuclease G. Although its ability to induce caspase-independent DNA fragmentation has been reported (53) , its relevance to genome digestion in cells undergoing apoptosis is uncertain, and has been recently challenged by evidence of normal nuclear apoptosis in endonuclease G null mice (54) . Energy dynamics in endonuclease G-dependent cell death still wait to be investigated. Overall, the statement that the mitochondrial apoptotic pathway requires ATP is oversimplified. The current view is that the intrinsic route bifurcates at the postmitochondrial level, with a branch being ATP and caspase dependent and another independent of both (Fig. 2) .


   NECROSIS: NOT JUST A PASSIVE COLLAPSE
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 ABSTRACT
 INTRODUCTION
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 ENERGY-INDEPENDENT PATHWAYS IN...
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A long-standing tenet is that necrosis is an unregulated cell demise characterized by collapse of cellular structures because of generalized lysis of organelles and plasma membrane (55 , 56) . New findings, however, indicate that this is not always the case. For instance, in addition to the classic necrosis caused by intense physicochemical stimuli (1 , 8 , 55 , 57) , a necrotic demise resulting from failure of the apoptotic process to keep on because of energy depletion has been described. The finding that under these circumstances necrosis is unusually slow (34 , 35) suggests that this death mode can be somehow regulated. Accordingly, necrotic cell death occurs during physiological maintenance of human intestinal epithelium (58) and mouse embryo digit formation (59) . It is possible, therefore, that necrosis and apoptosis share initial common pathways, whereas specific death subroutines originate at the mitochondrial and postmitochondrial levels (14) . In agreement with this, mitochondria-interacting apoptotic mediators regulate necrotic cell death. For instance, the anti-apoptotic protein Bcl-2 prevents necrosis in various cells (60 61 62 63 64) whereas AIF release and AIF-induced DNA fragmentation take place during necrosis (41) . As further evidence that apoptotic and necrotic pathways have common upstream mediators, chemicophysical injuries can trigger apoptosis or necrosis depending on the intensity of insult (see Fig. 1 and refs 57 , 65 ). New data on cyclophilin D null cells suggest that mitochondrial permeability transition, widely considered a central event in apoptosis, is a key regulator of necrotic but not apoptotic demise (66 , 67) . As mentioned above, a key inducer of necrosis is PARP-1 (68 , 69) (Fig. 1) . Notably, cleavage of PARP-1 by caspase-3 or -7 prevents PARP-1-dependent energy consumption and maintains cellular ATP up to levels necessary to prevent necrotic collapse and fuel execution of the apoptotic program (70 , 71) . This can well be a regulatory step in PARP-1-depdendent necrosis. The latter has been also interpreted as an evolutionarily conserved necrotic program adopted by multicellular organisms to get rid of excessively DNA-damaged, potentially neoplastic cells (72) . The finding that Ca2+-dependent activation of calpains promotes rapid neuronal lysis due to cleavage of the plasma membrane Na+/Ca2+ exchanger (73) provides additional evidence that necrosis can be triggered by specific biochemical subroutines. To make the story more complicated, several reports hint that necrosis can be fuelled by energy. For instance, proteolysis of plasma membrane Ca2+ pump by caspases leads to excessive intracellular Ca2+ accumulation and neural cell necrosis (74) . Given that caspase activation is ATP-dependent, these findings imply that execution of particular types of necrosis requires energy at some steps. Consistently, ATP from glycolysis sustains DNA damage-induced necrotic death of lymphocytes (75) . Finally, additional evidence for ATP-driven programmed necrosis stems from findings showing that death receptor-dependent necrotic cell death of T lymphocytes (76) and fibroblasts (77) requires RIP1 kinase activity. Protein synthesis, a well known ATP-consuming process, is maintained in cells undergoing necrosis (78) . Overall, thanks to the advancement in knowledge on the links between apoptosis and necrosis, clues on specific "necrotic programs" and their reliance on energy availability are emerging. The central dogma that necrosis is always a passive process seems irreversibly mined.


