Autophagy In Different Types Research Articles

Mechanisms and implications of podocyte autophagy in chronic kidney disease.

Autophagy is a protective mechanism through which cells degrade and recycle proteins and organelles to maintain cellular homeostasis and integrity. An accumulating body of evidence underscores the significant impact of dysregulated autophagy on podocyte injury in chronic kidney disease (CKD). In this review, we provide a comprehensive overview of the diverse types of autophagy and their regulation in cellular homeostasis, with a specific emphasis on podocytes. Furthermore, we discuss recent findings that focus on the functional role of different types of autophagy during podocyte injury in chronic kidney disease. The intricate interplay between different types of autophagy and podocyte health requires further research, which is critical for understanding the pathogenesis of CKD and developing targeted therapeutic interventions.

Knowledge domain and emerging trends of autophagy in cardiovascular research: A bibliometric analysis.

Autophagy is essential for the homeostasis and function of the cardiovascular system. Citespace is a visual analysis software developed in the context of scientometrics and data visualization. The purpose of this study is to use Citespace software to conduct bibliometric and visual analysis of the research on autophagy in cardiovascular diseases, identify the current status, hot spots and trends in this field, help researchers clarify the future research focus and direction of autophagy in cardiovascular diseases, and provide more positive and broader ideas for the treatment and drug development of cardiovascular diseases. In the Web of Science Core Collection database to download the data from 2004 to 2022 regarding autophagy in cardiovascular research. CitespaceV was used to collect the research status, hotspots and development trends for visual analysis. The 3568 articles were published by 547 authors from 397 institutions in 75 countries. From 2004 to 2021, the annual publications increased over time. The top 3 productive nations were China, the United States, and Germany. The leading institution was China's Fudan University. The most cited paper is Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). The research hotpots include monitoring methods for autophagy activity, changes in autophagy levels in different types of cardiovascular diseases, autophagy signal transduction mechanism in cardiovascular diseases, etc. Bibliometric analysis provided valuable information for autophagy research in cardiovascular disease, which is full of opportunities and challenges. The research of autophagy in the field of cardiovascular diseases is still worthy of in-depth exploration. A challenge with autophagy-targeted therapies is their dichotomy in which the goal is to target maladaptive autophagy while maintaining a baseline level of cell survival to optimize a beneficial outcome. It is necessary for scientists to develop new methods to evaluate the level of autophagy from basic application to human body and reveal the signaling mechanism of autophagy in different types of cardiovascular diseases.

The role of glial autophagy in Alzheimer's disease.

Although Alzheimer's disease is the most pervasive neurodegenerative disorder, the mechanism underlying its development is still not precisely understood. Available data indicate that pathophysiology of this disease may involve impaired autophagy in glial cells. The dysfunction is manifested as reduced ability of astrocytes and microglia to clear abnormal protein aggregates. Consequently, excessive accumulation of amyloid beta plaques and neurofibrillary tangles activates microglia and astrocytes leading to decreased number of mature myelinated oligodendrocytes and death of neurons. These pathologic effects of autophagy dysfunction can be rescued by pharmacological activation of autophagy. Therefore, a deeper understanding of the molecular mechanisms involved in autophagy dysfunction in glial cells in Alzheimer's disease may lead to the development of new therapeutic strategies. However, such strategies need to take into consideration differences in regulation of autophagy in different types of neuroglia.

AutophagyNet: high-resolution data source for the analysis of autophagy and its regulation

