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Factors regulating lysosomal membrane permeabilization. This schematic presents a number of factors that may be responsible for lysosomal membrane permeabilization (LMP). The relative importance of each mechanism likely depends on the cell type and death stimulus. Mechanisms that are believed to safeguard lysosomal integrity and protect from lysosome-mediated cell death are also shown. ''Changes in membrane lipid composition'' includes membrane destabilizing factors such as phospholipase A2 and sphingosine, as well as LPM protective substances e.g., cholesterol and sphingomyelin. Abbreviations: JNK, c-Jun N-terminal kinase; LAPF, lysosome-associated apoptosis-inducing protein containing the pleckstrin homology and FYVE domains; Hsp, heat shock protein; ROS, reactive oxygen species; ANT, adenine nucleotide translocator; Ahr, aryl hydrocarbon receptor; LEDGF, lens epithelium-derived growth factor; LAMP, lysosome-associated membrane protein
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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...
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... LMP have received increased attention. As outlined above, there are many proteinaceous and non-proteinaceous factors, including Bcl-2 family proteins, ROS, caspases, cathepsins, cholesterol, and Hsps, that influence the stability of the lysosomal membrane, and their individual importance appears to depend on the cell type and death stimulus (Fig. 5). However, the main mechanism responsible for apoptosis-associated LMP, if any, remains to be identified. A deeper understanding of the regulation of LMP and other apoptosis signaling events could enable the development of novel therapies for dis- eases associated with excessive or insufficient apoptosis such as neurodegenerative ...
Citations
... In cancer cells, lysosomal dysfunction can trigger various forms of cell death, including apoptosis, necroptosis, ferroptosis, and autophagy depending on the cellular context [26][27][28][29]. To elucidate the mechanism underlying the cytotoxicity of perphenazine, we sought to investigate the induction of these different forms of cell death. ...
The repurposing of medications developed for central nervous system (CNS) disorders, possessing favorable safety profiles and blood-brain barrier permeability, represents a promising strategy for identifying new therapies to combat glioblastoma (GBM). In this study, we investigated the anti-GBM activity of specific antipsychotics and antidepressants in vitro and in vivo. Our results demonstrate that these compounds share a common mechanism of action in GBM, disrupting lysosomal function and subsequently inducing lysosomal membrane rupture and cell death. Notably, PTEN intact GBMs possess an increased sensitivity to these compounds. The inhibition of lysosomal function synergized with inhibitors targeting the EGFR-PI3K-Akt pathway, leading to an energetic and antioxidant collapse. These findings provide a foundation for the potential clinical application of CNS drugs in GBM treatment. Additionally, this work offers critical insights into the mechanisms and determinants of cytotoxicity for drugs currently undergoing clinical trials as repurposing agents for various cancers, including Fluoxetine, Sertraline, Thioridazine, Chlorpromazine, and Fluphenazine.
... Hydrolases, under an acidic pH, initiate a degradative process that helps recycle the cargo content. Some stress stimuli can result in the perforation of lysosomal membranes and result in lysosomal membrane permeabilization (LMP) [17,78]. In the early stages of an injury, any limited damage can be reversed thanks to the endosomal sorting complex required for the transport (ESCRT) machinery [79,80]. ...
Studies trying to understand cell death, this ultimate biological process, can be traced back to a century ago. Yet, unlike many other fashionable research interests, research on cell death is more alive than ever. New modes of cell death are discovered in specific contexts, as are new molecular pathways. But what is “cell death”, really? This question has not found a definitive answer yet. Nevertheless, part of the answer is irreversibility, whereby cells can no longer recover from stress or injury. Here, we identify the most distinctive features of different modes of cell death, focusing on the executive final stages. In addition to the final stages, these modes can differ in their triggering stimulus, thus referring to the initial stages. Within this framework, we use a few illustrative examples to examine how intercellular communication factors in the demise of cells. First, we discuss the interplay between cell–cell communication and cell death during a few steps in the early development of multicellular organisms. Next, we will discuss this interplay in a fully developed and functional tissue, the gut, which is among the most rapidly renewing tissues in the body and, therefore, makes extensive use of cell death. Furthermore, we will discuss how the balance between cell death and communication is modified during a pathological condition, i.e., colon tumorigenesis, and how it could shed light on resistance to cancer therapy. Finally, we briefly review data on the role of cell–cell communication modes in the propagation of cell death signals and how this has been considered as a potential therapeutic approach. Far from vainly trying to provide a comprehensive review, we launch an invitation to ponder over the significance of cell death diversity and how it provides multiple opportunities for the contribution of various modes of intercellular communication.
