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Biomolecules Aug 2023Autophagy is the key process by which the cell degrades parts of itself within the lysosomes. It maintains cell survival and homeostasis by removing molecules... (Review)
Review
Autophagy is the key process by which the cell degrades parts of itself within the lysosomes. It maintains cell survival and homeostasis by removing molecules (particularly proteins), subcellular organelles, damaged cytoplasmic macromolecules, and by recycling the degradation products. The selective removal or degradation of mitochondria is a particular type of autophagy called mitophagy. Various forms of cellular stress (oxidative stress (OS), hypoxia, pathogen infections) affect autophagy by inducing free radicals and reactive oxygen species (ROS) formation to promote the antioxidant response. Dysfunctional mechanisms of autophagy have been found in different respiratory diseases such as chronic obstructive lung disease (COPD) and asthma, involving epithelial cells. Several existing clinically approved drugs may modulate autophagy to varying extents. However, these drugs are nonspecific and not currently utilized to manipulate autophagy in airway diseases. In this review, we provide an overview of different autophagic pathways with particular attention on the dysfunctional mechanisms of autophagy in the epithelial cells during asthma and COPD. Our aim is to further deepen and disclose the research in this direction to stimulate the develop of new and selective drugs to regulate autophagy for asthma and COPD treatment.
Topics: Humans; Mitophagy; Autophagy; Respiration Disorders; Oxidative Stress; Asthma; Pulmonary Disease, Chronic Obstructive; Epithelial Cells; Lysosomes
PubMed: 37627282
DOI: 10.3390/biom13081217 -
Aging Cell Aug 2021The mechanistic target of rapamycin (mTOR) has gathered significant attention as a ubiquitously expressed multimeric kinase with key implications for cell growth,... (Review)
Review
The mechanistic target of rapamycin (mTOR) has gathered significant attention as a ubiquitously expressed multimeric kinase with key implications for cell growth, proliferation, and survival. This kinase forms the central core of two distinct complexes, mTORC1 and mTORC2, which share the ability of integrating environmental, nutritional, and hormonal cues but which regulate separate molecular pathways that result in different cellular responses. Particularly, mTORC1 has been described as a major negative regulator of endosomal biogenesis and autophagy, a catabolic process that degrades intracellular components and organelles within the lysosomes and is thought to play a key role in human health and disease. In contrast, the role of mTORC2 in the regulation of autophagy has been considerably less studied despite mounting evidence this complex may regulate autophagy in a different and perhaps complementary manner to that of mTORC1. Genetic ablation of unique subunits is currently being utilized to study the differential effects of the two mTOR complexes. RICTOR is the best-described subunit specific to mTORC2 and as such has become a useful tool for investigating the specific actions of this complex. The development of complex-specific inhibitors for mTORC2 is also an area of intense interest. Studies to date have demonstrated that mTORC1/2 complexes each signal to a variety of exclusive downstream molecules with distinct biological roles. Pinpointing the particular effects of these downstream effectors is crucial toward the development of novel therapies aimed at accurately modulating autophagy in the context of human aging and disease.
Topics: Autophagy; Humans; Mechanistic Target of Rapamycin Complex 2
PubMed: 34250734
DOI: 10.1111/acel.13431 -
Trends in Genetics : TIG Jul 2022Cellular trafficking is essential to maintain critical biological functions. Mutations in 346 genes, most of them described in the last 5 years, are associated with... (Review)
Review
Cellular trafficking is essential to maintain critical biological functions. Mutations in 346 genes, most of them described in the last 5 years, are associated with disorders of cellular trafficking. Whereas initially restricted to membrane trafficking, the recent detection of many diseases has contributed to the discovery of new biological pathways. Accordingly, we propose to redesign this rapidly growing group of diseases combining biological mechanisms and clinical presentation into the following categories: (i) membrane trafficking (including organelle-related); (ii) membrane contact sites; (iii) autophagy; (iv) cytoskeleton-related. We present the most recently described pathophysiological findings, disorders and phenotypes. Although all tissues and organs are affected, the nervous system is especially vulnerable.
Topics: Autophagy; Cytoskeleton; Organelles
PubMed: 35367088
DOI: 10.1016/j.tig.2022.02.012 -
Autophagy Feb 2022Nucleophagy, the selective subtype of autophagy that predominantly targets only a selected and (nonessential) portion of the nucleus, and rarely the nucleus in its...