ABSTRACT Macroautophagy/autophagy is a highly-conserved catabolic procss eliminating dysfunctional cellular components and invading pathogens. Autophagy malfunction contributes to disorders such as cancer, neurodegenerative and inflammatory diseases. Understanding autophagy regulation in health and disease has been the focus of the last decades. We previously provided an integrated database for autophagy research, the Autophagy Regulatory Network (ARN). For the last eight years, this resource has been used by thousands of users. Here, we present a new and upgraded resource, AutophagyNet. It builds on the previous database but contains major improvements to address user feedback and novel needs due to the advancement in omics data availability. AutophagyNet contains updated interaction curation and integration of over 280,000 experimentally verified interactions between core autophagy proteins and their protein, transcriptional and post-transcriptional regulators as well as their potential upstream pathway connections. AutophagyNet provides annotations for each core protein about their role: 1) in different types of autophagy (mitophagy, xenophagy, etc.); 2) in distinct stages of autophagy (initiation, expansion, termination, etc.); 3) with subcellular and tissue-specific localization. These annotations can be used to filter the dataset, providing customizable download options tailored to the user’s needs. The resource is available in various file formats (e.g. CSV, BioPAX and PSI-MI), and data can be analyzed and visualized directly in Cytoscape. The multi-layered regulation of autophagy can be analyzed by combining AutophagyNet with tissue- or cell type-specific (multi-)omics datasets (e.g. transcriptomic or proteomic data). The resource is publicly accessible at http://autophagynet.org. Abbreviations: ARN: Autophagy Regulatory Network; ATG: autophagy related; BCR: B cell receptor pathway; BECN1: beclin 1; GABARAP: GABA type A receptor-associated protein; IIP: innate immune pathway; LIR: LC3-interacting region; lncRNA: long non-coding RNA; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; miRNA: microRNA; NHR: nuclear hormone receptor; PTM: post-translational modification; RTK: receptor tyrosine kinase; TCR: T cell receptor; TLR: toll like receptor.

Autophagy and Its Lineage-Specific Roles in the Hematopoietic System.

Autophagy is a dynamic process that regulates the selective and nonselective degradation of cytoplasmic components, such as damaged organelles and protein aggregates inside lysosomes to maintain tissue homeostasis. Different types of autophagy including macroautophagy, microautophagy, and chaperon-mediated autophagy (CMA) have been implicated in a variety of pathological conditions, such as cancer, aging, neurodegeneration, and developmental disorders. Furthermore, the molecular mechanism and biological functions of autophagy have been extensively studied in vertebrate hematopoiesis and human blood malignancies. In recent years, the hematopoietic lineage-specific roles of different autophagy-related (ATG) genes have gained more attention. The evolution of gene-editing technology and the easy access nature of hematopoietic stem cells (HSCs), hematopoietic progenitors, and precursor cells have facilitated the autophagy research to better understand how ATG genes function in the hematopoietic system. Taking advantage of the gene-editing platform, this review has summarized the roles of different ATGs at the hematopoietic cell level, their dysregulation, and pathological consequences throughout hematopoiesis.

Autophagy-Based Intervention Strategy in the Management of Hepatotoxicity.

Significance: Ample evidence has demonstrated an important role for autophagy as either a protective mechanism or a cause for hepatotoxicity, denoting the likely potentials for targeting autophagy in the prevention or treatment of hepatotoxicity. Recent Advances: The functional role of autophagy in the pathogenesis of hepatotoxicity has been gradually recognized. Mechanistically, the autophagy-mediated protective or promoting effect on hepatotoxicity is attributed to its functions in regulation of oxidative stress, endoplasmic reticulum (ER) stress, lipid metabolism, iron homeostasis, inflammatory response, and programmed cell death. Targeting autophagy as a novel strategy for fighting against hepatotoxicity has demonstrated encouraging efficacy in a number of models. Critical Issues: Clarifying the precise functional role of autophagy in different types of hepatotoxicity is essential for developing a type-specific autophagy-based intervention. Identification of molecular targets and novel agents for effectively and accurately manipulating autophagy is needed for better utilization of an autophagy-based approach to exert beneficial effects on hepatotoxicity. Future Directions: Well-designed clinical trials are needed to validate the efficacy of an autophagy-targeting intervention strategy for hepatotoxicity. Further studies should be also focused on developing novel autophagy-targeting agents that can accurately regulate autophagy based on the characteristics of each type of hepatotoxicity. Antioxid. Redox Signal. 38, 1082-1100.

Autophagy and pluripotency: self-eating your way to eternal youth.

Pluripotent stem cells (PSCs) can self-renew indefinitely in culture while retaining the potential to differentiate into virtually all normal cell types in the adult animal. Due to these remarkable properties, PSCs not only provide a superb system to investigate mammalian development and model diseases, but also hold promise for regenerative therapies. Autophagy is a self-digestive process that targets proteins, organelles, and other cellular contents for lysosomal degradation. Here, we review recent literature on the mechanistic role of different types of autophagy in embryonic development, embryonic stem cells (ESCs), and induced PSCs (iPSCs), focusing on their remodeling functions on protein, metabolism, and epigenetics. We present a perspective on unsolved issues and propose that autophagy is a promising target to modulate acquisition, maintenance, and directed differentiation of PSCs.

