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Mediators of Inflammation 2015Autophagy is an intracellular catabolic pathway essential for the recycling of proteins and larger substrates such as aggregates, apoptotic corpses, or long-lived and... (Review)
Review
Autophagy is an intracellular catabolic pathway essential for the recycling of proteins and larger substrates such as aggregates, apoptotic corpses, or long-lived and superfluous organelles whose accumulation could be toxic for cells. Because of its unique feature to engulf part of cytoplasm in double-membrane cup-shaped structures, which further fuses with lysosomes, autophagy is also involved in the elimination of host cell invaders and takes an active part of the innate and adaptive immune response. Its pivotal role in maintenance of the inflammatory balance makes dysfunctions of the autophagy process having important pathological consequences. Indeed, defects in autophagy are associated with a wide range of human diseases including metabolic disorders (diabetes and obesity), inflammatory bowel disease (IBD), and cancer. In this review, we will focus on interrelations that exist between inflammation and autophagy. We will discuss in particular how mediators of inflammation can regulate autophagy activity and, conversely, how autophagy shapes the inflammatory response. Impact of genetic polymorphisms in autophagy-related gene on inflammatory bowel disease will be also discussed.
Topics: Animals; Autophagy; Humans; Inflammation; Inflammatory Bowel Diseases; Polymorphism, Genetic
PubMed: 26221063
DOI: 10.1155/2015/398483 -
Journal of Molecular Medicine (Berlin,... Jul 2015Autophagy is a protective and life-sustaining process in which cytoplasmic components are packaged into double-membrane vesicles and targeted to lysosomes for... (Review)
Review
Autophagy is a protective and life-sustaining process in which cytoplasmic components are packaged into double-membrane vesicles and targeted to lysosomes for degradation. This process of cellular self-digestion is an essential stress response and is cytoprotective by removing damaged organelles and proteins that threaten the cell's survival. Key outcomes include energy generation and recycling of metabolic precursors. In the immune system, autophagy regulates processes such as antigen uptake and presentation, removal of pathogens, survival of short- and long-lived immune cells, and cytokine-dependent inflammation. In all cases, a window of optimal autophagic activity appears critical to balance catabolic, reparative, and inflammation-inducing processes. Dysregulation of autophagosome formation and autophagic flux can have deleterious consequences, ranging from a failure to "clean house" to the induction of autophagy-induced cell death. Abnormalities in the autophagic pathway have been implicated in numerous autoimmune diseases. Genome-wide association studies have linked polymorphisms in autophagy-related genes with predisposition for tissue-destructive inflammatory disease, specifically in inflammatory bowel disease and systemic lupus erythematosus. Although the precise mechanisms by which dysfunctional autophagy renders the host susceptible to continuous inflammation remain unclear, autophagy's role in regulating the long-term survival of adaptive immune cells has recently surfaced as a defect in multiple sclerosis and rheumatoid arthritis. Efforts are underway to identify autophagy-inducing and autophagy-suppressing pharmacologic interventions that can be added to immunosuppressive therapy to improve outcomes of patients with autoimmune disease.
Topics: Autoimmune Diseases; Autophagy; Humans; Inflammation; Lysosomes; T-Lymphocytes
PubMed: 26054920
DOI: 10.1007/s00109-015-1297-8 -
Cancer Biology & Therapy Jan 2011Although autophagy has been shown to have a clear role as a tumor suppressor mechanism, its role in cancer treatment is still controversial. Because autophagy is a... (Review)
Review
Although autophagy has been shown to have a clear role as a tumor suppressor mechanism, its role in cancer treatment is still controversial. Because autophagy is a survival pathway activated during nutrient deprivation and other stresses, it is reasonable to think that autophagy can function as a tumor cell survival mechanism activated after cancer treatment. Such a mechanism could be widely important because most cancer treatments induce autophagy in tumor cells. Indeed, many papers have presented data suggesting that tumor cell autophagy induced by anti-cancer treatment inhibits tumor cell killing. However, it has also been proposed that autophagy is a cell death mechanism that could function as a backup when apoptosis is disabled. The fact that there are active clinical trials in patients both using autophagy inhibitors or inducers together with other cancer treatments underscores the importance of understanding and distinguishing between these opposing ideas. Here we discuss some of the recent work studying the role of autophagy with different cancer therapies.
Topics: Apoptosis; Autophagy; Cell Survival; Drug Resistance, Neoplasm; Humans; Neoplasms
PubMed: 21178393
DOI: 10.4161/cbt.11.2.14627 -
Cell Death and Differentiation Mar 2019Autophagy and mitophagy act in cancer as bimodal processes, whose differential functions strictly depend on cancer ontogenesis, progression, and type. For instance, they... (Review)
Review
Autophagy and mitophagy act in cancer as bimodal processes, whose differential functions strictly depend on cancer ontogenesis, progression, and type. For instance, they can act to promote cancer progression by helping cancer cells survive stress or, instead, when mutated or abnormal, to induce carcinogenesis by influencing cell signaling or promoting intracellular toxicity. For this reason, the study of autophagy in cancer is the main focus of many researchers and several clinical trials are already ongoing to manipulate autophagy and by this way determine the outcome of disease therapy. Since the establishment of the cancer stem cell (CSC) theory and the discovery of CSCs in individual cancer types, autophagy and mitophagy have been proposed as key mechanisms in their homeostasis, dismissal or spread, even though we still miss a comprehensive view of how and by which regulatory molecules these two processes drive cell fate. In this review, we will dive into the deep water of autophagy, mitophagy, and CSCs and offer novel viewpoints on possible therapeutic strategies, based on the modulation of these degradative systems.
