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Brain Pathology (Zurich, Switzerland) Jan 2012Lysosomal myopathies are hereditary myopathies characterized morphologically by the presence of autophagic vacuoles. In mammals, autophagy plays an important role for... (Review)
Review
Lysosomal myopathies are hereditary myopathies characterized morphologically by the presence of autophagic vacuoles. In mammals, autophagy plays an important role for the turnover of cellular components, particularly in response to starvation or glucagons. In normal muscle, autolysosomes or autophagosomes are typically inconspicuous. In distinct neuromuscular disorders, however, lysosomes become structurally abnormal and functionally impaired, leading to the accumulation of autophagic vacuoles in myofibers. In some instances, the accumulation of autophagic vacuoles can be a prominent feature, implicating autophagy as a contributor to disease pathomechanism and/or progression. At present, there are two disorders in the muscle that are associated with a primary defect in lysosomal proteins, namely Pompe disease and Danon disease. This review will give a brief discussion on these disorders, highlighting the role of autophagy in disease progression.
Topics: Animals; Autophagy; Glycogen Storage Disease Type II; Glycogen Storage Disease Type IIb; Humans; Lysosomes; Muscle, Striated; Myositis
PubMed: 22150923
DOI: 10.1111/j.1750-3639.2011.00543.x -
Autophagy Jan 2022Ion exchange between intracellular and extracellular spaces is the basic mechanism for controlling cell metabolism and signal transduction. This process is mediated by...
Ion exchange between intracellular and extracellular spaces is the basic mechanism for controlling cell metabolism and signal transduction. This process is mediated by ion channels and transporters on the plasma membrane, or intracellular membranes that surround various organelles, in response to environmental stimuli. Macroautophagy (hereafter referred to as autophagy) is one of the lysosomal-dependent degradation pathways that maintains homeostasis through the degradation and recycling of cellular components (e.g., dysfunctional proteins and damaged organelles). Although autophagy-related (ATG) proteins play a central role in regulating the formation of autophagy-related member structures (e.g., phagophores, autophagosomes, and autolysosomes), the autophagic process also involves changes in expression and function of ion channels and transporters. Here we discuss current knowledge of the mechanisms that regulate autophagy in mammalian cells, with special attention to the ion channels and transporters. We also highlight prospects for the development of drugs targeting ion channels and transporters in autophagy.
Topics: Animals; Autophagosomes; Autophagy; Intracellular Membranes; Ion Channels; Lysosomes; Mammals
PubMed: 33657975
DOI: 10.1080/15548627.2021.1885147 -
Cell Structure and Function Feb 2002Mouse SKD1 AAA ATPase is involved in the sorting and transport from endosomes; cells overexpressing a dominant-negative mutant, SKD1(E235Q) were defective in endosomal...
Mouse SKD1 AAA ATPase is involved in the sorting and transport from endosomes; cells overexpressing a dominant-negative mutant, SKD1(E235Q) were defective in endosomal transport to both the plasma membranes and lysosomes (Yoshimori et al., 2000). In the present study, we demonstrated that overexpression of SKD1(E235Q) using an adenovirus delivery system caused a defect in autophagy-dependent bulk protein degradation. Morphological observations suggested that this inhibition of autophagy results from an impairment of autolysosome formation. SKD1(E235Q) overexpression also inhibited transport from endosomes to autophagosomes, an event normally occurring prior to fusion with lysosomes. These results indicate that SKD1-dependent endosomal membrane trafficking is required for formation of autolysosomes.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Adenoviridae; Amino Acid Substitution; Autophagy; Biological Transport; Endosomal Sorting Complexes Required for Transport; Endosomes; HeLa Cells; Humans; Lipid Metabolism; Lysosomes; Membrane Fusion; Phagosomes; Point Mutation; Repressor Proteins; Vacuolar Proton-Translocating ATPases; Vesicular Transport Proteins
PubMed: 11937716
DOI: 10.1247/csf.27.29 -
Oncogene Apr 2013Rapidly dividing and invasive cancer cells are strongly dependent on effective lysosomal function. Accordingly, transformation and cancer progression are characterized... (Review)
Review
Rapidly dividing and invasive cancer cells are strongly dependent on effective lysosomal function. Accordingly, transformation and cancer progression are characterized by dramatic changes in lysosomal volume, composition and cellular distribution. Depending on one's point of view, the cancer-associated changes in the lysosomal compartment can be regarded as friends or foes. Most of them are clearly transforming as they promote invasive growth, angiogenesis and drug resistance. The same changes can, however, strongly sensitize cells to lysosomal membrane permeabilization and thereby to lysosome-targeting anti-cancer drugs. In this review we compile our current knowledge on cancer-associated changes in lysosomal composition and discuss the consequences of these alterations to cancer progression and the possibilities they can bring to cancer therapy.
Topics: Animals; Apoptosis; Cell Death; Humans; Lysosomes; Neoplasm Metastasis; Neoplasms
PubMed: 22777359
DOI: 10.1038/onc.2012.292 -
Chembiochem : a European Journal of... Jun 2024Lysosomes are membrane-enclosed organelles that play key roles in degrading and recycling cellular debris, cellular signaling, and energy metabolism processes.... (Review)
Review
Lysosomes are membrane-enclosed organelles that play key roles in degrading and recycling cellular debris, cellular signaling, and energy metabolism processes. Confinement of amphiphilic peptides in the lysosome to construct functional nanostructures through noncovalent interactions is an emerging approach to tune the homeostasis of lysosome. After briefly introducing the importance of lysosome and its functions, we discuss the advantages of lysosomal nanostructure formation for disease therapy. We next discuss the strategy for triggering the self-assembly of peptides in the lysosome, followed by a concise outlook of the future perspective about this emerging research direction.
Topics: Lysosomes; Humans; Peptides; Nanostructures; Animals
PubMed: 38660742
DOI: 10.1002/cbic.202400232 -
Autophagy Nov 2022Genetic evidence has increasingly linked lysosome dysfunction to an impaired autophagy-lysosomal pathway (ALP) flux in Alzheimer disease (AD) although the relationship...
Genetic evidence has increasingly linked lysosome dysfunction to an impaired autophagy-lysosomal pathway (ALP) flux in Alzheimer disease (AD) although the relationship of these abnormalities to other pathologies is unclear. In our recent investigation on the origin of impaired autophagic flux in AD, we established the critical early role of defective lysosomes in five mouse AD models. To assess alterations of autophagy and ALP vesicle acidification, we expressed eGFP-mRFP-LC3 specifically in neurons. We discovered that autophagy dysfunction in these models arises from exceptionally early failure of autolysosome/lysosome acidification, which then drives downstream AD pathogenesis. Extreme autophagic stress in compromised but still intact neurons causes autophagic vacuoles (AVs) containing toxic APP metabolites, Aβ/β-CTFs, to pack into huge blebs and protrude from the perikaryon membrane. Most notably, AVs also coalesce with ER tubules and yield fibrillar β-amyloid within these tubules. Collectively, amyloid immunoreactivity within these intact neurons assumes the appearance of amyloid-plaques, and indeed, their eventual death transforms them into extracellular plaque lesions. Quantitative analysis confirms that neurons undergoing this transformation are the principal source of β-amyloid-plaques in APP-AD models. These findings prompt reconsideration of the conventionally accepted sequence of events in plaque formation and may help explain the inefficacy of Aβ/amyloid vaccine therapies.
Topics: Animals; Mice; Alzheimer Disease; Amyloid beta-Protein Precursor; Autophagy; Amyloid beta-Peptides; Lysosomes; Plaque, Amyloid; Disease Models, Animal; Hydrogen-Ion Concentration; Mice, Transgenic
PubMed: 35947489
DOI: 10.1080/15548627.2022.2110729 -
Autophagy Feb 2011Determination of autophagic flux is essential to assess and differentiate between the induction or suppression of autophagy. Western blot analysis for free GFP fragments...
Determination of autophagic flux is essential to assess and differentiate between the induction or suppression of autophagy. Western blot analysis for free GFP fragments resulting from the degradation of GFP-LC3 within the autolysosome has been proposed as one of the autophagic flux assays. However, the exact dynamics of GFP-LC3 during the autophagy process are not clear. Moreover, the characterization of this assay in mammalian cells is limited. Here we found that lysosomal acidity is an important regulating factor for the step-wise degradation of GFP-LC3, in which the free GFP fragments are first generated but accumulate only when the lysosomal acidity is moderate, such as during rapamycin treatment. When the lysosomal acidity is high, such as during starvation in Earle's balanced salt solution (EBSS), the GFP fragments are further degraded and thus do not accumulate. Much to our surprise, we found that the level of free GFP fragments increased in the presence of several late stage autophagy inhibitors, such as chloroquine or E64D plus pepstatin A. Furthermore, the amount of free GFP fragments depends on the concentrations of these inhibitors. Unsaturating concentrations of chloroquine or bafilomycin A1 increased the level of free GFP fragments while saturating concentrations did not. Data from the present study demonstrate that GFP-LC3 is degraded in a step-wise fashion in the autolysosome, in which the LC3 portion of the fusion protein appears to be more rapidly degraded than GFP. However, the amount of free GFP fragments does not necessarily correlate with autophagic flux if the lysosomal enzyme activity and pH are changed. Therefore, caution must be used when conducting the GFP-LC3 cleavage assay as a determinant of autophagic flux. In order to accurately assess autophagy, it is more appropriate to assess GFP-LC3 cleavage in the presence or absence of saturating or unsaturating concentrations of chloroquine or bafilomycin A1 together with other autophagy markers, such as levels of p62 and endogenous LC3-II.
