Cell Death and Differentiation (2008) 15, 1153–1162 & 2008 Nature Publishing Group All rights reserved 1350-9047/08 $30.00 www.nature.com/cdd Review Death through a tragedy: mitotic catastrophe H Vakifahmetoglu1, M Olsson1 and B Zhivotovsky*,1 Mitotic catastrophe (MC) has long been considered as a mode of cell death that results from premature or inappropriate entry of cells into mitosis and can be caused by chemical or physical stresses. Whereas it initially was depicted as the main form of cell death induced by ionizing radiation, it is today known to be triggered also by treatment with agents influencing the stability of microtubule, various anticancer drugs and mitotic failure caused by defective cell cycle checkpoints. Although various descriptions explaining MC exist, there is still no general accepted definition of this phenomenon. Here, we present evidences indicating that death-associated MC is not a separate mode of cell death, rather a process (‘prestage’) preceding cell death, which can occur through necrosis or apoptosis. The final outcome of MC depends on the molecular profile of the cell. Cell Death and Differentiation (2008) 15, 1153–1162; doi:10.1038/cdd.2008.47; published online 11 April 2008 Historical Remarks defective cell cycle checkpoints.8 MC was also depicted as the main form of cell death induced by ionizing radiation. During mitosis, proliferating cells undergo several structural The first observations of MC were made in the late 1930s and molecular changes, characterized by chromatin conden- and early 1940s when cells in exponential growth phase were sation, spindle formation, nuclear envelope fragmentation and exposed to radiation.9,10 It was noticed that the fraction of cells cytoskeleton reorganization.1 Chromosome segregation is in the mitotic stage instantly declined in response to radiation carried out by a complex machinery – the mitotic spindle – that and did not reappear until several hours following treatment. is based on a bipolar array of microtubules. Microtubules are Microscopy examinations revealed that cells began to die at or highly dynamic polymers that continuously grow and shrink, after the first post-irradiation mitotic peak (reappearance of and in the spindle, this behavior is regulated by proteins that mitotic cells)11 and were shown to display abnormal config- bind to the sides or ends of microtubules.2 The rate of urations and spatial rearrangements of chromosomes. microtubule disassembly, from a state of polymerization to Accordingly, this death was called mitotic or division death, depolymerization, is designated as the catastrophe rate.3,4 which emphasized the association with mitosis and cell The process of microtubule disintegration was described in division, or delayed death, which highlighted the appearance 1984 as a ‘microtubule catastrophe’.5 Thereby, the first link of dead cells several hours after irradiation. between two words – catastrophe and mitosis – became apparent. However, the expression ‘mitotic catastrophe’ (MC) was not utilized until 1986, when it was used in an attempt to illustrate the phenotype of a yeast strain raised from The Current Concept of MC combining an activated cdc2 allele (cdc2-3w) with a recessive Mitotic catastrophe has been described as an aberrant form of 6 temperature-sensitive weel mutation (wee 1–50). These mitosis associated with various morphological and biochem- cells were not arrested in the cell cycle; instead, they entered ical changes (see below). The final step of MC is almost mitosis prematurely without completing it effectively. The always characterized by the formation of nuclear envelopes lethal phenotype of this yeast strain was not due to premature around individual clusters of missegregated chromosomes. entry into mitosis, it rather seemed to be an aberrant execution MC is also correlated with incomplete DNA synthesis and of mitosis, particularly with respect to chromosome segrega- premature chromosome condensation (PCC).12,13 Initially, 7 tion and septum formation. Nowadays, the term ‘mitotic PCC was not linked to mitotic events, as the appearance of catastrophe’ is used to explain a mechanism of a delayed multinucleated cells with ‘pulverized’ chromosomes was mitotic-linked cell death, a sequence of events that results observed when interphase and mitotic cells were fused using from premature or inappropriate entry of cells into mitosis that Sendai virus. The interphase chromatin was in this case can be caused by chemical or physical stresses. It can be forced to condense into discrete units known as prematurely triggered with agents influencing the stability of microtubule, condensed chromosomes.14,15 Later, another type of PCC various anticancer drugs