Nucleophagy, the selective subtype of autophagy that predominantly targets only a selected and (nonessential) portion of the nucleus, and rarely the nucleus in its entirety, for degradation, reinforces the paradigm that nucleophagy recycling is a meticulous and highly delicate process guarded by fail-safe mechanisms. Our goal in this commentary is to encourage autophagy researchers and other scientists to explore nucleophagy blind spots and gain advanced insights into the diverse roles of this process and its selective modality as they pertain to intranuclear quality control and cellular homeostasis. Identifying and deciphering nucleophagic signaling, regulation, molecular mechanism(s) and its mediators, cargo composition and nuclear membrane dynamics under numerous physiological and/or pathological settings will provide important advances in our understanding of this critical type of organelle-selective autophagy.: INM, inner nuclear membrane; LN, late nucleophagy; mRNA, messenger RNA; NE, nuclear envelope; NL, nuclear lamina; NPC(s), nuclear pore complex(es); NVJ(s), nucleus-vacuole junction(s); ONM, outer nuclear membrane; PMN, piecemeal microautophagy of the nucleus; PND, programmed nuclear death; PNuD, programmed nuclear destruction; rDNArRNA, ribosomal DNA/RNA.
Topics: Autophagy; Cell Nucleus; DNA, Ribosomal; Microautophagy; Nuclear Envelope; Saccharomyces cerevisiae
PubMed: 34643473
DOI: 10.1080/15548627.2021.1971380 -
Genes Feb 2023Lipotoxicity is a phenomenon of lipid-induced cellular injury in nonadipose tissue. Excess of free saturated fatty acids (SFAs) contributes to hepatic injury in... (Review)
Review
Lipotoxicity is a phenomenon of lipid-induced cellular injury in nonadipose tissue. Excess of free saturated fatty acids (SFAs) contributes to hepatic injury in nonalcoholic fatty liver disease (NAFLD), which has been growing at an unprecedented rate in recent years. SFAs and their derivatives such as ceramides and membrane phospholipids have been shown to induce intrahepatic oxidative damage and ER stress. Autophagy represents a cellular housekeeping mechanism to counter the perturbation in organelle function and activation of stress signals within the cell. Several aspects of autophagy, including lipid droplet assembly, lipophagy, mitophagy, redox signaling and ER-phagy, play a critical role in mounting a strong defense against lipotoxic lipid species within the hepatic cells. This review provides a succinct overview of our current understanding of autophagy-lipotoxicity interaction and its pharmacological and nonpharmacological modulation in treating NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Autophagy; Hepatocytes; Mitophagy; Ceramides; Fatty Acids, Nonesterified
PubMed: 36874473
DOI: 10.3390/genes14030553 -
Cells Dec 2022Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in... (Review)
Review
Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury.
Topics: Humans; Aged; Liver; Autophagy; Mitochondria; Mitophagy; Reperfusion Injury; Ischemia
PubMed: 36552847
DOI: 10.3390/cells11244083 -
International Journal of Molecular... May 2023A number of muscular disorders are hallmarked by the aggregation of misfolded proteins within muscle fibers. A specialized form of macroautophagy, termed aggrephagy, is... (Review)
Review
A number of muscular disorders are hallmarked by the aggregation of misfolded proteins within muscle fibers. A specialized form of macroautophagy, termed aggrephagy, is designated to remove and degrade protein aggregates. This review aims to summarize what has been studied so far about the direct involvement of aggrephagy and the activation of the key players, among others, p62, NBR1, Alfy, Tollip, Optineurin, TAX1BP1 and CCT2 in muscular diseases. In the first part of the review, we describe the aggrephagy pathway with the involved proteins; then, we illustrate the muscular disorder histologically characterized by protein aggregates, highlighting the role of aggrephagy pathway abnormalities in these muscular disorders.
