[Abstract unavailable

Lysosomes are ubiquitous membrane-bound intracellular organelles with an acidic interior. They are central for degradation and recycling of macromolecules delivered by endocytosis, phagocytosis, and autophagy. In contrast to the rather simplified view of lysosomes as waste bags, nowadays lysosomes are recognized as advanced organelles involved in many cellular processes and are considered crucial regulators of cell homeostasis. The function of lysosomes is critically dependent on soluble lysosomal hydrolases (e.g. cathepsins) as well as lysosomal membrane proteins (e.g. lysosome-associated membrane proteins). This review focuses on lysosomal involvement in digestion of intra- and extracellular material, plasma membrane repair, cholesterol homeostasis, and cell death. Regulation of lysosomal biogenesis and function via the transcription factor EB (TFEB) will also be discussed. In addition, lysosomal contribution to diseases, including lysosomal storage disorders, neurodegenerative disorders, cancer, and cardiovascular diseases, is presented.

Lysosomal membrane permeabilization (LMP) occurs in response to a large variety of cell death stimuli causing release of cathepsins from the lysosomal lumen into the cytosol where they participate in apoptosis signaling. In some settings, apoptosis induction is dependent on an early release of cathepsins, while under other circumstances LMP occurs late in the cell death process and contributes to amplification of the death signal. The mechanism underlying LMP is still incompletely understood; however, a growing body of evidence suggests that LMP may be governed by several distinct mechanisms that are likely engaged in a death stimulus- and cell-type-dependent fashion. In this review, factors contributing to permeabilization of the lysosomal membrane including reactive oxygen species, lysosomal membrane lipid composition, proteases, p53, and Bcl-2 family proteins, are described. Potential mechanisms to safeguard lysosomal integrity and confer resistance to lysosome-dependent cell death are also discussed.

It has been suggested that lysosomes and the lysosomal proteases cathepsin D and B act as proapoptotic mediators of apoptosis, in addition to mitochondrial release of cytochrome c and the activation of the caspase family of proteases. We found that cathepsin D was implicated in the onset of apoptosis in fibroblasts exposed to oxidative stress generated by redox cycling of naphthazarin (NZ) (5,8-dihydroxy-1,4-naphthoquinon). At the start of NZ treatment, the intracellular reduced glutathione concentration was diminished and cathepsins D, B, and L were all translocated from lysosomes to the cytosol before any biochemical or morphological signs of apoptosis were detected. Increase in cathepsin D activity and in the level of p53 protein, a transcription factor for cathepsin D, was observed before activation of caspase-3. Moreover, pretreatment with the cathepsin D inhibitor pepstatin A or the caspase-3 inhibitor Ac-DEVD-CHO prevented apoptosis, although the increase of cathepsin D activity was still detected when caspase-3 was inhibited. Cathepsin B activity decreased following oxidative stress, and inhibition of the protease did not affect the apoptotic process. We suggest that translocation of lysosomal proteases is an early event in NZ-induced apoptosis and that the release and increased activity of cathepsin D allow this protease to exert an apoptosis-mediating effect upstream of the caspase cascade.Keywords: caspases • cell death • naphthazarin p53 • pepstatin A poptosis is a physiologically and morphologically well-defined form of cell death that plays an important role in regulation of tissue development and homeostasis (1). Imbalance in the apoptosis machinery is associated with the progression of serious diseases, such as AIDS, cancer, and neurodegenerative disorders (2-4). The process of apoptosis is evolutionarily conserved among different organisms featuring multiple apoptotic mechanisms in which caspases, a family of cysteine proteases, and their regulators play an important role. Different organisms share certain features of apoptosis, such as nuclear condensation, DNA fragmentation, dilated endoplasmic reticulum, loss of mitochondrial membrane potential, and formation of apoptotic bodies, all of which are assumed to be strongly associated with the activity of caspases (reviewed by (5)). In addition to caspases, the growing list of proteases that act as positive mediators of apoptosis can be extended to include the lysosomal aspartic protease A cathepsin D and a few lysosomal cysteine proteases, for instance cathepsins B and L. Deiss and co-workers (6) found that cathepsin D anti-sense RNA protected HeLa cells from IFN-γ-and Fas-induced cell death. It has also been demonstrated that p53, which accumulates rapidly after various types of stress, has two binding sites located at the cathepsin D promoter gene, and that cathepsin D participates in p53-dependent apoptosis (7). Apoptosis induced in hepatocytes by bile salts also appears to be regulated by cathepsin D, possibly through a cathepsin-D-mediated in...

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