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Molecules and Cells Aug 2023Lipofuscins are oxidized lipid and protein complexes that accumulate during cellular senescence and tissue aging, regarded as markers for cellular oxidative damage,...
Lipofuscins are oxidized lipid and protein complexes that accumulate during cellular senescence and tissue aging, regarded as markers for cellular oxidative damage, tissue aging, and certain aging-associated diseases. Therefore, understanding their cellular biological properties is crucial for effective treatment development. Through traditional microscopy, lipofuscins are readily observed as fluorescent granules thought to accumulate in lysosomes. However, lipofuscin granule formation and accumulation in senescent cells are poorly understood. Thus, this study examined lipofuscin accumulation in human fibroblasts exposed to various stressors. Our results substantiate that in glucose-starved or replicative senescence cells, where elevated oxidative stress levels activate autophagy, lipofuscins predominately appear as granules that co-localize with autolysosomes due to lysosomal acidity or impairment. Meanwhile, autophagosome formation is attenuated in cells experiencing oxidative stress induced by a doxorubicin pulse and chase, and lipofuscin fluorescence granules seldom manifest in the cytoplasm. As Torin-1 treatment activates autophagy, granular lipofuscins intensify and dominate, indicating that autophagy activation triggers their accumulation. Our results suggest that high oxidative stress activates autophagy but fails in lipofuscin removal, leaving an abundance of lipofuscin-filled impaired autolysosomes, referred to as residual bodies. Therefore, future endeavors in treating lipofuscin pathology-associated diseases and dysfunctions through autophagy activation demand meticulous consideration.
Topics: Humans; Lipofuscin; Aging; Cellular Senescence; Oxidative Stress; Lysosomes; Autophagy
PubMed: 37438887
DOI: 10.14348/molcells.2023.0019 -
Journal of Cell Science Jun 2022Lysosomes exert pleiotropic functions to maintain cellular homeostasis and degrade autophagy cargo. Despite the great advances that have boosted our understanding of... (Review)
Review
Lysosomes exert pleiotropic functions to maintain cellular homeostasis and degrade autophagy cargo. Despite the great advances that have boosted our understanding of autophagy and lysosomes in both physiology and pathology, their function in mitosis is still controversial. During mitosis, most organelles are reshaped or repurposed to allow the correct distribution of chromosomes. Mitotic entry is accompanied by a reduction in sites of autophagy initiation, supporting the idea of an inhibition of autophagy to protect the genetic material against harmful degradation. However, there is accumulating evidence revealing the requirement of selective autophagy and functional lysosomes for a faithful chromosome segregation. Degradation is the most-studied lysosomal activity, but recently described alternative functions that operate in mitosis highlight the lysosomes as guardians of mitotic progression. Because the involvement of autophagy in mitosis remains controversial, it is important to consider the specific contribution of signalling cascades, the functions of autophagic proteins and the multiple roles of lysosomes, as three entangled, but independent, factors controlling genomic stability. In this Review, we discuss the latest advances in this area and highlight the therapeutic potential of targeting autophagy for drug development.
Topics: Autophagy; Lysosomes; Mitosis; Phagocytosis; Signal Transduction
PubMed: 35686549
DOI: 10.1242/jcs.255802 -
Cellular Physiology and Biochemistry :... May 2021The lysosome is a single ubiquitous membrane-enclosed intracellular organelle with an acidic pH present in all eukaryotic cells, which contains large numbers of... (Review)
Review
The lysosome is a single ubiquitous membrane-enclosed intracellular organelle with an acidic pH present in all eukaryotic cells, which contains large numbers of hydrolytic enzymes with their maximal enzymatic activity at a low pH (pH ≤ 5) such as proteases, nucleases, and phosphatases that are able to degrade extracellular and intracellular components. It is well known that lysosomes act as a center for degradation and recycling of large numbers of macromolecules delivered by endocytosis, phagocytosis, and autophagy. Lysosomes are recognized as key organelles for cellular clearance and are involved in many cellular processes and maintain cellular homeostasis. Recently, it has been shown that lysosome function and its related pathways are of particular importance in vascular regulation and related diseases. In this review, we highlighted studies that have improved our understanding of the connection between lysosome function and vascular physiological and pathophysiological activities in arterial smooth muscle cells (SMCs) and endothelial cells (ECs). Sphingolipids-metabolizingenzymes in lysosomes play critical roles in intracellular signaling events that influence cellular behavior and function in SMCs and ECs. The focus of this review will be to define the mechanism by which the lysosome contributes to cardiovascular regulation and diseases. It is believed that exploring the role of lysosomal function and its sphingolipid metabolism in the initiation and progression of vascular disease and regulation may provide novel insights into the understanding of vascular pathobiology and helps develop more effective therapeutic strategies for vascular diseases.