... Published data demonstrated that Cu + cations induced lysosomal membrane damaged through ROS production contributing to the leak of proteases (cathepsins) and resulting in cell death [39,40]. Lysosomal membrane damaged is followed by the translocation of cathepsins from the lysosomes to the cytosol leading to the apoptosis [41][42][43]. To investigate cathepsin release, A2780 and SK-OV-3 cells were treated with Cu(I)NP, Cu(II)NP (10 μg/ml), CisPt (6 μg /ml) for 6, 12 and 24 h. ...
The clinical application of nanomaterials for chemodynamic therapy (CDT), which generate multiple reactive oxygen species (ROS), presents significant challenges. These challenges arise due to insufficient levels of endogenous hydrogen peroxide and catalytic ions necessary to initiate Fenton reactions. As a result, sophisticated additional delivery systems are required. In this study, a novel bimetallic copper (II) pentacyanonitrosylferrate
(Cu(II)NP, Cu[Fe(CN) 5 NO]) material was developed to address these limitations. This material functions as a multiple ROS generator at tumoral sites by self-inducing hydrogen peroxide and producing peroxynitrite (ONOO-) species. The research findings demonstrate that this material exhibits low toxicity towards normal liver organoids, yet shows potent antitumoral effects on High Grade Serous Ovarian Cancer (HGSOC) organoid patients, regardless of platinum resistance. Significantly, this research introduces a promising therapeutic opportunity by proposing a single system capable of replacing the need for H2O2, additional catalysts, and NO-based delivery systems. This innovative system exhibits remarkable multiple therapeutic mechanisms, paving the way for potential advancements in clinical treatments.
... The function of lysosomes is to maintain the cellular homeostasis by degradation and recycling of cellular waste using digestive enzymes [12]. Yet, a release of digestive enzymes in lysosomes by lysosomal membrane permeabilization or lysosomal rupture become lethal threat to cellular integrity, leading to apoptosis [13][14][15]. Therefore, lysosomes are emerging as attractive targets for anticancer therapy with PTT. ...
... Endolysosomes are generated by the fusion of late endosome and lysosome, and decompose endogenous and exogenous biomolecules such as carbohydrates, lipids, nucleic acids, and peptides [17,18]. When the membrane of endolysosome is damaged, the contents including digestive enzymes within the endolysosome leak out, causing apoptosis [13][14][15]. As endocytosis has been reported to be more prevalent in cancer cells than that in normal cells [19], endolysosomal membrane would be an attractive target for cancer therapy. ...
... Lysosome damage may also affect other types of autophagy, such as endoplasmic reticulum-phagy and peroxphagy. LMP is capable of inducing apoptosis via the mitochondria-independent pathway (46). However, mitochondria-independent mechanisms, such as LMP-mediated non-mitochondrial apoptosis, were unlikely to play a role in the present study because mitochondrion-deficient A549 cells (ρ 0 cells) exhibited complete resistance to the cytotoxic action of AZM during hypoxia exposure, validating our notion that the accumulation of damaged mitochondria plays a primary role in the induction of apoptosis by AZM treatment under hypoxic conditions. ...
Solid tumors are predisposed to hypoxia, which induces tumor progression, and causes resistance to treatment. Hypoxic tumor cells exploit auto- and mitophagy to facilitate metabolism and mitochondrial renewal. Azithromycin (AZM), a widely used macrolide, inhibits autophagy in cancer cells. The aim of the present study was to determine whether AZM targeted hypoxic cancer cells by inhibiting mitophagy. Lung cancer cell lines (A549, H1299 and NCI-H441) were cultured for up to 72 h under normoxic (20% O2) or hypoxic (0.3% O2) conditions in the presence or absence of AZM (≤25 µM), and the cell survival, autophagy flux and mitophagy flux were evaluated. AZM treatment reduced cell survival under hypoxic conditions, caused mitolysosome dysfunction with raised lysosomal pH and impaired the efficient removal of hypoxia-damaged mitochondria, eventually inducing apoptosis in the cancer cells. The cytotoxic effect of AZM under hypoxic conditions was abolished in mitochondria-deficient A549 cells (ρ° cells). The present study demonstrated that AZM reduced lung cancer cell survival under hypoxic conditions by interfering with the efficient removal of damaged mitochondria through mitophagy inhibition. Thus, AZM may be considered as a promising anticancer drug that targets the mitochondrial vulnerability of hypoxic lung cancer cells.
