Lysosomal function and dysfunction: Mechanism and disease
ABSTRACT SIGNIFICANCE: Lysosomes are organelles in which cellular degradation occurs in a controlled manner, separated from other cellular components. As several pathways terminate in the lysosome, lysosomal dysfunction has a profound impact on cell homeostasis, resulting in manifold pathological situations, including infectious diseases, neurodegeneration, and aging. RECENT ADVANCES: Lysosomal biology demonstrates that in addition to regulating the final steps of catabolic processes, lysosomes are essential up-stream modulators of autophagy and other essential lysosomal pathways. FUTURE DIRECTIONS AND CRITICAL ISSUES: Lysosomal membrane permeabilization offers therapeutic potential in the treatment of cancer, though the molecular regulators of this process remain obscure. This review focuses on recent discoveries in lysosomal function and dysfunction, primarily in in vivo situations.
- SourceAvailable from: Taotao Wei
Protein & Cell 07/2014; 5(8). DOI:10.1007/s13238-014-0085-5 · 2.85 Impact Factor
- "In the present investigation, we revealed an uncanonical mechanism of lysosomal chymotrypsin-mediated calcineurin activation that bridges the LMP with the mitochondrial dynamics in apoptotic cells. Lysosomes, which are acidic organelles containing dozens of hydrolytic enzymes (Boya, 2012), are tightly linked with apoptosis (Aits and Jaattela, 2013). Signaling pathways that lead to lysosome-dependent apoptosis have been extensively investigated. "
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ABSTRACT: Autophagy is implicated in the pathogenesis of major neurodegenerative disorders although concepts about how it influences these diseases are still evolving. Once proposed to be mainly an alternative cell death pathway, autophagy is now widely viewed as both a vital homeostatic mechanism in healthy cells and as an important cytoprotective response mobilized in the face of aging- and disease-related metabolic challenges. In Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and other diseases, impairment at different stages of autophagy leads to the buildup of pathogenic proteins and damaged organelles, while defeating autophagy's crucial prosurvival and antiapoptotic effects on neurons. The differences in the location of defects within the autophagy pathway and their molecular basis influence the pattern and pace of neuronal cell death in the various neurological disorders. Future therapeutic strategies for these disorders will be guided in part by understanding the manifold impact of autophagy disruption on neurodegenerative diseases.Cold Spring Harbor perspectives in biology 09/2012; 4(10). DOI:10.1101/cshperspect.a008839 · 8.23 Impact Factor
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ABSTRACT: (-)-Epigallocatechin-3-gallate (EGCG) is the most extensive studied tea polyphenol for its anti-cancer function. In this study, we report a novel mechanism of action for EGCG-mediated cell death by identifying the critical role of lysosomal membrane permeabilization (LMP). First, EGCG-induced cell death in human cancer cells (both HepG2 and HeLa) was found to be caspase-independent and accompanied by evident cytosolic vacuolization, only observable when cells were treated in serum-free medium. The cytosolic vacuolization observed in EGCG-treated cells was most probably caused by lysosomal dilation. Interestingly, EGCG was able to disrupt autophagic flux at the degradation stage by impairment of lysosomal function, and EGCG-induced cell death was independent of Atg5 or autophagy. The key finding of this study is that EGCG is able to trigger LMP, as evidenced by Lyso-Tracker Red staining, cathepsin D cytosolic translocation and cytosolic acidification. Consistently, a lysosomotropic agent, chloroquine, effectively rescues the cell death via suppressing LMP-caused cytosolic acidification. Lastly, we found that EGCG promotes production of intracellular ROS upstream of LMP and cell death, as evidenced by increased level of ROS in cells treated with EGCG and the protective effects of antioxidant N-acetylcysteine (NAC) against EGCG-mediated LMP and cell death. Taken together, data from our study reveal a novel mechanism underlying EGCG-induced cell death involving ROS and LMP. Therefore, understanding this lysosome-associated cell death pathway shed new lights on the anti-cancer effects of EGCG.PLoS ONE 10/2012; 7(10):e46749. DOI:10.1371/journal.pone.0046749 · 3.53 Impact Factor