Topics: Animals; Cardiovascular Diseases; Endothelial Cells; Humans; Lysosomes; Myocytes, Smooth Muscle; Sphingolipids
PubMed: 34019755
DOI: 10.33594/000000373 -
Future Microbiology Sep 2023HSV can evade host defenses and cause lifelong infection and severe illness. Lysosomes are catabolic organelles that play an important role in the regulation of... (Review)
Review
HSV can evade host defenses and cause lifelong infection and severe illness. Lysosomes are catabolic organelles that play an important role in the regulation of cellular homeostasis. Lysosomal dysfunction and alterations in the process of autophagy have been identified in a variety of diseases, including HSV infection, and targeting lysosomes is a potential anti-HSV therapeutic strategy. This article reviews the role of lysosomes and lysosome-associated proteins in HSV infection, providing attractive targets and novel strategies for the treatment of HSV infection.
Topics: Homeostasis; Autophagy; Lysosomes
PubMed: 37584568
DOI: 10.2217/fmb-2023-0090 -
Trends in Biochemical Sciences Oct 2020Autophagy is a highly conserved degradation pathway that ensures nutrient recycling and removal of unwanted substrates. This process has a fundamental role in stress... (Review)
Review
Autophagy is a highly conserved degradation pathway that ensures nutrient recycling and removal of unwanted substrates. This process has a fundamental role in stress adaptation and maintenance of cellular homeostasis. Here, we discuss emerging aspects of the autophagy-RNA interplay, including autophagy-mediated degradation of RNA, RNA-binding proteins (RBPs), and ribonucleoprotein (RNP) complexes. Beyond degradation, we review new roles for autophagy players in the secretion and intracellular transport of RNA and related complexes. We discuss the physiological importance of these events for RNA homeostasis and gene expression programs, as well as their implications for disease, including cancer and neurodegeneration. Lastly, we examine how post-transcriptional regulation of autophagy, through specialized processing and selective translation of key transcripts, challenges and updates our current view of autophagy complexity.
Topics: Autophagy; Biological Transport; Homeostasis; Hydrolysis; Lysosomes; RNA; Ribonucleoproteins
PubMed: 32828649
DOI: 10.1016/j.tibs.2020.07.007 -
Drug Discovery Today Nov 2023Recently, targeted protein degradation technologies based on lysosomal pathways have been developed. Lysosome-based targeted protein degradation technology has a broad... (Review)
Review
Recently, targeted protein degradation technologies based on lysosomal pathways have been developed. Lysosome-based targeted protein degradation technology has a broad range of substrates and the potential to degrade intracellular and extracellular proteins, protein aggregates, damaged organelles and non-protein molecules. Thus, they hold great promise for drug R&D. This study has focused on the biogenesis of lysosomes, their basic functions, lysosome-associated diseases and targeted protein degradation technologies through the lysosomal pathway. In addition, we thoroughly examine the potential applications and limitations of this technology and engage in insightful discussions on potential avenues for future research. Our primary objective is to foster preclinical research on this technology and facilitate its successful clinical implementation.
Topics: Proteolysis; Lysosomes; Proteins; Autophagy
PubMed: 37708931
DOI: 10.1016/j.drudis.2023.103767 -
Journal of Trace Elements in Medicine... Dec 2020Autophagy is a conserved catabolic process that plays an important role in cellular homeostasis. The study of the interplay between autophagy and zinc has gained... (Review)
Review
Autophagy is a conserved catabolic process that plays an important role in cellular homeostasis. The study of the interplay between autophagy and zinc has gained interest over the last years. Multiple studies have indicated that zinc stimulates autophagy and is critical for basal and induced autophagy in mammalian cells. Conversely, autophagy is induced by zinc starvation in yeast. There are no studies analyzing the role of zinc in either Microautophagy or Chaperone-Mediated-Autophagy. The mechanisms by which zinc modulates autophagy are still poorly understood. Studies examining loss of function of genes involved in cellular zinc homeostasis have provided novel insights into the role of zinc in autophagy. Autophagy may help cells adapt to changes in zinc availability in medium by controlling zinc mobilization, recycling, and secretion. Zinc is a key player in toxic and protective autophagy.
