Regulation of apoptosis-associated lysosomal membrane permeabilization

Abstract

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.

Autophagy-Lysosome Pathway in Renal Tubular Epithelial Cells Is Disrupted by Advanced Glycation End Products in Diabetic Nephropathy

“…In addition to the cathepsin leakage and irregular LAMP1 expression, the decreased LTR fluorescence also suggested the occurrence of LMP (20), which is likely a primary cause of lysosomal dysfunction. LMP is susceptible to oxidative stress, suggesting that overproduced ROS plays a key role in governing LMP (28). Furthermore, the cytoplasmic active cathepsins released from lysosomes might play an important role in triggering TEC apoptosis as reported previously (29).…”

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

“…Cathepsins have been described as being involved in programmed cell death that occurs under experimental and disease conditions in various forms, such as apoptosis, autophagy, among others Lockshin and Zakeri, 2002;Guicciardi et al, 2004;Chwieralski et al, 2006;Boya and Kroemer, 2008;Johansson et al, 2010). However, to date the role of cathepsins in retinal cell death has received little attention.…”

Lysosomes in programmed cell death pathways: from initiators to amplifiers

“…Another important factor in the sphingosine detergent activity seems to be also cathepsin B, which degrades sphingosine into the anti-apoptotic sphingosine 1-phosphate. In addition, sphingosine membranolytic properties depend on pH and lipid composition (Johansson et al, 2010;Young et al, 2013;Villamil Giraldo et al, 2014). In addition, destabilization of lysosomal membrane can be mediated also by non-permeable compounds that accumulate in lysosomes after delivery by endocytosis (Aits and Jaattela, 2013;Repnik et al, 2014;Villamil Giraldo et al, 2014).…”

“…Lysosomal integrity can be maintained by vitamins C and E, coenzyme Q10, glutathione, catalase, superoxide dismutase, etc. However, their anti-oxidative properties can be diminished by the low lysosomal pH (Johansson et al, 2010;Kurz et al, 2011;Aits and Jaattela, 2013;Marino et al, 2013;Bogdan et al, 2016).…”

“…Also several other toxins, such as tetanus, botulinum an anthrax toxin, nigericin, leukotoxin, mycotoxins, venom toxins from cobra and rattlesnake, have been associated with LMP. On the other hand, viral proteins can initiate LMP by generating lysosomal membrane rupture, pore formation, membrane curvature stress or vesicular swelling or even by detergent-like activity (Tosteson and Chow, 1997;Fuchs and Blaas, 2010;Johansson et al, 2010;Maier et al, 2010;Aits and Jaattela, 2013;Jiang and Mizushima, 2014;Ju et al, 2015). In addition, proapoptotic Bcl2 family members Bax and Bak that are primarily involved in mitochondrial membrane permeabilization, and Bid, were also suggested to be involved in triggering LMP (Johansson et al, 2010).…”