and mitotic failure caused by that occurred in only a fraction of metaphase chromosomes 1Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden *Corresponding author: B Zhivotovsky, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Tel: 0046 8 524 875 88; Fax: 0046 8 32 90 41; E-mail: [email protected] Keywords: apoptosis; cell cycle; mitotic catastrophe; necrosis Abbreviations: MC, mitotic catastrophe; PCC, premature chromosome condensation; Chk1-2, checkpoint kinase; MAP, microtubule-associated protein; PLK1, Polo- like kinase 1; ATM, ataxia-telangiectasia-mutated; ATR, ataxia-telangiectasia and Rad3-related Received 06.2.08; revised 14.3.08; accepted 14.3.08; Edited by G Melino; published online 11.4.08 Mitotic catastrophe H Vakifahmetoglu et al 1154 was described. This metaphase-associated PCC, also called has been classified not as a mode of cell death but as a special spontaneous PCC, appeared in cells possessing micronuclei example of apoptosis. This classification is based on the as a result of radiation-induced incomplete DNA synth- observation that MC shares several biochemical hallmarks esis.16,17 Interestingly, the well-defined mode of cell death – with apoptosis, namely mitochondrial membrane permeabili- apoptosis – is also characterized by chromatin condensation; zation and caspase activation.27,28 However, it is still unclear however, the morphology of apoptosis is distinguished from whether MC results in death that requires caspase-dependent MC and illustrated by cytoplasm shrinkage and nuclear or caspase-independent mechanisms.29 In fact, arguments fragmentation. In heated HeLa cells, the appearance of have raised the more general question of whether MC is a spontaneous PCC is followed by asymmetric segregation of mode of cell death or whether this is a process that leads to chromatid clusters and premature reformation of the nuclear apoptosis or necrosis.30–33 In addition, there are several membrane. Then, instead of nuclear fragmentation, cells are examples that permit to define MC as a cell survival characterized by an accumulation of multiple micronuclei that, mechanism of tumors.34 Moreover, in some cases, MC may subsequently, exhibit features similar to necrotic cell death.18 represent a process through which cells switch from an Mitotic catastrophe has also been described as a delayed abnormal to mitotic cell cycle.35 Despite, or maybe owing to, form of reproductive death based on observations that the these various definitions at present, there is no generally multinucleated giant cells can be temporarily viable.19,20 The accepted classification of MC. Here, we present evidence term ‘reproductive death’ denotes the loss of the ability of a indicating that death-associated MC is a process (‘prestage’) cell to generate viable progeny that reproduced continu- preceding necrosis or apoptosis (Figure 1). ously.21 As most of the cells undergoing MC eventually die, cellular processes that lead to irreversible growth arrest and DNA Damage-Induced MC those that are termed ‘reproductive death’ may better fit to conditions known as senescence.22 Senescent cells are It is well known that tumors differ in their sensitivity to generally characterized by a reduction in proliferative capa- treatment. Sensitive cells, in response to various chemother- city, adoption of a flattened and enlarged cell shape and an apeutic agents, are dying in interphase, before entering increase of b-galactosidase (SA-b-gal) activity.23 Although mitosis. Even low doses of irradiation can induce interphase senescence was associated with MC,24,25 it has been shown death of some tumors, especially of hematopoietic origin. In that the polyploid giant cells expressing senescent marker this case, morphology and biochemistry of dying cells (SA-b-gal activity) may overcome the state of growth arrest resemble apoptosis. Cells that do not undergo death in and even undergo de-polyploidization.26 interphase may become arrested in G1 and/or G2. If the Based on observations that abnormalities in the cell cycle cellular machinery is not able to repair the injury during the and mitosis eventually lead to cell death, MC has been defined arrest, DNA damage can lead to different death-associated in morphological terms as a mechanism of cell death consequences. Alternatively, when repair processes are occurring during or after aberrant mitosis.8 Alternatively, MC accomplished, cells reenter the cell cycle. Checkpoint MC as a mechanism of cell death MC as a special example of MC as a survival mechanism MC as a prestage necrosis or apoptosis occurring during or after aberrant apoptosis of tumors mitosis Inducer Inducer Inducer Inducer Aberrant mitosis Caspase-2 activation No caspase activation