Topics: Humans; Macroautophagy; Protein Aggregates; Autophagy; Apoptosis Regulatory Proteins; Muscular Diseases
PubMed: 37176163
DOI: 10.3390/ijms24098456 -
British Journal of Pharmacology Jul 2023Ageing is the main risk factor common to most primary neurodegenerative disorders. Indeed, age-related brain alterations have been long considered to predispose to... (Review)
Review
Ageing is the main risk factor common to most primary neurodegenerative disorders. Indeed, age-related brain alterations have been long considered to predispose to neurodegeneration. Although protein misfolding and the accumulation of toxic protein aggregates have been considered as causative events in neurodegeneration, several other biological pathways affected by brain ageing also contribute to pathogenesis. Here, we discuss the evidence showing the involvement of the mechanisms controlling neuronal structure, gene expression, autophagy, cell metabolism and neuroinflammation in the onset and progression of neurodegenerative disorders. Furthermore, we review the therapeutic strategies currently under development or as future approaches designed to normalize these pathways, which may then increase brain resilience to cope with toxic protein species. In addition to therapies targeting the insoluble protein aggregates specifically associated with each neurodegenerative disorder, these novel pharmacological approaches may be part of combined therapies designed to rescue brain function.
Topics: Humans; Protein Aggregates; Neurodegenerative Diseases; Proteins; Autophagy
PubMed: 36965025
DOI: 10.1111/bph.16078 -
Current Opinion in Critical Care Aug 2023Critical illness imposes a severe insult on the body, with various stressors triggering pronounced cell damage. This compromises cellular function, leading to a high... (Review)
Review
PURPOSE OF REVIEW
Critical illness imposes a severe insult on the body, with various stressors triggering pronounced cell damage. This compromises cellular function, leading to a high risk of multiple organ failure. Autophagy can remove damaged molecules and organelles but appears insufficiently activated during critical illness. This review discusses insight into the role of autophagy in critical illness and the involvement of artificial feeding in insufficient autophagy activation in critical illness.
RECENT FINDINGS
Animal studies manipulating autophagy have shown its protective effects against kidney, lung, liver, and intestinal injury after several critical insults. Autophagy activation also protected peripheral, respiratory, and cardiac muscle function, despite aggravated muscle atrophy. Its role in acute brain injury is more equivocal. Animal and patient studies showed that artificial feeding suppressed autophagy activation in critical illness, particularly with high protein/amino acid doses. Feeding-suppressed autophagy may explain short and long-term harm by early enhanced calorie/protein feeding in large randomized controlled trials.
SUMMARY
Insufficient autophagy during critical illness is at least partly explained by feeding-induced suppression. This may explain why early enhanced nutrition failed to benefit critically ill patients or even induced harm. Safe, specific activation of autophagy avoiding prolonged starvation opens perspectives for improving outcomes of critical illness.
Topics: Animals; Humans; Critical Illness; Autophagy; Nutritional Support; Nutritional Status; Liver
PubMed: 37306474
DOI: 10.1097/MCC.0000000000001056 -
Biomedicine & Pharmacotherapy =... Feb 2020Astrocytes can serve multiple functions in maintaining cellular homeostasis of the central nervous system (CNS), and normal functions for autophagy in astrocytes is... (Review)
Review
Astrocytes can serve multiple functions in maintaining cellular homeostasis of the central nervous system (CNS), and normal functions for autophagy in astrocytes is considered to have very vital roles in the pathogenesis of aging and neurodegenerative diseases. Autophagy is a major intracellular lysosomal (or its yeast analog, vacuolar) clearance pathways involved in the degradation and recycling of long-lived proteins, oxidatively damaged proteins and dysfunctional organelles by lysosomes. Current evidence has shown that autophagy might influence inflammation, oxidative stress, aging and function of astrocytes. Although the interrelation between autophagy and inflammation, oxidative stress, aging or neurological disorders have been addressed in detail, the influence of astrocytes mediated-autophagy in aging and neurodegenerative disorders has yet to be fully reviewed. In this review, we will summarize the most up-to-date findings and highlight the role of autophagy in astrocytes and link autophagy of astrocytes to aging and neurodegenerative diseases. Due to the prominent roles of astrocytic autophagy in age-related neurodegenerative diseases, we believe that we can provide new suggestions for the treatment of these disorders.
Topics: Aging; Animals; Astrocytes; Autophagy; Humans; Inflammation; Lysosomes; Mitophagy; Neurodegenerative Diseases; Oxidative Stress
PubMed: 31786465
DOI: 10.1016/j.biopha.2019.109691