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Cells Nov 2021For many years, it was thought that and played a pivotal role in autophagy, and that the knockdown of one of these genes would result in its inhibition. However, cells... (Review)
Review
For many years, it was thought that and played a pivotal role in autophagy, and that the knockdown of one of these genes would result in its inhibition. However, cells with or depletion still generate autophagic vacuoles with mainly -Golgi-originated isolation membranes and do not die. This indicates that autophagy can occur via ATG5/ATG7-independent alternative autophagy. Its molecular mechanism differs from that of the canonical pathway, including inter alia the phosphorylation of ULK1, and lack of LC3 modifications. As the alternative autophagy pathway has only recently been described, little is known of its precise role; however, a considerable body of evidence suggests that alternative autophagy participates in mitochondrion removal. This review summarizes the latest progress made in research on alternative autophagy and describes its possible molecular mechanism, roles and methods of detection, and possible modulators. There is a need for further research focused on types of autophagy, as this can elucidate the functioning of various cell types and the pathogenesis of human and animal diseases.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Humans; Models, Biological; Mutagens
PubMed: 34831462
DOI: 10.3390/cells10113241 -
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 -
ELife Sep 2021Removal of damaged organelles via the process of selective autophagy constitutes a major form of cellular quality control. Damaged organelles are recognized by a...
Removal of damaged organelles via the process of selective autophagy constitutes a major form of cellular quality control. Damaged organelles are recognized by a dedicated surveillance machinery, leading to the assembly of an autophagosome around the damaged organelle, prior to fusion with the degradative lysosomal compartment. Lysosomes themselves are also prone to damage and are degraded through the process of lysophagy. While early steps involve recognition of ruptured lysosomal membranes by glycan-binding galectins and ubiquitylation of transmembrane lysosomal proteins, many steps in the process, and their interrelationships, remain poorly understood, including the role and identity of cargo receptors required for completion of lysophagy. Here, we employ quantitative organelle capture and proximity biotinylation proteomics of autophagy adaptors, cargo receptors, and galectins in response to acute lysosomal damage, thereby revealing the landscape of lysosome-associated proteome remodeling during lysophagy. Among the proteins dynamically recruited to damaged lysosomes were ubiquitin-binding autophagic cargo receptors. Using newly developed lysophagic flux reporters including Lyso-Keima, we demonstrate that TAX1BP1, together with its associated kinase TBK1, are both necessary and sufficient to promote lysophagic flux in both HeLa cells and induced neurons (iNeurons). While the related receptor Optineurin (OPTN) can drive damage-dependent lysophagy when overexpressed, cells lacking either OPTN or CALCOCO2 still maintain significant lysophagic flux in HeLa cells. Mechanistically, TAX1BP1-driven lysophagy requires its N-terminal SKICH domain, which binds both TBK1 and the autophagy regulatory factor RB1CC1, and requires upstream ubiquitylation events for efficient recruitment and lysophagic flux. These results identify TAX1BP1 as a central component in the lysophagy pathway and provide a proteomic resource for future studies of the lysophagy process.
Topics: Autophagy; Humans; Lysosomes; Macroautophagy; Protein Binding; Proteomics; Ubiquitin
PubMed: 34585663
DOI: 10.7554/eLife.72328 -
Advances in Experimental Medicine and... 2020Autophagy is critical for the survival and stemness maintenance of cancer stem cells (CSCs) and is an enhancer of CSC tumorigenesis. At the same time, autophagy... (Review)
Review
Autophagy is critical for the survival and stemness maintenance of cancer stem cells (CSCs) and is an enhancer of CSC tumorigenesis. At the same time, autophagy contributes to conditions optimal for facilitating the invasion and metastasis of CSCs. Moreover, autophagy induces the dormant state of CSCs to help them resist the cytotoxic effects of chemotherapy and radiotherapy, thereby improving the likelihood of their survival. The combination of autophagy inhibitors with specific drugs targeting specific CSC subpopulations is expected to act specifically on CSCs and produce fewer toxic side effects on normal tissues. This in-depth study is very timely and important for further identifying the potential role of autophagy in different states of CSCs and places a particular emphasis on exploring molecular mechanisms in the regulation of autophagy via advanced techniques based on molecular biology.
Topics: Autophagy; Humans; Neoplasms; Neoplastic Stem Cells
PubMed: 32671756
DOI: 10.1007/978-981-15-4272-5_21 -
Autophagy Oct 2022Atherosclerosis, the leading cause of cardiovascular death, is driven by hyperlipidemia, inflammation and aggravated by aging. As chaperone-mediated autophagy (CMA), a...
Atherosclerosis, the leading cause of cardiovascular death, is driven by hyperlipidemia, inflammation and aggravated by aging. As chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation for intracellular proteins, diminishes with age and is inhibited by lipid excess, we studied if the decline in CMA could contribute to atherosclerosis pathogenesis. We found that CMA declines in human and murine vasculature with disease progression. Inhibition and reactivation of CMA using transgenic mouse models establishes a protective effect of CMA against atherogenesis. CMA upregulation ameliorates both systemic metabolic parameters, and vascular cell function. Our work suggests CMA reactivation could be a viable therapeutic strategy to prevent and reduce cardiovascular disease.
