The lysosome: from waste bag to potential therapeutic target

Appelqvist, Hanna; Wäster, Petra; Kågedal, Katarina; Öllinger, Karin

doi:10.1093/jmcb/mjt022

Cited by 655 publications

(534 citation statements)

References 187 publications

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“…An accumulation of autophagosomes may cause the release of lysosomal proteases to the cytosol and eventually induce cell death [26] . Cathepsin B is one of the major lysosomal proteases, and thus, the level and redistribution of cathepsin B may influence lysosomal function [27] . Cathepsin B is required for autolysosome maturation [28] .…”

Section: Resultsmentioning

confidence: 99%

Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats

et al. 2014

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Aim: Sevoflurane postconditioning (SpostC) has been shown to protect the heart from ischemia-reperfusion (I/R) injury. In this study, we examined whether SpostC affected autophagic flux in myocardial tissues that contributed to its cardioprotective effects in rats following acute I/R injury. Methods: SD rats underwent 30 min of left anterior descending coronary artery ligation followed by 120 min of reperfusion. The rats were subjected to inhalation of 2.4% (v/v) sevoflurane during the first 5 min of reperfusion, and chloroquine (10 mg/kg, ip) was injected 1 h before I/R. Myocardial infarct size was estimated using TTC staining. Autophagosomes in myocardial tissues were detected under TEM. Expression of LC3B-II, beclin-1, p62/SQSTM1, cathepsin B, caspase-3 and cleaved PARP was assessed using Western blot analysis. Plasma cardiac troponin I was measured using ELISA. Cardiomyocyte apoptosis was evaluated with TUNEL staining. Results: I/R procedure produced severe myocardium infarct and apoptosis accompanied by markedly increased number of autophagosomes, as well as increased levels of LC3B-II, beclin-1 and p62 in myocardial tissues. SpostC significantly reduced infarct size, attenuated myocardial apoptosis, restored intact autophagic flux and improved the lysosomal function in myocardial tissues. Administration of chloroquine that blocked autophagic flux abrogated the cardioprotective effects of SpostC. Conclusion: SpostC exerts its cardioprotective effects in rats following I/R injury via restoring autophagic flux in myocardial tissues.

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Section: Resultsmentioning

confidence: 99%

Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats

et al. 2014

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“…To determine the nature of the membrane delimiting these vacuoles, we first co-stained them with markers of endosomes and lysosomes, the main cellular vesicular system (39). The vacuoles were negative for early endosome (Rab5) and recycling endosome (Rab11) markers 4 but positive for the late endosome/lysosomal markers LAMP1 (Fig.…”

Section: Mitochondrial Dysfunction Causes the Appearance Of Largementioning

confidence: 99%

Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

205

193

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Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases.A prominent feature of neurodegenerative diseases, including Parkinson disease (PD) 3 and Alzheimer disease, is the accumulation of undigested protein aggregates (1, 2). Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1, 3).In healthy cells, protein aggregates and damaged cellular components are delivered to lysosomes to be degraded through a process termed autophagy (1, 2, 4, 5). As such, autophagy plays an important neuroprotective role. Nevertheless, the defects in degradation pathways observed in neurodegenerative diseases extend well beyond alterations in autophagy. Specifically, disruption of lysosomal function has been linked to neuronal loss in several neurodegenerative diseases. For example, mutations in the lysosomal ATPase ATP13A2 cause PD, whereas lysosomal dysfunction in Gaucher disease leads to Parkinsonism and the appearance of Lewy bodies (6, 7). In addition, the ␣-synuclein-containing Lewy bodies found in PD are positive for lysosomal markers, suggesting that they represent lysosomes that failed to degrade their content (8). In fact, lysosomal alterations are a common feature of PD (8 -11). Nevertheless, the pathological consequences of a loss of lysosomal function extend well beyond PD, because a wide variety of mutations that impair lysosomes and cause the accumulation of intracellular material (lysosomal storage diseases) show features of neurodegeneration (12).A second key metabolic pathway required for neuronal survival is mitochondrial activity. In fact, mitochondrial dysfunction is a common feature of neurodegenerative diseases. For example, decreased activity of complex I of the electron transport chain (ETC) is present in a number of PD cases (13, 14), whereas amyloid ␤, Tau tangles, and Htt aggregates all cause mitochondrial dysfunction (15-17). In addition, several genes mutated in PD (including PINK1, Parkin, and DJ-1) affect mitochondrial function and turnover (18 -21), whereas deregulation of mitochon...

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“…Cathepsins are the most studied lysosomal proteases that participate in autophagic degradation. 29 We next investigated whether WA treatment affects the expression and maturation process of 2 main cathepsins, CTSB (cathepsin B) and CTSD (cathepsin D). As shown in Fig.…”

Section: Wa Inhibits the Fusion Of Lysosomes And Autophagosomesmentioning

confidence: 99%

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Feng

Jiang

et al. 2016

Autophagy

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In contrast to normal tissue, cancer cells display profound alterations in protein synthesis and degradation. Therefore, proteins that regulate endoplasmic reticulum (ER) homeostasis are being increasingly recognized as potential therapeutic targets. The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. However, interactions between autophagy, the proteasome, and ER stress pathways in cancer remain largely undefined. This study demonstrated that withaferin-A (WA), the biologically active withanolide extracted from Withania somnifera, significantly increased autophagosomes, but blocked the degradation of autophagic cargo by inhibiting SNARE-mediated fusion of autophagosomes and lysosomes in human pancreatic cancer (PC) cells. WA specifically induced proteasome inhibition and promoted the accumulation of ubiquitinated proteins, which resulted in ER stress-mediated apoptosis. Meanwhile, the impaired autophagy at early stage induced by WA was likely activated in response to ER stress. Importantly, combining WA with a series of ER stress aggravators enhanced apoptosis synergistically. WA was well tolerated in mice, and displayed synergism with ER stress aggravators to inhibit tumor growth in PC xenografts. Taken together, these findings indicate that simultaneous suppression of 2 key intracellular protein degradation systems rendered PC cells vulnerable to ER stress, which may represent an avenue for new therapeutic combinations for this disease.

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The lysosome: from waste bag to potential therapeutic target

Cited by 655 publications

References 187 publications

Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats

Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats

Loss of Mitochondrial Function Impairs Lysosomes

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

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