Lysosomal Function and Dysfunction: Mechanism and Disease

Department of Cell Proliferation and Development, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
Antioxidants & Redox Signaling (Impact Factor: 7.41). 11/2011; 17(5):766-74. DOI: 10.1089/ars.2011.4405
Source: PubMed


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.

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    • "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. "

    Protein & Cell 07/2014; 5(8). DOI:10.1007/s13238-014-0085-5 · 3.25 Impact Factor
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    • "In particular, they enter the macrophages—the very immune cells deployed to kill invading pathogens. The inability of most research labs to culture cell wall deficient (CWD) bacteria has been an obstacle to their acceptance, and reliance on Koch’s postulates has made it difficult to correlate CWD bacteria to specific diseases [72]. But some researchers believe Koch’s postulates may have to be redefined in terms of molecular data when dormant and non-culturable bacteria are implicated as causative agents of mysterious diseases [73]. "
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    ABSTRACT: Introduction: Inflammation is believed to be a contributing factor to many chronic diseases. The influence of vitamin D deficiency on inflammation is being explored but studies have not demonstrated a causative effect. Methods: Low serum 25(OH)D is also found in healthy persons exposed to adequate sunlight. Despite increased vitamin D supplementation inflammatory diseases are increasing. The current method of determining vitamin D status may be at fault. The level of 25(OH)D does not always reflect the level of 1,25(OH)2D. Assessment of both metabolites often reveals elevated 1,25(OH)2D, indicating abnormal vitamin D endocrine function. Findings: This article reviews vitamin D's influence on the immune system, examines the myths regarding vitamin D photosynthesis, discusses ways to accurately assess vitamin D status, describes the risks of supplementation, explains the effect of persistent infection on vitamin D metabolism and presents a novel immunotherapy which provides evidence of an infection connection to inflammation. Conclusion: Some authorities now believe that low 25(OH)D is a consequence of chronic inflammation rather than the cause. Research points to a bacterial etiology pathogenesis for an inflammatory disease process which results in high 1,25(OH)2D and low 25(OH)D. Immunotherapy, directed at eradicating persistent intracellular pathogens, corrects dysregulated vitamin D metabolism and resolves inflammatory symptoms.
    Inflammation Research 07/2014; 63(10). DOI:10.1007/s00011-014-0755-z · 2.35 Impact Factor
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    • "Lysosomal defects in LSDs are triggered by mutations of soluble lysosomal enzymes, non-enzymatic lysosomal proteins or non-lysosomal proteins that regulate lysosomal functions. Many LSDs are associated with autophagy defects and autophagosome accumulation [37] as a result of lysosomal dysfunction. Additionally, for various pathological conditions, including neurodegeneration, lysosomal and autophagy dysfunction occur concomitantly and both contribute to the disease progression [38,39], further supporting the close connection between lysosomal dysfunction and autophagy inhibition. "
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    ABSTRACT: Autophagy refers to the catabolic process in eukaryotic cells that delivers cytoplasmic material to lysosomes for degradation. This highly conserved process is involved in the clearance of long-lived proteins and damaged organelles. Consequently, autophagy is important in providing nutrients to maintain cellular function under starvation, maintaining cellular homeostasis, and promoting cell survival under certain conditions. Several pathways, including mTOR, have been shown to regulate autophagy. However, the impact of lysosomal function impairment on the autophagy process has not been fully explored. Basic lipophilic compounds can accumulate in lysosomes via pH partitioning leading to perturbation of lysosomal function. Our hypothesis is that these types of compounds can disturb the autophagy process. Eleven drugs previously shown to accumulate in lysosomes were selected and evaluated for their effects on cytotoxicity and autophagy using ATP depletion and LC3 assessment, respectively. All eleven drugs induced increased staining of endogenous LC3 and exogenous GFP-LC3, even at non toxic dose levels. In addition, an increase in the abundance of SQSTM1/p62 by all tested compounds denotes that the increase in LC3 is due to autophagy perturbation rather than enhancement. Furthermore, the gene expression profile resulting from in vitro treatment with these drugs revealed the suppression of plentiful long-lived proteins, including structural cytoskeletal and associated proteins, and extracellular matrix proteins. This finding indicates a retardation of protein turnover which further supports the notion of autophagy inhibition. Interestingly, upregulation of genes containing antioxidant response elements, e.g. glutathione S transferase and NAD(P)H dehydrogenase quinone 1 was observed, suggesting activation of Nrf2 transcription factor. These gene expression changes could be related to an increase in SQSTM1/p62 resulting from autophagy deficiency. In summary, our data indicate that lysosomal accumulation due to the basic lipophilic nature of xenobiotics could be a general mechanism contributing to the perturbation of the autophagy process.
    PLoS ONE 11/2013; 8(11):e82481. DOI:10.1371/journal.pone.0082481 · 3.23 Impact Factor
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