Coordinative regulation of ERAD and selective autophagy in plants.

Endoplasmic reticulum-associated degradation (ERAD) plays important roles in plant development, hormone signaling, and plant-environment stress interactions by promoting the clearance of certain proteins or soluble misfolded proteins through the ubiquitin-proteasome system. Selective autophagy is involved in the autophagic degradation of protein aggregates mediated by specific selective autophagy receptors. These two major degradation routes co-operate with each other to relieve the cytotoxicity caused by ER stress. In this review, we analyze ERAD and different types of autophagy, including nonselective macroautophagy and ubiquitin-dependent and ubiquitin-independent selective autophagy in plants, and specifically summarize the selective autophagy receptors characterized in plants. In addition to being a part of selective autophagy, ERAD components also serve as their cargos. Moreover, an ubiquitinated substrate can be delivered to two distinguishable degradation systems, while the underlying determinants remain elusive. These excellent findings suggest an interdependent but complicated relationship between ERAD and selective autophagy. According to this point, we propose several key issues that need to be addressed in the future.

Lifespan Increase of Podospora anserina by Oleic Acid Is Linked to Alterations in Energy Metabolism, Membrane Trafficking and Autophagy.

The maintenance of cellular homeostasis over time is essential to avoid the degeneration of biological systems leading to aging and disease. Several interconnected pathways are active in this kind of quality control. One of them is autophagy, the vacuolar degradation of cellular components. The absence of the sorting nexin PaATG24 (SNX4 in other organisms) has been demonstrated to result in impairments in different types of autophagy and lead to a shortened lifespan. In addition, the growth rate and the size of vacuoles are strongly reduced. Here, we report how an oleic acid diet leads to longevity of the wild type and a PaAtg24 deletion mutant (ΔPaAtg24). The lifespan extension is linked to altered membrane trafficking, which abrogates the observed autophagy defects in ΔPaAtg24 by restoring vacuole size and the proper localization of SNARE protein PaSNC1. In addition, an oleic acid diet leads to an altered use of the mitochondrial respiratory chain: complex I and II are bypassed, leading to reduced reactive oxygen species (ROS) production. Overall, our study uncovers multiple effects of an oleic acid diet, which extends the lifespan of P. anserina and provides perspectives to explain the positive nutritional effects on human aging.

A dynamically evolving war between autophagy and pathogenic microorganisms.

Autophagy is an intracellular degradation process that maintains cellular homeostasis. It is essential for protecting organisms from environmental stress. Autophagy can help the host to eliminate invading pathogens, including bacteria, viruses, fungi, and parasites. However, pathogens have evolved multiple strategies to interfere with autophagic signaling pathways or inhibit the fusion of autophagosomes with lysosomes to form autolysosomes. Moreover, host cell matrix degradation by different types of autophagy can be used for the proliferation and reproduction of pathogens. Thus, determining the roles and mechanisms of autophagy during pathogen infections will promote understanding of the mechanisms of pathogen‍‒‍host interactions and provide new strategies for the treatment of infectious diseases.

Conserved and Diversified Mechanism of Autophagy between Plants and Animals upon Various Stresses.

Autophagy is a highly conserved degradation mechanism in eukaryotes, executing the breakdown of unwanted cell components and subsequent recycling of cellular material for stress relief through vacuole-dependence in plants and yeast while it is lysosome-dependent in animal manner. Upon stress, different types of autophagy are stimulated to operate certain biological processes by employing specific selective autophagy receptors (SARs), which hijack the cargo proteins or organelles to the autophagy machinery for subsequent destruction in the vacuole/lysosome. Despite recent advances in autophagy, the conserved and diversified mechanism of autophagy in response to various stresses between plants and animals still remain a mystery. In this review, we intend to summarize and discuss the characterization of the SARs and their corresponding processes, expectantly advancing the scope and perspective of the evolutionary fate of autophagy between plants and animals.

