REVIEW Lysosomal membrane permeabilization in cell death P Boya 1 and G Kroemer 2,3,4 1 3D Lab (Development, Differentiation and Degeneration), Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biolo´gicas, CSIC, Madrid, Spain; 2 INSERM U848, Pavillon de Recherche 1, Villejuif, France; 3 Institut Gustave Roussy, Pavillon de Recherche 1, Villejuif, France and 4 Universite´Paris Sud/Paris 11, Pavillon de Recherche 1, Villejuif, France Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activ- ity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapop- totic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues. Oncogene (2008) 27, 6434–6451; doi:10.1038/onc.2008.310 Keywords: lysosomal membrane permeabilization; cathepsins; programmed cell death; apoptosis; autophagy Introduction Physiological and pathological cell death have been classified according to morphological criteria into at least three categories: type I cell death or apoptosis; type II cell death or autophagic cell death; and type III cell death or necrosis (Clarke, 1990; Kroemer et al., 2005; Galluzzi et al., 2007). Apoptosis or type I programmed cell death is characterized by cell rounding and nuclear condensation. The cell diminishes in size, the plasma membrane starts to bleb and the cell finally fragments into apoptotic bodies that are engulfed by neighboring cells where they are degraded within phagolysosomes. This type of cell death has been extensively studied and (some of) the molecular pathways have now been elucidated. Among these, mitochondrial outer mem- brane permeabilization (MOMP) and caspase activation have prominent functions: the former determines the point of no return of the lethal process; the latter orchestrates the morphological and biochemical changes that characterize apoptosis (Taylor et al., 2008; Youle and Strasser, 2008). MOMP is regulated by the Bcl-2 family of proteins, which act as inducers or blockers of the process. As a result of MOMP, proapoptotic molecules such as cytochrome c are released into the cytosol and contribute to the activation of caspases (Kroemer et al., 2007; Taylor et al., 2008; Youle and Strasser, 2008). Caspases are aspartic proteases that are responsible for the degradation of hundreds of cyto- plasmic and nuclear proteins in the apoptotic cell. Caspases can be activated after MOMP or indepen- dently of MOMP (Taylor et al., 2008). Other mitochon- drial proteins such as the apoptosis-inducing factor (AIF) are also released from the mitochondria during apoptosis and activate caspase-independent cell death pathways (Modjtahedi et al., 2006). Autophagy is a lysosomal degradative pathway by which cells degrade and recycle macromolecules and organelles (Mizushima, 2007). As a result of the discovery of the proteins responsible for this pheno- menon—the autophagy (Atg) proteins—and the impli- cation of autophagy in a plethora of pathological situations, this process has received great attention (Klionsky, 2007; Levine and Kroemer, 2008). Although autophagy was initially described as a type of cellular demise, it remains unclear whether autophagy represents an independent mode of programmed cell death, a backup mechanism of cell death when apoptosis is inhibited or simply a stress response that is activated in damaged cells (Maiuri et al., 2007). Indeed, one possible explanation for the frequent presence of autophago- somes in dying cells is that cells upregulate autophagy in an attempt to eliminate toxic molecules or damaged organelles and that cells die from apoptosis or necrosis only once the autophagic system of defense has been Correspondence: Dr P Boya, Centro de Investigaciones Biolo´gicas, Consejo Superior de Investigaciones Cientı´ficas, Ramiro de Maetzu 9, E-28040 Madrid, Spain. E-mail: pboya@cib.csic.es or Dr G Kroemer, INSERM U848, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France. E-mail: kroemer@igr.fr Oncogene (2008) 27, 6434–6451 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc