**9. Mitotic catastrophe**

80 Apoptosis and Medicine

membrane protein (LAMP) type 2a [83].

range of human pathologies, including cancer.

cases, autophagy can selectively eliminate some organelles, such as damaged peroxisomes, mitochondria or ER. In contrast, **CMA** does not involve vesicular traffic and is specific for the degradation of proteins. During this process, proteins are delivered to lysosomes with the help of molecular chaperones and a lysosomal receptor. Cytosolic proteins with a specific peptide sequence motif (''KFERQ'' motif) are recognized by a complex of molecular chaperones (Hsc70) and then bind to a lysosomal receptor called lysosome associated

Macroautophagy (hereafter referred to as autophagy) is the most studied and prevalent form of autophagy in cells. This process begins with the formation of a "C" shaped doublemembrane structure in the cytosol, called "omegasome", which is formed from the ER (Initiation phase). Following this, the omegasome grows to form the "isolation membrane", which elongates to engulf cytoplasmic components (Elongation phase). Then, the "isolation membrane" curves and closes to form a vacuole called the autophagosome (Maturation phase). As a result, portions of the cell cytoplasm and some organelles are sequestered in this vacuole. Finally, the outer membrane of the autophagosome fuses with the lysosomal membrane and the inner membrane (the autophagic body) carrying the cytosolic constituents enters the lysosome. The autophagic body is degraded in the lysosome by hydrolases and the resulting free amino acids and macromolecules are transported back into the cytosol for reuse [84]. In this way, autophagy contributes to the maintenance of the cellular energy homeostasis, to the clearance of damaged organelles and to adaptation to environmental stresses [85]. Accordingly, autophagy defects have been linked to a wide

**Figure 6. Autophagy.** Three different forms of autophagy are depicted: Macroautophagy,

Microautophagy and Chaperone-mediated autophagy (CMA) (taken from Yen and Klionsky, 2008).

The cell death process that takes place when mitosis cannot be completed is called mitotic catastrophe. This phenomenon is triggered as a consequence of perturbations of the mitotic machinery that governs appropriate chromosome segregation. The main hallmark of mitotic catastrophe is the enlarged cell size accompanied by multinucleation [5]. Other features are chromatin condensation, DNA degradation, MMP, cyrochrome c release from the mitochondria and caspase activation [86]. Some types of mitotic catastrophe, however, take place without intervention of caspases, what has been named caspase-independent mitotic death [87]. Mitotic catastrophe results form the combination of deficient checkpoints (DNA and mitotic spindle) and DNA damage. Cells that evade the mitotic checkpoint and do not undergo apoptosis are prone to generate aneuploidy. Therefore, mitotic catastrophe is conceived as a device to avoid genomic instability. The players that take part in mitotic catastrophe are: cell cycle-dependent kinases (Cdk1, Aurora, Plk), cell cycle-check points proteins (Chk2, p53, p73), survivin, MCl-2, Blc-2 proteins, caspase-2, etc. [86]. Mitotic catastrophe is a poorly defined molecular signalling pathway that precedes apoptosis, necrosis or senescence [88].

**Figure 7. Mitotic catastrophe. a)** In the absence of perturbations cells progress normally. A mitotic defect is detected and: **b)** cells die without exiting mitosis, **c)** cells undergo mitotic arrest, exit mitosis (mitotic slippage), reach the subsequent G1 and die or **d)** undergo senescence (taken from Galluzzi et al. 2012).