... These substances may trigger lysosomal membrane damage, a process linked to inflammation and neurodegeneration (Lawrence and Zoncu, 2019;Papadopoulos and Meyer, 2017). Importantly, lysosomal membrane damage without efficient repair has been reported to result in different forms of cell death including apoptosis, necrosis and pyroptosis (Boya and Kroemer, 2008;Chen et al., 2019;Johansson et al., 2010;Radulovic et al., 2018;Skowyra et al., 2018). Endolysosomal damage triggers LRRK2 activation, Rab phosphorylation and endomembrane repair in murine macrophages, specifically RAW 264.7 cells (Herbst et al., 2020). ...
LRRK2 is commonly mutated in Parkinsons disease and has cell type-specific mechanisms of activation and function. In macrophages, LRRK2 is associated with lysosomes and is activated following lysosomal damage. However, effects of pathogenic LRRK2-G2019S in macrophages are unknown. Here, using primary mouse and human iPSC-derived macrophage (iPSDM) models of LRRK2-G2019S, we defined the substrates of LRRK2 after lysosomal damage. Using phosphoproteomics we found that LRRK2-G2019S and wild-type macrophages showed similar levels of Rab phosphorylation after lysosomal damage, with the exceptions of Rab12 and Rab35, which were increased and decreased, respectively, in LRRK2-G2019S. LRRK2-G2019S macrophages showed a LRRK2 kinase activity-independent deficit in lysosomal membrane repair which resulted in more cell death and increased apoptosis. Importantly, we recapitulated this phenotype in iPSDM from patients carrying the G2019S mutation, but not in isogenic control iPSDM. Altogether, we define here the signaling downstream of G2019S in macrophages and identify susceptibility to cell death after lysosomal damage as an important phenotype of this mutation.
... Cholesterol likely plays an essential role in maintaining lysosomal membrane integrity [90][91][92]. It was confirmed that cholesterol depletion with CD decreased lysosomal membrane stability, although the experimental setup included a 24 h chase step after CD treatment [93]. ...
... While the changes in fluorescence indicated the intracellular rupturing of lysosomes in the NIH-3T3 cells, the alterations in the 3T3-MDR1 cells indicated a different mechanism for the loss of lysosomes. Based on our LAMP1 and LAMP2 observations, the latter Cholesterol likely plays an essential role in maintaining lysosomal membrane integrity [90][91][92]. It was confirmed that cholesterol depletion with CD decreased lysosomal membrane stability, although the experimental setup included a 24 h chase step after CD treatment [93]. ...
The human P-glycoprotein (P-gp), a transporter responsible for multidrug resistance, is present in the plasma membrane’s raft and non-raft domains. One specific conformation of P-gp that binds to the monoclonal antibody UIC2 is primarily associated with raft domains and displays heightened internalization in cells overexpressing P-gp, such as in NIH-3T3 MDR1 cells. Our primary objective was to investigate whether the trafficking of this particular P-gp conformer is dependent on cholesterol levels. Surprisingly, depleting cholesterol using cyclodextrin resulted in an unexpected increase in the proportion of raft-associated P-gp within the cell membrane, as determined by UIC2-reactive P-gp. This increase appears to be a compensatory response to cholesterol loss from the plasma membrane, whereby cholesterol-rich raft micro-domains are delivered to the cell surface through an augmented exocytosis process. Furthermore, this exocytotic event is found to be part of a complex trafficking mechanism involving lysosomal exocytosis, which contributes to membrane repair after cholesterol reduction induced by cyclodextrin treatment. Notably, cells overexpressing P-gp demonstrated higher total cellular cholesterol levels, an increased abundance of stable lysosomes, and more effective membrane repair following cholesterol modifications. These modifications encompassed exocytotic events that involved the transport of P-gp-carrying rafts. Importantly, the enhanced membrane repair capability resulted in a durable phenotype for MDR1 expressing cells, as evidenced by significantly improved viabilities of multidrug-resistant Pgp-overexpressing immortal NIH-3T3 MDR1 and MDCK-MDR1 cells compared to their parents when subjected to cholesterol alterations.
... Previous studies have demonstrated that ER stressinduced apoptosis may independently of the mitochondrial damage results in lysosomal destabilization followed by the release of cathepsin B from lysosomes into the cytosol 123 . This, in turn, triggers apoptosis execution 123,124 . Therefore, we examined the sub-cellular localization of cathepsin B by immunofluorescence. ...