   CONCLUDING REMARKS
TOP
 ABSTRACT
 INTRODUCTION
 ENERGY-DEPENDENT STEPS IN...
 ENERGY-INDEPENDENT PATHWAYS IN...
 NECROSIS: NOT JUST A...
 CONCLUDING REMARKS
REFERENCES
 
During the last decade, clues on the relationship between energy metabolism and cell demise have provided a picture of cell death programs more complex than previously envisaged. To date, the concepts that apoptosis always needs ATP, whereas necrosis is invariantly a disorganized cell collapse seem obsolete. The current understanding is that ATP availability is a key regulator of death machineries responsible for the execution of specific death subroutines interconnected at several levels. Despite the considerable advancement, however, several questions remain unsolved. For instance, a detailed analysis of ATP concentrations and intracellular compartmentalization in the different models of apoptosis is lacking. How much energy is used for apoptosis still waits to be unequivocally answered. Finally, whether and how low energy prompts the apoptotic machinery is in large part unknown (79) . Answering these questions will certainly help to have a deeper insight into mechanisms of cell death, and reach a unified picture of energy requirements during cell dismantling. This will also help to further blur the boundaries among the clear-cut categories of cell death that we have created so far, an inevitable consequence when initial ignorance in a specific field is overcome.

"Things must be as simple as possible, but not simpler ... ." A. Einstein


   FOOTNOTES
 
This review is dedicated to the memory of Alberto Giotti, leading figure in pharmacological sciences and mentor.


   REFERENCES
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 INTRODUCTION
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 ENERGY-INDEPENDENT PATHWAYS IN...
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 CONCLUDING REMARKS
 REFERENCES
 