Topics: Animals; Autophagy; Humans; Mitophagy; Neoplasms; Neoplastic Stem Cells; Signal Transduction; Tumor Microenvironment
PubMed: 30728463
DOI: 10.1038/s41418-019-0292-y -
Nature Reviews. Urology Sep 2014Autophagy, or 'self-eating', is an adaptive process that enables cells to cope with metabolic, toxic, and even infectious stressors. Although the adaptive capability of... (Review)
Review
Autophagy, or 'self-eating', is an adaptive process that enables cells to cope with metabolic, toxic, and even infectious stressors. Although the adaptive capability of autophagy is generally considered beneficial, autophagy can also enhance nutrient utilization and improve growth characteristics of cancer cells. Moreover, autophagy can promote greater cellular robustness in the context of therapeutic intervention. In advanced prostate cancer, preclinical data provide evidence that autophagy facilitates both disease progression and therapeutic resistance. Notably, androgen deprivation therapy, taxane-based chemotherapy, targeted kinase inhibition, and nutrient restriction all induce significant cellular distress and, subsequently, autophagy. Understanding the context-dependent role of autophagy in cancer development and treatment resistance has the potential to improve current treatment of advanced prostate cancer. Indeed, preclinical studies have shown that the pharmacological inhibition of autophagy (with agents including chloroquine, hydroxychloroquine, metformin, and desmethylclomipramine) can enhance the cell-killing effect of cancer therapeutics, and a number of these agents are currently under investigation in clinical trials. However, many of these autophagy modulators are relatively nonspecific, and cytotoxicity in noncancerous tissues is still a concern. Moving forward, refinement of autophagy modulation is needed.
Topics: Autophagy; Humans; Male; Prostatic Neoplasms
PubMed: 25134829
DOI: 10.1038/nrurol.2014.196 -
Developmental Neurobiology Mar 2018Autophagy is a lysosomal degradation pathway that is critical to maintaining neuronal homeostasis and viability. Autophagy sequesters damaged and aged cellular... (Review)
Review
Autophagy is a lysosomal degradation pathway that is critical to maintaining neuronal homeostasis and viability. Autophagy sequesters damaged and aged cellular components from the intracellular environment, and shuttles these diverse macromolecules to lysosomes for destruction. This active surveillance of the quality of the cytoplasm and organelles is essential in neurons to sustain their long-term functionality and viability. Indeed, defective autophagy is linked to neurodevelopmental abnormalities and neurodegeneration in mammals. Here, we review the mechanisms of autophagy in neurons and functional roles for autophagy in neuronal homeostasis. We focus on the compartment-specific dynamics of autophagy in neurons, and how autophagy might perform non-canonical functions critical for neurons. We suggest the existence of multiple populations of autophagosomes with compartment-specific functions important for neural activity and function. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 298-310, 2018.
Topics: Animals; Autophagy; Humans; Neurons
PubMed: 29197160
DOI: 10.1002/dneu.22562 -
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 -
Autophagy Jun 2013Autophagy is a highly conserved cellular process by which cytoplasmic components are sequestered in autophagosomes and delivered to lysosomes for degradation. As a major... (Review)
Review
Autophagy is a highly conserved cellular process by which cytoplasmic components are sequestered in autophagosomes and delivered to lysosomes for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future.
Topics: Animals; Autophagy; Cell Differentiation; Humans; Mitophagy; Models, Biological; Stem Cells
PubMed: 23486312
DOI: 10.4161/auto.24132 -
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 -
Cells Feb 2021Cardiovascular disease (CVD) is one of the greatest health problems affecting people worldwide. Atherosclerosis, in turn, is one of the most common causes of... (Review)
Review
Cardiovascular disease (CVD) is one of the greatest health problems affecting people worldwide. Atherosclerosis, in turn, is one of the most common causes of cardiovascular disease. Due to the high mortality rate from cardiovascular diseases, prevention and treatment at the earliest stages become especially important. This requires developing a deep understanding of the mechanisms underlying the development of atherosclerosis. It is well-known that atherogenesis is a complex multi-component process that includes lipid metabolism disorders, inflammation, oxidative stress, autophagy disorders and mitochondrial dysfunction. Autophagy is a cellular control mechanism that is critical to maintaining health and survival. One of the specific forms of autophagy is mitophagy, which aims to control and remove defective mitochondria from the cell. Particularly defective mitophagy has been shown to be associated with atherogenesis. In this review, we consider the role of autophagy, focusing on a special type of it-mitophagy-in the context of its role in the development of atherosclerosis.
Topics: Atherosclerosis; Autophagy; Cardiovascular Diseases; Humans; Mitophagy
PubMed: 33669743
DOI: 10.3390/cells10020443