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Handbook of Experimental Pharmacology 2023Lysosomes are acidic membrane-bound organelles that use hydrolytic enzymes to break down material through pathways such as endocytosis, phagocytosis, mitophagy, and... (Review)
Review
Lysosomes are acidic membrane-bound organelles that use hydrolytic enzymes to break down material through pathways such as endocytosis, phagocytosis, mitophagy, and autophagy. To function properly, intralysosomal environments are strictly controlled by a set of integral membrane proteins such as ion channels and transporters. Potassium ion (K) channels are a large and diverse family of membrane proteins that control K flux across both the plasma membrane and intracellular membranes. In the plasma membrane, they are essential in both excitable and non-excitable cells for the control of membrane potential and cell signaling. However, our understanding of intracellular K channels is very limited. In this review, we summarize the recent development in studies of K channels in the lysosome. We focus on their characterization, potential roles in maintaining lysosomal membrane potential and lysosomal function, and pathological implications.
Topics: Humans; Potassium Channels; Lysosomes; Ion Channels; Cell Membrane; Endocytosis
PubMed: 35879576
DOI: 10.1007/164_2022_600 -
Autophagy Oct 2023Inter-organelle contacts enable crosstalk among organelles, facilitating the exchange of materials and coordination of cellular events. In this study, we demonstrated...
Inter-organelle contacts enable crosstalk among organelles, facilitating the exchange of materials and coordination of cellular events. In this study, we demonstrated that, upon starvation, autolysosomes recruit Pi4KIIα (Phosphatidylinositol 4-kinase II α) to generate phosphatidylinositol-4-phosphate (PtdIns4P) on their surface and establish endoplasmic reticulum (ER)-autolysosome contacts through PtdIns4P binding proteins Osbp (Oxysterol binding protein) and cert (ceramide transfer protein). We found that the Sac1 (Sac1 phosphatase), Osbp, and cert proteins are required for the reduction of PtdIns4P on autolysosomes. Loss of any of these proteins leads to defective macroautophagy/autophagy and neurodegeneration. Osbp, cert, and Sac1 are required for ER-Golgi contacts in fed cells. Our data establishes a new mode of organelle contact formation - the ER-Golgi contact machinery can be reused by ER-autolysosome contacts by re-locating PtdIns4P from the Golgi apparatus to autolysosomes when faced with starvation. Atg1: Autophagy-related 1; Atg8: Autophagy-related 8; Atg9: Autophagy-related 9; Atg12: Autophagy-related 12; cert: ceramide transfer protein; Cp1/CathL: cysteine proteinase-1; CTL: control; ER: endoplasmic reticulum; ERMCS: ER-mitochondria contact site; fwd: four wheel drive; GM130: Golgi matrix protein 130 kD; Osbp: Oxysterol binding protein; PG: phagophore; PtdIns4K: phosphatidylinositol 4-kinase; Pi4KIIα: Phosphatidylinositol 4-kinase II α; Pi4KIIIα: Phosphatidylinositol 4-kinase III α; PtdIns4P: phosphatidylinositol-4-phosphate; PR: photoreceptor cell; RT: room temperature; Sac1: Sac1 phosphatase; Stv: starvation; Syx17: Syntaxin 17; TEM: transmission electron microscopy; VAP: VAMP-associated protein.
Topics: 1-Phosphatidylinositol 4-Kinase; Autophagy; Endoplasmic Reticulum; Lysosomes; Carrier Proteins; Homeostasis; Ceramides; Phosphoric Monoester Hydrolases
PubMed: 37289040
DOI: 10.1080/15548627.2023.2222556 -
Biochimica Et Biophysica Acta.... Mar 2020Autophagy (greek auto: self; phagein: eating) is a highly conserved process within eukaryotes that degrades long-lived proteins and organelles within lysosomes. Its... (Review)
Review
Autophagy (greek auto: self; phagein: eating) is a highly conserved process within eukaryotes that degrades long-lived proteins and organelles within lysosomes. Its accurate and constant operation in basal conditions ensures cellular homeostasis by degrading damaged cellular components and thereby acting not only as a quality control but as well as an energy supplier. An increasing body of evidence indicates a major role of autophagy in the regulation of cardiac homeostasis and function. In this review, we describe the different forms of mammalian autophagy, their regulations and monitoring with a specific emphasis on the heart. Furthermore, we address the role of autophagy in several forms of cardiomyopathy and the options for therapy.
Topics: Autophagy; Cardiomyopathies; Energy Metabolism; Homeostasis; Humans; Lysosomes; Proteolysis
PubMed: 30831130
DOI: 10.1016/j.bbamcr.2019.01.013 -
Traffic (Copenhagen, Denmark) Jan 2020Lysosomes are key cellular catabolic centers that also perform fundamental metabolic, signaling and quality control functions. Lysosomes are not static and they respond... (Review)
Review
Lysosomes are key cellular catabolic centers that also perform fundamental metabolic, signaling and quality control functions. Lysosomes are not static and they respond dynamically to intra- and extracellular stimuli triggering changes in organelle numbers, size and position. Such physical changes have a strong impact on lysosomal activity ultimately influencing cellular homeostasis. In this review, we summarize the current knowledge on lysosomal size regulation, on its physiological role(s) and association to several disease conditions.
Topics: Autophagy; Homeostasis; Lysosomes; Signal Transduction
PubMed: 31808235
DOI: 10.1111/tra.12714 -
Cell Calcium Jul 2023Multiple forms of regulated cell death (RCD) have been characterized, each of which originates from the activation of a dedicated molecular machinery. RCD can occur in... (Review)
Review
Multiple forms of regulated cell death (RCD) have been characterized, each of which originates from the activation of a dedicated molecular machinery. RCD can occur in purely physiological settings or upon failing cellular adaptation to stress. Caions have been shown to physically interact with - and hence regulate - various components of the RCD machinery. Moreover, intracellular Ca accumulation can promote organellar dysfunction to degree that can be overtly cytotoxic or sensitize cells to RCD elicited by other stressors. Here, we provide an overview of the main links between Caand different forms of RCD, including apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, lysosome-dependent cell death, and parthanatos.
Topics: Humans; Apoptosis; Cell Death; Lysosomes; Necrosis; Signal Transduction
PubMed: 37210868
DOI: 10.1016/j.ceca.2023.102759 -
Methods in Cell Biology 2021Ferroptosis is an iron-dependent form of regulated cell death, driven by the accumulation of lipid peroxidation. Autophagy is a lysosome-dependent degradation process...
Ferroptosis is an iron-dependent form of regulated cell death, driven by the accumulation of lipid peroxidation. Autophagy is a lysosome-dependent degradation process that can be used to remove and recover intracellular components, such as dysfunctional proteins and damaged organelles. By regulating iron storage and oxidative stress, excessive autophagy is involved in the induction and execution of ferroptosis. In particular, several types of selective autophagy (e.g., ferritinophagy, lipophagy, clockophagy, and chaperone-mediated autophagy) increase the susceptibility to ferroptotic cell death by degrading anti-ferroptotic regulators (e.g., ferritin, GPX4, ARNTL, and lipid droplets). These two integrated biological processes play a pathological role in the occurrence and development of human diseases, such as cancer, neurodegenerative disorders, ischemia and reperfusion injury. Therefore, it is important to develop reliable methods to evaluate the kinetics of autophagosome formation, iron accumulation, and lipid peroxidation. Here, we introduce some protocols (such as western blotting, lipid peroxidation assay kits and probes, and iron probes) to monitor the process of autophagy-dependent ferroptosis.
Topics: Autophagy; Ferritins; Ferroptosis; Iron; Lysosomes
PubMed: 34311865
DOI: 10.1016/bs.mcb.2020.10.012 -
Autophagy Aug 2021Different types of autophagy co-exist in all mammalian cells, however, the specific contribution of each of these autophagic pathways to the maintenance of cellular... (Review)
Review
Different types of autophagy co-exist in all mammalian cells, however, the specific contribution of each of these autophagic pathways to the maintenance of cellular proteostasis and cellular function remains unknown. In this work, we have investigated the consequences of failure of chaperone-mediated autophagy (CMA) in neurons and compared the impact, on the neuronal proteome, of CMA loss to that of macroautophagy loss. We found that these autophagic pathways are non-redundant and that CMA is the main one responsible for maintenance of the metastable proteome (the one at risk of aggregation). We demonstrate that loss of CMA, as the one that occurs in aging, has a synergistic effect with the proteotoxicity associated with neurodegenerative conditions such as Alzheimer disease (AD) and, conversely, that, pharmacological enhancement of CMA is effective in improving both behavior and pathology in two different AD mouse models.
Topics: Aging; Animals; Autophagy; Chaperone-Mediated Autophagy; Humans; Lysosomes; Neurons; Proteostasis
PubMed: 34110247
DOI: 10.1080/15548627.2021.1935007 -
Current Opinion in Cell Biology Jun 2022Autophagy of the endoplasmic reticulum (ER), known as ER-phagy, is responsible for the degradation of ER portions by lysosomes. ER-phagy is induced in both physiological... (Review)
Review
Autophagy of the endoplasmic reticulum (ER), known as ER-phagy, is responsible for the degradation of ER portions by lysosomes. ER-phagy is induced in both physiological and stress conditions to maintain ER homeostasis and protein quality control. ER-phagy receptors and their interactors are key regulators of this process. Transcriptional and post-translational regulation of ER-phagy receptors have emerged as critical mechanisms for the modulation of ER-phagy, providing the first hints to understand how this process responds to the cellular needs. Here, we concisely review the main mechanisms regulating ER-phagy receptors and discuss their potential implications in diseases.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Lysosomes; Membrane Proteins
PubMed: 35533527
DOI: 10.1016/j.ceb.2022.102084 -
Seminars in Cancer Biology Nov 2020Macroautophagy (herein autophagy) is an intracellular pathway in which cytoplasmic components are captured by double-membrane vesicles (autophagosomes) that eventually... (Review)
Review
Macroautophagy (herein autophagy) is an intracellular pathway in which cytoplasmic components are captured by double-membrane vesicles (autophagosomes) that eventually fuse with lysosomes to degrade the cargo. Basal levels of autophagy in all eukaryotic cells maintain cellular homeostasis and under conditions of stress, organelles and proteins not essential for survival are degraded. Apart from these functions, cargoes like aggregated proteins, damaged organelles and intracellular pathogens, which are otherwise harmful to cells, are also selectively captured by autophagy and are destined for degradation. In terms of infectious diseases, pathogens are cleared by a specific form of autophagy known as xenophagy. This lysosomal mediated degradation of pathogens also increases the antigen presentation of cells thereby inducing a further immune response. The process of xenophagy provides a broad spectrum of defense mechanism to capture bacterial, viral and protozoan pathogens. However, pathogens have developed ingenious mechanisms to modulate xenophagy to enhance their intracellular survival. Meanwhile, certain pathogens also induce deleterious effects such as chronic inflammation and overexpression of oncogenes in the host system. This over time can increase the susceptibility of the host for tumorigenesis. Hence targeting tumor through anti-microbial mechanisms like xenophagy could be a novel strategy for combinatorial anti-cancer therapy. The recent developments in understanding the role of xenophagy in combating cancer causing pathogens will be discussed in this review.
Topics: Animals; Cell Transformation, Neoplastic; Humans; Immunity; Lysosomes; Macroautophagy; Neoplasms; Oncogenes
PubMed: 32126260
DOI: 10.1016/j.semcancer.2020.02.015 -
Nature Cell Biology Sep 2023Lysosomes are catabolic organelles that govern numerous cellular processes, including macromolecule degradation, nutrient signalling and ion homeostasis. Aberrant... (Review)
Review
Lysosomes are catabolic organelles that govern numerous cellular processes, including macromolecule degradation, nutrient signalling and ion homeostasis. Aberrant changes in lysosome abundance are implicated in human diseases. Here we outline the mechanisms of lysosome biogenesis and turnover, and discuss how changes in the lysosome pool impact physiological and pathophysiological processes.
Topics: Humans; Lysosomes; Organelles; Homeostasis; Signal Transduction; Autophagy
PubMed: 37580388
DOI: 10.1038/s41556-023-01197-7