  1. Kerr, J. F. (2002) History of the events leading to the formulation of the apoptosis concept. Toxicology 181,471-474
  2. Van Cruchten, S., Van den, B. W. (2002) Morphological and biochemical aspects of apoptosis, oncosis and necrosis. Anat. Histol. Embryol. 31,214-223[CrossRef][Medline]
  3. Formigli, L., Papucci, L., Tani, A., Schiavone, N., Tempestini, A., Orlandini, G. E., Capaccioli, S., Orlandini, S. Z. (2000) Aponecrosis: morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J. Cell. Physiol. 182,41-49[CrossRef][Medline]
  4. Cuervo, A. M. (2004) Autophagy: many paths to the same end. Mol. Cell. Biochem. 263,55-72[CrossRef][Medline]
  5. Lockshin, R. A., Zakeri, Z. (2004) Caspase-independent cell death?. Oncogene 23,2766-2773[CrossRef][Medline]
  6. Lockshin, R. A., Zakeri, Z. (2004) Apoptosis, autophagy, and more. Int. J. Biochem. Cell Biol. 36,2405-2419[CrossRef][Medline]
  7. Kerr, J. F., Wyllie, A. H., Currie, A. R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26,239-257[Medline]
  8. Ankarcrona, M., Dypbukt, J. M., Bonfoco, E., Zhivotovsky, B., Orrenius, O., Nicotera, P. (1995) Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15,961-973[CrossRef][Medline]
  9. Liu, X., Kim, C. N., Yang, J., Jemmerson, R., Wang, X. (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86,147-157[CrossRef][Medline]
  10. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., Wang, X. (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91,479-489[CrossRef][Medline]
  11. Skoog, L., Bjursell, G. (1974) Nuclear and cytoplasmic pools of deoxyribonucleoside triphosphates in Chinese hamster ovary cells. J. Biol. Chem. 249,6434-6438[Abstract/Free Full Text]
  12. Tsujimoto, Y. (1997) Apoptosis and necrosis: intracellular ATP level as a determinant for cell death modes. Cell Death Differ. 4,429-434
  13. Nicotera, P., Leist, M., Ferrando-May, E. (1998) Intracellular ATP, a switch in the decision between apoptosis and necrosis. Toxicol. Lett. 102–103,139-142
  14. Nicotera, P., Melino, G. (2004) Regulation of the apoptosis-necrosis switch. Oncogene 23,2757-2765[CrossRef][Medline]
  15. Cecconi, F. (1999) Apaf1 and the apoptotic machinery. Cell Death Differ. 6,1087-1098[CrossRef][Medline]
  16. Saleh, A., Srinivasula, S. M., Acharya, S., Fishel, R., Alnemri, E. S. (1999) Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase-9 activation. J. Biol. Chem. 274,17941-17945[Abstract/Free Full Text]
  17. Chinnaiyan, A. M., Chaudhary, D., O'Rourke, K., Koonin, E. V., Dixit, V. M. (1997) Role of CED-4 in the activation of CED-3. Nature (London) 388,728-729[CrossRef][Medline]
  18. Chinnaiyan, A. M., O'Rourke, K., Lane, B. R., Dixit, V. M. (1997) Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science 275,1122-1126[Abstract/Free Full Text]
  19. Seshagiri, S., Miller, L. K. (1997) Caenorhabditis elegans CED-4 stimulates CED-3 processing and CED-3-induced apoptosis. Curr. Biol. 7,455-460[CrossRef][Medline]
  20. James, C., Gschmeissner, S., Fraser, A., Evan, G. I. (1997) CED-4 induces chromatin condensation in Schizosaccharomyces pombe and is inhibited by direct physical association with CED-9. Curr. Biol. 7,246-252[CrossRef][Medline]
  21. Hu, Y., Benedict, M. A., Ding, L., Nunez, G. (1999) Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J. 18,3586-3595[CrossRef][Medline]
  22. Riedl, S. J., Li, W., Chao, W., Schwarzenbacher, R., Shi, Y. (2005) Structure of the apoptotic protease-activating factor 1 bound to ADP. Nature (London) 434,926-933[CrossRef][Medline]
  23. Acehan, D., Jiang, X., Morgan, D. G., Heuser, J. E., Wang, X., Akey, C. W. (2002) Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol. Cell 9,423-432[CrossRef][Medline]
  24. Katona, K., Herczegh, P., Kappelmayer, J., Fesus, L., Aradi, J. (2005) Deoxy-adenosine-monophosphate (dAMP) di-n-butylester induces apoptosis by increasing the dATP level in HL-60 cells. Cancer Lett. In press
  25. Ferrari, D., Stepczynska, A., Los, M., Wesselborg, S., Schulze-Osthoff, K. (1998) Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during. J. Exp. Med. 188,979-984[Abstract/Free Full Text]
  26. Eguchi, Y., Srinivasan, A., Tomaselli, K. J., Shimizu, S., Tsujimoto, Y. (1999) ATP-dependent steps in apoptotic signal transduction. Cancer Res. 59,2174-2181[Abstract/Free Full Text]
  27. Eguchi, Y., Shimizu, S., Tsujimoto, Y. (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res. 57,1835-1840[Abstract/Free Full Text]
  28. Yasuhara, N., Eguchi, Y., Tachibana, T., Imamoto, N., Yoneda, Y., Tsujimoto, Y. (1997) Essential role of active nuclear transport in apoptosis. Genes Cells 2,55-64[Abstract]
  29. Kass, G. E., Eriksson, J. E., Weis, M., Orrenius, S., Chow, S. C. (1996) Chromatin condensation during apoptosis requires ATP. Biochem. J. 318,749-752