Topics: Amino Acids; Animals; Autophagy; Cell Compartmentation; Chloroquine; Culture Media; Fluorescence; Green Fluorescent Proteins; HCT116 Cells; HeLa Cells; Humans; Hydrogen-Ion Concentration; Luminescent Proteins; Lysosomes; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Models, Biological; Recombinant Fusion Proteins; Sirolimus; Red Fluorescent Protein
PubMed: 21107021
DOI: 10.4161/auto.7.2.14181 -
Journal of Biochemical and Molecular... Nov 2012Anthocyanidins, which are polyphenols that are believed to be effective for preventing cancer, are composed of a basic structure of the plant pigment anthocyanin. In...
Anthocyanidins, which are polyphenols that are believed to be effective for preventing cancer, are composed of a basic structure of the plant pigment anthocyanin. In this study, we investigated the biological activity of anthocyanidins, including delphinidin, against HeLa cells. The cytotoxicity observed in the anthocyanidins-treated cells was well correlated with the inhibitory effects of anthocyanidins on c-Jun-dependent transcriptional activity. Remarkably, anthocyanidin induced autophagosome formation but lacked the ability to induce apoptosis. Notably, delphinidin enhanced autolysosome formation as well as autophagosome formation. Delphinidin treatment resulted in the accumulation of the lipidated form of Map1lc3b protein in an Atg5-dependent manner in mouse embryonic fibroblasts. Finally, we revealed that the cytotoxicity induced by delphinidin was more severe in Atg5-deficient mouse embryonic fibroblasts than in wild-type cells. Taken together, these results indicate that the cytotoxicity induced by delphinidin was accompanied by autophagy and delphinidin-induced autophagy exerted a cell protective role.
Topics: Animals; Anthocyanins; Anticarcinogenic Agents; Autophagy; Autophagy-Related Protein 5; Cell Survival; Cells, Cultured; Embryo, Mammalian; Fibroblasts; HeLa Cells; Humans; Lysosomes; MAP Kinase Signaling System; Mice; Mice, Knockout; Microtubule-Associated Proteins; Osmolar Concentration; Phagosomes; Recombinant Fusion Proteins
PubMed: 23129091
DOI: 10.1002/jbt.21443 -
Autophagosomes, phagosomes, autolysosomes, phagolysosomes, autophagolysosomes... wait, I'm confused.Autophagy Apr 2014When an autophagosome or an amphisome fuse with a lysosome, the resulting compartment is referred to as an autolysosome. Some people writing papers on the topic of...
When an autophagosome or an amphisome fuse with a lysosome, the resulting compartment is referred to as an autolysosome. Some people writing papers on the topic of autophagy use the terms "autolysosome" and "autophagolysosome" interchangeably. We contend that these words should be used to denote 2 different compartments, and that it is worthwhile maintaining this distinction-the autophagolysosome has a particular origin in the process of xenophagy that makes it distinct from an autolysosome.
Topics: Animals; Autophagy; Humans; Lysosomes; Phagosomes; Terminology as Topic
PubMed: 24657946
DOI: 10.4161/auto.28448 -
The Journal of Cell Biology Sep 2023Formation and fission of tubules from autolysosomes, endolysosomes, or phagolysosomes are required for lysosome reformation. However, the mechanisms governing these...
Formation and fission of tubules from autolysosomes, endolysosomes, or phagolysosomes are required for lysosome reformation. However, the mechanisms governing these processes in these different lysosomal organelles are poorly understood. Thus, the role of phosphatidylinositol-4-phosphate (PI(4)P) is unclear as it was shown to promote the formation of tubules from phagolysosomes but was proposed to inhibit tubule formation on autolysosomes because the loss of PI4KIIIβ causes extensive lysosomal tubulation. Using super-resolution live-cell imaging, we show that Arf1-PI4KIIIβ positive vesicles are recruited to tubule fission sites from autolysosomes, endolysosomes, and phagolysosomes. Moreover, we show that PI(4)P is required to form autolysosomal tubules and that increased lysosomal tubulation caused by loss of PI4KIIIβ represents impaired tubule fission. At the site of fission, we propose that Arf1-PI4KIIIβ positive vesicles mediate a PI(3)P signal on lysosomes in a process requiring the lipid transfer protein SEC14L2. Our findings indicate that Arf1-PI4KIIIβ positive vesicles and their regulation of PI(3)P are critical components of the lysosomal tubule fission machinery.
Topics: Lysosomes; Signal Transduction; ADP-Ribosylation Factor 1; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 37289133
DOI: 10.1083/jcb.202205128