Lysosomal–mitochondrial cross-talk during cell death Urška Repnik a , Boris Turk a,b, ⁎ a Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia b Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, SI-1000 Ljubljana, Slovenia abstract article info Article history: Received 9 February 2010 Received in revised form 15 July 2010 Accepted 23 July 2010 Available online 7 August 2010 Keywords: Apoptosis Autophagy Lysosome Mitochondrion Cysteine cathepsin Lysosomes are membrane-bound organelles, which contain an arsenal of different hydrolases, enabling them to act as the terminal degradative compartment of the endocytotic, phagocytic and autophagic pathways. During the last decade, it was convincingly shown that destabilization of lysosomal membrane and release of lysosomal content into the cytosol can initiate the lysosomal apoptotic pathway, which is dependent on mitochondria destabilization. The cleavage of BID to t-BID and degradation of anti-apoptotic BCL-2 proteins by lysosomal cysteine cathepsins were identified as links to the mitochondrial cytochrome c release, which eventually leads to caspase activation. There have also been reports about the involvement of lysosome destabilization and lysosomal proteases in the extrinsic apoptotic pathway, although the molecular mechanism is still under debate. In the present article, we discuss the cross-talk between lysosomes and mitochondria during apoptosis and its consequences for the fate of the cell. © 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved. 1. Introduction Apoptosis is a form of programmed cell death that eliminates superfluous or damaged cells in a controlled manner that minimizes damage and disruption to neighboring cells and is vital for embryonic development, the immune system and tissue homeostasis. It is characterized by caspase (cysteine-dependent aspartate-specific protease) activation, chromatin condensation, nuclear fragmentation, phosphatidylserine exposure and formation of apoptotic bodies. Two main pathways of intracellular signaling lead to apoptosis: the extrinsic or death receptor pathway and the intrinsic or mitochondrial pathway. The two pathways differ in the initiator caspases that transmit the signal but later converge at the level of activation of executioner caspases (caspases-3, -6, and -7), which execute the cell death process by cleaving a large number of cellular proteins to drive forward the biochemical events that culminate in cell death and dismantling of the cell (Hengartner, 2000; Leist and Jäättelä, 2001; Ow et al., 2008; Riedl and Salvesen, 2007; Taylor et al., 2008). 2. Extrinsic apoptotic pathway The extrinsic pathway involves stimulation of members of the tumor necrosis factor receptor (TNFR) subfamily, such as TNFRI, CD95/Fas or TRAILR (death receptors), located at the cell surface, by their specific ligands, such as TNF-α, FasL or TRAIL, respectively. Recent evidence suggests that receptors exist as pre-assembled oligomers at the cell surface. Upon ligand binding the intracellular part of the receptor undergoes a conformational change that allows association between the receptors and exposes the death domain (DD), through which the adaptor proteins are recruited to form death- inducing signaling complex (DISC) that serves as a caspase-8 activating platform. In Fas and TRAILR signaling, Fas-associated death domain protein (FADD) is recruited directly to the receptor, whereas in TNFR signaling, TNFRI-associated death domain protein (TRADD) needs to bind to the receptor first. FADD then recruits procaspase-8 through the death effector domain (DED) (Chan, 2007; Ding and Yin, 2004; Leist and Jäättelä, 2001; Ow et al., 2008; Scott et al., 2009). Caspase-8 belongs to the initiator caspases, which contain long pro-domains and are activated by dimerization of the monomeric zymogens. Internal proteolysis does not activate these apical caspases but is a secondary event resulting in partial stabilization of the activated dimers (Boatright et al., 2003; Donepudi et al., 2003; Pop et al., 2007). Once activated, caspase-8 activates executioner caspase-3 and caspase-7 by proteolytic processing (Fuentes-Prior and Salvesen, 2004; Riedl et al., 2001). Association of TRADD, FADD and caspase-8 into the TNFRI-associated DISC is critically dependent on receptor endocytosis. Moreover, it is believed that even the assembly of Fas-associated DISC capable of mediating apoptotic signaling is dependent on Fas internalization. In contrast, TRAIL-induced DISC formation also occurs in the absence of receptor endocytosis (Schneider-Brachert et al., 2004; Schutze and Schneider-Brachert, 2009). 3. Intrinsic apoptotic pathway The intrinsic pathway is activated mainly by non-receptor stimuli, such as DNA damage, ER stress, metabolic stress, UV radiation or Mitochondrion 10 (2010) 662–669 ⁎ Corresponding author. Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia. Tel.: +386 1 47 73 772; fax: +386 1 47 73 984. E-mail addresses: urska.repnik@ijs.si (U. Repnik), boris.turk@ijs.si (B. Turk). 1567-7249/$ – see front matter © 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved. doi:10.1016/j.mito.2010.07.008 Contents lists available at ScienceDirect Mitochondrion journal homepage: www.elsevier.com/locate/mito