  30. Shi, L., Nishioka, W. K., Th'ng, J., Bradbury, E. M., Litchfield, D. W., Greenberg, A. H. (1994) Premature p34cdc2 activation required for apoptosis. Science 263,1143-1145[Abstract/Free Full Text]
  31. O'Connell, M. J., Norbury, C., Nurse, P. (1994) Premature chromatin condensation upon accumulation of NIMA. EMBO J. 13,4926-4937[Medline]
  32. Kyriakis, J. M. (2001) Life-or-death decisions. Nature (London) 414,265-266[CrossRef][Medline]
  33. Kyriakis, J. M., Avruch, J. (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81,807-869[Abstract/Free Full Text]
  34. Leist, M., Single, B., Castoldi, A. F., Kuhnle, S., Nicotera, P. (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J. Exp. Med. 185,1481-1486[Abstract/Free Full Text]
  35. Leist, M., Single, B., Naumann, H., Fava, E., Simon, B., Kuhnle, S., Nicotera, P. (1999) Inhibition of mitochondrial ATP generation by nitric oxide switches apoptosis to necrosis. Exp. Cell Res. 249,396-403[CrossRef][Medline]
  36. Abraham, M. C., Shaham, S. (2004) Death without caspases, caspases without death. Trends Cell Biol. 14,184-193[CrossRef][Medline]
  37. Shaham, S., Reddien, P. W., Davies, B., Horvitz, H. R. (1999) Mutational analysis of the Caenorhabditis elegans cell-death gene ced-3. Genetics 153,1655-1671[Abstract/Free Full Text]
  38. Cheng, E. H., Wei, M. C., Weiler, S., Flavell, R. A., Mak, T. W., Lindsten, T., Korsmeyer, S. J. (2001) BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell 8,705-711[CrossRef][Medline]
  39. van Loo, G., Saelens, X., van Gurp, M., MacFarlane, M., Martin, S. J., Vandenabeele, P. (2002) The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ. 9,1031-1042[CrossRef][Medline]
  40. Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., Brothers, G. M., Mangion, J., Jacotot, E., Costantini, P., Loeffler, M., et al (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature (London) 397,441-446[CrossRef][Medline]
  41. Daugas, E., Susin, S. A., Zamzami, N., Ferri, K. F., Irinopoulou, T., Larochette, N., Prevost, M. C., Leber, B., Andrews, D., Penninger, J., et al (2000) Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J. 14,729-739[Abstract/Free Full Text]
  42. Cande, C., Cohen, I., Daugas, E., Ravagnan, L., Larochette, N., Zamzami, N., Kroemer, G. (2002) Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie 84,215-222[Medline]
  43. Hong, S. J., Dawson, T. M., Dawson, V. L. (2004) Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol. Sci. 25,259-264[CrossRef][Medline]
  44. Cregan, S. P., Dawson, V. L., Slack, R. S. (2004) Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 23,2785-2796[CrossRef][Medline]
  45. Chiarugi, A. (2002) PARP-1: killer or conspirator? The suicide hypothesis revisited. Trends Pharmacol. Sci. 23,122-129[CrossRef][Medline]
  46. Scovassi, I. A., Poirier, G. G. (1999) Poly(ADP-ribosylation) and apoptosis. Mol. Cell. Biochem. 199,125-137[CrossRef][Medline]
  47. Scovassi, A. I., Diederich, M. (2004) Modulation of poly(ADP-ribosylation) in apoptotic cells. Biochem. Pharmacol. 68,1041-1047[CrossRef][Medline]
  48. Yu, S. W., Poitras, M. F., Coombs, C., Bowers, W. J., Federoff, H. J., Poirier, G. G., Dawson, T. M., Dawson, V. L. (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297,259-263[Abstract/Free Full Text]
  49. Wang, H., Yu, S. W., Koh, D. W., Lew, J., Coombs, C., Bowers, W., Federoff, H. J., Poirier, G. G., Dawson, T. M., Dawson, V. L. (2004) Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J. Neurosci. 24,10963-10973[Abstract/Free Full Text]
  50. Alano, C. C., Ying, W., Swanson, R. A. (2004) Poly(ADP-ribose) polymerase-1-mediated cell death in astrocytes requires NAD+ depletion and mitochondrial permeability transition. J. Biol. Chem. 279,18895-18902[Abstract/Free Full Text]
  51. Cipriani, G., Rapizzi, E., Vannacci, A., Rizzuto, R., Moroni, F., Chiarugi, A. (2005) Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. J. Biol. Chem. 280,17227-17234[Abstract/Free Full Text]
  52. Chipuk, J. E., Green, D. R. (2005) Do inducers of apoptosis trigger caspase-independent cell death?. Nat. Rev. Mol. Cell Biol. 6,268-275[CrossRef][Medline]
  53. Li, L. Y., Luo, X., Wang, X. (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature (London) 412,95-99[CrossRef][Medline]
  54. Irvine, R. A., Adachi, N., Shibata, D. K., Cassell, G. D., Yu, K., Karanjawala, Z. E., Hsieh, C. L., Lieber, M. R. (2005) Generation and characterization of endonuclease G null mice. Mol. Cell. Biol. 25,294-302[Abstract/Free Full Text]
  55. Majno, G., Joris, I. (1995) Apoptosis, oncosis, and necrosis. An overview of cell death. Am. J. Pathol. 146,3-15[Abstract]
  56. Kanduc, D., Mittelman, A., Serpico, R., Sinigaglia, E., Sinha, A. A., Natale, C., Santacroce, R., Di Corcia, M. G., Lucchese, A., Dini, L., et al (2002) Cell death: apoptosis versus necrosis (review). Int. J. Oncol. 21,165-170[Medline]