Topics: Animals; Atherosclerosis; Autophagy; Chaperone-Mediated Autophagy; Humans; Lipids; Lysosomes; Mice; Mice, Transgenic; Molecular Chaperones
PubMed: 35787098
DOI: 10.1080/15548627.2022.2096397 -
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 -
Molecular Medicine (Cambridge, Mass.) Oct 2023Autophagy is an explicit cellular process to deliver dissimilar cytoplasmic misfolded proteins, lipids and damaged organelles to the lysosomes for degradation and... (Review)
Review
Autophagy is an explicit cellular process to deliver dissimilar cytoplasmic misfolded proteins, lipids and damaged organelles to the lysosomes for degradation and elimination. The mechanistic target of rapamycin (mTOR) is the main negative regulator of autophagy. The mTOR pathway is involved in regulating neurogenesis, synaptic plasticity, neuronal development and excitability. Exaggerated mTOR activity is associated with the development of temporal lobe epilepsy, genetic and acquired epilepsy, and experimental epilepsy. In particular, mTOR complex 1 (mTORC1) is mainly involved in epileptogenesis. The investigation of autophagy's involvement in epilepsy has recently been conducted, focusing on the critical role of rapamycin, an autophagy inducer, in reducing the severity of induced seizures in animal model studies. The induction of autophagy could be an innovative therapeutic strategy in managing epilepsy. Despite the protective role of autophagy against epileptogenesis and epilepsy, its role in status epilepticus (SE) is perplexing and might be beneficial or detrimental. Therefore, the present review aims to revise the possible role of autophagy in epilepsy.
Topics: Animals; Epilepsy; Signal Transduction; TOR Serine-Threonine Kinases; Sirolimus; Autophagy; Disease Models, Animal
PubMed: 37880579
DOI: 10.1186/s10020-023-00742-2 -
DNA and Cell Biology Feb 2020Propofol is a widely used intravenous agent for the induction and maintenance of anesthesia. An increasing number of studies have shown that propofol modulates... (Review)
Review
Propofol is a widely used intravenous agent for the induction and maintenance of anesthesia. An increasing number of studies have shown that propofol modulates autophagy, which is an evolutionarily conserved catabolic process that maintains cellular homeostasis by degrading long-lived proteins and damaged cellular proteins or organelles. Extensive studies have been performed to better understand the regulation of autophagy by propofol, the majority of which have demonstrated that the effects of propofol on autophagy are beneficial to organs and tissues. In this review, we retrospectively analyzed studies to assess the effects of propofol on autophagy in different diseases and evaluated the underlying mechanisms.
Topics: Animals; Autophagy; Central Nervous System; Homeostasis; Humans; Propofol; Retrospective Studies; Signal Transduction
PubMed: 31880481
DOI: 10.1089/dna.2019.4745 -
Annual Review of Pathology Jan 2020Autophagy is an evolutionarily conserved catabolic process that targets different types of cytoplasmic cargo (such as bulk cytoplasm, damaged cellular organelles, and... (Review)
Review
Autophagy is an evolutionarily conserved catabolic process that targets different types of cytoplasmic cargo (such as bulk cytoplasm, damaged cellular organelles, and misfolded protein aggregates) for lysosomal degradation. Autophagy is activated in response to biological stress and also plays a critical role in the maintenance of normal cellular homeostasis; the latter function is particularly important for the integrity of postmitotic, metabolically active tissues, such as skeletal muscle. Through impairment of muscle homeostasis, autophagy dysfunction contributes to the pathogenesis of many different skeletal myopathies; the observed autophagy defects differ from disease to disease but have been shown to involve all steps of the autophagic cascade (from induction to lysosomal cargo degradation) and to impair both bulk and selective autophagy. To highlight the molecular and cellular mechanisms that are shared among different myopathies with deficient autophagy, these disorders are discussed based on the nature of the underlying autophagic defect rather than etiology or clinical presentation.
Topics: Animals; Autophagy; Humans; Lysosomes; Muscle, Skeletal; Muscular Diseases; Protein Aggregation, Pathological
PubMed: 31594457
DOI: 10.1146/annurev-pathmechdis-012419-032618 -
Viruses May 2021Selective autophagy has emerged as a key mechanism of quality and quantity control responsible for the autophagic degradation of specific subcellular organelles and... (Review)
Review
Selective autophagy has emerged as a key mechanism of quality and quantity control responsible for the autophagic degradation of specific subcellular organelles and materials. In addition, a specific type of selective autophagy (xenophagy) is also activated as a line of defense against invading intracellular pathogens, such as viruses. However, viruses have evolved strategies to counteract the host's antiviral defense and even to activate some proviral types of selective autophagy, such as mitophagy, for their successful infection and replication. This review discusses the current knowledge on the regulation of selective autophagy by human herpesviruses.
Topics: Autophagy; Gene Expression Regulation; Herpesviridae; Host-Pathogen Interactions; Humans; Macroautophagy; Mitophagy
PubMed: 34062931
DOI: 10.3390/v13050820