Iron oxide nanoparticles (IONPs) are being actively researched in various biomedical applications, particularly as magnetic resonance imaging (MRI) contrast agents for diagnosing various liver pathologies like nonalcoholic fatty liver diseases, nonalcoholic steatohepatitis, and cirrhosis. Emerging evidence suggests that IONPs may exacerbate hepatic steatosis and liver injury in susceptible livers such as those with nonalcoholic fatty liver disease. However, our understanding of how IONPs may affect steatotic cells at the sub-cellular level is still fragmented. Generally, there is a lack of studies identifying the molecular mechanisms of potential toxic and/or adverse effects of IONPs on "non-heathy" in vitro models. In this study, we demonstrate that IONPs, at a dose that does not cause general toxicity in hepatic cells (Alexander and HepG2), induce significant toxicity in steatotic cells (cells loaded with non-toxic doses of palmitic acid). Mechanistically, co-treatment with PA and IONPs resulted in endoplasmic reticulum (ER) stress, accompanied by the release of cathepsin B from lysosomes to the cytosol. The release of cathepsin B, along with ER stress, led to the activation of apoptotic cell death. Our results suggest that it is necessary to consider the interaction between IONPs and the liver, especially in susceptible livers. This study provides important basic knowledge for the future optimization of IONPs as MRI contrast agents for various biomedical applications.
... As the primary catabolic compartments of eukaryotic cells, lysosomes contain numerous hydrolases to degrade cellular components [80]. Lysosomal membrane permeabilization (LMP), caused by various stimuli such as cathepsins, leads to the leakage of lysosomal contents into the cytosol and results in lysosomal cell death (LCD) [81][82][83][84]. Lysosomes can repair minor damage to the lysosomal membrane by recruiting the endosomal sorting complexes required for the transport complex. ...
Cyclic GMP‐AMP synthase (cGAS) monitors dsDNA in the cytosol in response to pathogenic invasion or tissue injury, initiating cGAS‐STING signaling cascades that regulate various cellular physiologies, including IFN /cytokine production, autophagy, protein synthesis, metabolism, senescence, and distinct types of cell death. cGAS‐STING signaling is crucial for host defense and tissue homeostasis; however, its dysfunction frequently leads to infectious, autoimmune, inflammatory, degenerative, and cancerous diseases. Our knowledge regarding the relationships between cGAS‐STING signaling and cell death is rapidly evolving, highlighting their essential roles in pathogenesis and disease progression. Nevertheless, the direct control of cell death by cGAS‐STING signaling, rather than IFN/NF‐κB‐mediated transcriptional regulation, remains relatively unexplored. This review examines the mechanistic interplays between cGAS‐STING cascades and apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagic/lysosomal cell death. We will also discuss their pathological implications in human diseases, particularly in autoimmunity, cancer, and organ injury scenarios. We hope that this summary will stimulate discussion for further exploration of the complex life‐or‐death responses to cellular damage mediated by cGAS‐STING signaling.
... In addition to the potential role in releasing lysosomal contents, lysosomal exocytosis is likely involved in the removal of damaged lysosomes as one of endolysosomal damage-response mechanisms 51 . Lysosomal membrane permeabilization (LMP) is characterized by the lysosomal membrane damage, leading to the leakage of the lysosomal acid hydrolases into the cytosol and consequent lysosomal-dependent cell death (LDCD) and other types of cell death such as apoptosis [51][52][53][54] . U exposure could induce LMP 55 . ...
Uranium (U) is a well-known nephrotoxicant which forms precipitates in the lysosomes of renal proximal tubular epithelial cells (PTECs) after U-exposure at a cytotoxic dose. However, the roles of lysosomes in U decorporation and detoxification remain to be elucidated. Mucolipin transient receptor potential channel 1 (TRPML1) is a major lysosomal Ca²⁺ channel regulating lysosomal exocytosis. We herein demonstrate that the delayed administration of the specific TRPML1 agonist ML-SA1 significantly decreases U accumulation in the kidney, mitigates renal proximal tubular injury, increases apical exocytosis of lysosomes and reduces lysosomal membrane permeabilization (LMP) in renal PTECs of male mice with single-dose U poisoning or multiple-dose U exposure. Mechanistic studies reveal that ML-SA1 stimulates intracellular U removal and reduces U-induced LMP and cell death through activating the positive TRPML1-TFEB feedback loop and consequent lysosomal exocytosis and biogenesis in U-loaded PTECs in vitro. Together, our studies demonstrate that TRPML1 activation is an attractive therapeutic strategy for the treatment of U-induced nephrotoxicity.