  57. Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P., Lipton, S. A. (1997) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxid/superoxide in cortical cell cultures. Proc. Natl. Acad. Sci. USA 92,7162-7166
  58. Barkla, D. H., Gibson, P. R. (1999) The fate of epithelial cells in the human large intestine. Pathology 31,230-238[CrossRef][Medline]
  59. Chautan, M., Chazal, G., Cecconi, F., Gruss, P., Golstein, P. (1999) Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr. Biol. 9,967-970[CrossRef][Medline]
  60. Jacobson, M. D., Burne, J. F., Raff, M. C. (1994) Mechanisms of programmed cell death and Bcl-2 protection. Biochem. Soc. Trans. 22,600-602[Medline]
  61. Kane, D. J., Ord, T., Anton, R., Bredesen, D. E. (1995) Expression of bcl-2 inhibits necrotic neural cell death. J. Neurosci. Res. 40,269-275[CrossRef][Medline]
  62. Shimizu, S., Eguchi, Y., Kosaka, H., Kamiike, W., Matsuda, H., Tsujimoto, Y. (1995) Prevention of hypoxia-induced cell death by Bcl-2 and Bcl-xL. Nature (London) 374,811-813[CrossRef][Medline]
  63. Shimizu, S., Eguchi, Y., Kamiike, W., Itoh, Y., Hasegawa, J., Yamabe, K., Otsuki, Y., Matsuda, H., Tsujimoto, Y. (1996) Induction of apoptosis as well as necrosis by hypoxia and predominant prevention of apoptosis by Bcl-2 and Bcl-XL. Cancer Res. 56,2161-2166[Abstract/Free Full Text]
  64. Shimizu, S., Eguchi, Y., Kamiike, W., Waguri, S., Uchiyama, Y., Matsuda, H., Tsujimoto, Y. (1996) Retardation of chemical hypoxia-induced necrotic cell death by Bcl-2 and ICE inhibitors: possible involvement of common mediators in apoptotic and necrotic signal transductions. Oncogene 12,2045-2050[Medline]
  65. Nicotera, P., Leist, M., Ferrando-May, E. (1999) Apoptosis and necrosis: different execution of the same death. Biochem. Soc. Symp. 66,69-73[Medline]
  66. Nakagawa, T., Shimizu, S., Watanabe, T., Yamaguchi, O., Otsu, K., Yamagata, H., Inohara, H., Kubo, T., Tsujimoto, Y. (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature (London) 434,652-658[CrossRef][Medline]
  67. Baines, C. P., Kaiser, R. A., Purcell, N. H., Blair, N. S., Osinska, H., Hambleton, M. A., Brunskill, E. W., Sayen, M. R., Gottlieb, R. A., Dorn, G. W., et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature (London) 434,658-662[CrossRef][Medline]
  68. Ha, H. C., Snyder, S. H. (1999) Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc. Natl. Acad. Sci. USA 69,13978-13982
  69. Moroni, F., Meli, E., Peruginelli, F., Chiarugi, A., Cozzi, A., Picca, R., Romagnoli, P., Pellicciari, R., Pellegrini-Giampietro, D. E. (2001) Poly(ADP-ribose) polymerase inhibitors attenuate necrotic but not apoptotic neuronal death in experimental models of cerebral ischemia. Cell Death Differ. 8,921-932[CrossRef][Medline]
  70. Germain, M., Affar, E. B., D'Amours, D., Dixit, V. M., Salvesen, G. S., Poirier, G. G. (1999) Cleavage of automodified poly(ADP-ribose) polymerase during apoptosis. Evidence for involvement of caspase-7. J. Biol. Chem. 274,28379-28384[Abstract/Free Full Text]
  71. Soldani, C., Scovassi, A. I. (2002) Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis 7,321-328[CrossRef][Medline]
  72. Berger, N. A. (1985) Poly (ADP-ribose) in the cellular response to DNA damage. Radiat. Res. 101,4-15[Medline]
  73. Bano, D., Young, K. W., Guerin, C. J., Lefeuvre, R., Rothwell, N. J., Naldini, L., Rizzuto, R., Carafoli, E., Nicotera, P. (2005) Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell 120,275-285[CrossRef][Medline]
  74. Schwab, B. L., Guerini, D., Didszun, C., Bano, D., Ferrando-May, E., Fava, E., Tam, J., Xu, D., Xanthoudakis, S., Nicholson, D. W., et al (2002) Cleavage of plasma membrane calcium pumps by caspases: a link between apoptosis and necrosis. Cell Death Differ. 9,818-831[CrossRef][Medline]
  75. Zong, W. X., Ditsworth, D., Bauer, D. E., Wang, Z. Q., Thompson, C. B. (2004) Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 18,1272-1282[Abstract/Free Full Text]
  76. Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J. L., Schneider, P., Seed, B., Tschopp, J. (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1,489-495[CrossRef][Medline]
  77. Lin, Y., Choksi, S., Shen, H. M., Yang, Q. F., Hur, G. M., Kim, Y. S., Tran, J. H., Nedospasov, S. A., Liu, Z. G. (2004) Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation. J. Biol. Chem. 279,10822-10828[Abstract/Free Full Text]
  78. Saelens, X., Festjens, N., Parthoens, E., Vanoverberghe, I., Kalai, M., van Kuppeveld, F., Vandenabeele, P. (2005) Protein synthesis persists during necrotic cell death. J. Cell Biol. 168,545-551[Abstract/Free Full Text]
  79. Newmeyer, D. D., Ferguson-Miller, S. (2003) Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112,481-490[CrossRef][Medline]



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