Topics: Animals; Autophagy; Humans; Lysosomes; Metallothionein; Mitophagy; Zinc
PubMed: 32957075
DOI: 10.1016/j.jtemb.2020.126636 -
Neuroscience Letters Sep 2021Lysosomal storage diseases were recognized and defined over a century ago as a class of disorders affecting mostly children and causing systemic disease often...
Lysosomal storage diseases were recognized and defined over a century ago as a class of disorders affecting mostly children and causing systemic disease often accompanied by major neurological consequences. Since their discovery, research focused on understanding their causes has been an important driver of our ever-expanding knowledge of cell biology and the central role that lysosomes play in cell function. Today we recognize over 50 so-called storage diseases, with most understood at the level of gene, protein and pathway involvement, but few fully clarified in terms of how the defective lysosomal function causes brain disease; even fewer have therapies that can effectively rescue brain function. Importantly, we also recognize that storage diseases are not simply a class of lysosomal disorders all by themselves, as increasingly a critical role for the greater lysosomal system with its endosomal, autophagosomal and salvage streams has also emerged in a host of neurodevelopmental and neurodegenerative diseases. Despite persistent challenges across all aspects of these complex disorders, and as reflected in this and other articles focused on lysosomal storage diseases in this special issue of Neuroscience Letters, the progress and promise to both understand and effectively treat these conditions has never been greater.
Topics: Animals; Humans; Lysosomal Storage Diseases; Lysosomes
PubMed: 34358625
DOI: 10.1016/j.neulet.2021.136155 -
Journal of Leukocyte Biology Nov 2023Lysosomal compartments undergo extensive remodeling during dendritic cell (DC) activation to meet the dynamic functional requirements of DCs. Instead of being regarded... (Review)
Review
Lysosomal compartments undergo extensive remodeling during dendritic cell (DC) activation to meet the dynamic functional requirements of DCs. Instead of being regarded as stationary and digestive organelles, recent studies have increasingly appreciated the versatile roles of lysosomes in regulating key aspects of DC biology. Lysosomes actively control DC motility by linking calcium efflux to the actomyosin contraction, while enhanced DC lysosomal membrane permeability contributes to the inflammasome activation. Besides, lysosomes provide a platform for the transduction of innate immune signaling and the intricate host-pathogen interplay. Lysosomes and lysosome-associated structures are also critically engaged in antigen presentation and cross-presentation processes, which are pivotal for the induction of antigen-specific adaptive immune response. Through the current review, we emphasize that lysosome targeting strategies serve as vital DC-based immunotherapies in fighting against tumor, infectious diseases, and autoinflammatory disorders.
Topics: Dendritic Cells; Antigen Presentation; Cross-Priming; Signal Transduction; Lysosomes
PubMed: 37774493
DOI: 10.1093/jleuko/qiad117 -
Biochemistry. Biokhimiia Jan 2024Autophagy is the process by which cell contents, such as aggregated proteins, dysfunctional organelles, and cell structures are sequestered by autophagosome and... (Review)
Review
Autophagy is the process by which cell contents, such as aggregated proteins, dysfunctional organelles, and cell structures are sequestered by autophagosome and delivered to lysosomes for degradation. As a process that allows the cell to get rid of non-functional components that tend to accumulate with age, autophagy has been associated with many human diseases. In this regard, the search for autophagy activators and the study of their mechanism of action is an important task for treatment of many diseases, as well as for increasing healthy life expectancy. Plants are rich sources of autophagy activators, containing large amounts of polyphenolic compounds in their composition, which can be autophagy activators in their original form, or can be metabolized by the intestinal microbiota to active compounds. This review is devoted to the plant-based autophagy activators with emphasis on the sources of their production, mechanism of action, and application in various diseases. The review also describes companies commercializing natural autophagy activators.
Topics: Humans; Autophagy; Plants; Lysosomes
PubMed: 38467543
DOI: 10.1134/S0006297924010012