A perspective on the role of autophagy in cancer

Autophagy refers to a ubiquitous set of catabolic pathways required to achieve proper cellular homeostasis. Aberrant autophagy has been implicated in a multitude of diseases including cancer. In this review, we highlight pioneering and groundbreaking research that centers on delineating the role of autophagy in cancer initiation, proliferation and metastasis. First, we discuss the autophagy-related (ATG) proteins and their respective roles in the de novo formation of autophagosomes and the subsequent delivery of cargo to the lysosome for recycling. Next, we touch upon the history of cancer research that centers upon ATG proteins and regulatory mechanisms that control an appropriate autophagic response and how these are altered in the diseased state. Then, we discuss the various discoveries that led to the idea of autophagy as a double-edged sword when it comes to cancer therapy. This review also briefly narrates how different types of autophagy—selective macroautophagy and chaperone-mediated autophagy, have been linked to different cancers. Overall, these studies build upon a steadfast trajectory that aims to solve the monumentally daunting challenge of finding a cure for many types of cancer by modulating autophagy either through inhibition or induction.

Investigation the Role of Autophagy in Non-Small Cell Lung Cancer.

Objective:Recent studies have shown the role of autophagy in different types of cancer including lung cancer. MicroRNAs are considered as key factors in regulation of autophagy related genes. miR-30d, miR-204-5p and miR-20a are regulatory markers which can suppress the expression of beclin1, LC3, bcl2 and ULK1 as their target genes and they lead to decrement of autophagy in human cancer cells. Moreover, epigenetic modifications DNA methylation has been indicated in regulation of autophagy in different stages of cancer. Methods:In this study, the expression levels of miR-30d, miR-204-5p and miR-20a as well as their target genes were analyzed in 30 non-small cell lung cancers (NSCLCs) patients sample and adjacent normal tissues by real-time qPCR. In addition, DNA methylation of beclin1, LC3, bcl2 and ULK1 genes were assessed by MS-HRM method. Results: MiR-30d (p value= 0.01) and miR-204-5p (P=0.048) significantly down-regulated in tumor samples compared to normal adjacent tissues, while there was no significant change in expression level of miR-20a. On the other hand, target genes expression level was significantly increased in NSCLC tissues, however methylation pattern of the target gene promoters, did not show any significant alteration. Conclusion:These results indicate roles for miR-30d, miR-204-5p as tumor suppressor genes as well as target genes as oncogenes in NSCLC patients. Although these factors may have a significant role in NSCLC progression, further studies are necessary to investigate the implications of these findings for treatment of lung cancer.

Biomarkers of Autophagy.

Biomarkers (short for biological markers) are biological measures of a biological state. Autophagy biomarkers play an important role as an indicator of autophagy during normal physiological processes, pathogenic processes or pharmacological responses to drugs. In this chapter, some biomarkers of different types of autophagy, including macroautophagy, selective autophagy, chaperone-mediated autophagy, and microautophagy, as well as the lysosomal biomarkers are introduced. The described biomarkers may be used to detect the level of autophagy in cells or tissues in a dynamic, real-time, and quantitative manner. However, each biomarker has its specific significance and limitation. Therefore, the analysis of the autophagy level in cells or tissues through the detection of autophagy biomarkers should be carried out carefully.

Nonspecific Binding Correction for Single-Cell Mass Cytometric Analysis of Autophagy and Myoblast Differentiation.

Satellite cells provide regenerative capacity to the skeletal muscle after injury. In this process, termed myogenesis, satellite cells get activated, proliferate, and differentiate. Myogenesis is recapitulated in the tissue culture of myoblasts that differentiate by fusion and then by the formation of myotubes. Autophagy plays an important role in myogenesis, but the asynchronous and unique trajectory of differentiation of each myoblast along the myogenic lineage complicates teasing apart at what stages of differentiation autophagy plays a critical role. In this report, we describe a mass cytometric, multidimensional, individual cell analysis of differentiating myoblasts that characterizes autophagy flux (i.e., autophagy rate) at separate myogenesis stages. Because mass cytometry uses a set of lanthanide-tagged antibodies, each being specific for a desired molecular target, quantification of each molecular target could be exaggerated by nonspecific binding of its respective antibody to other nontarget cellular regions. In this report, we used lanthanide-tagged isotypes, which allowed for correction for nonspecific binding at the single-cell level. Using this approach, myoblasts were phenotypically identified by their position in the myogenic lineage, simultaneously with the quantification of autophagic flux in each identified subset. We found that generally autophagy flux is upregulated specifically during myoblast fusion and declines in myotubes. We also observed that mitophagy (i.e., selective autophagic degradation of mitochondria) is also active after myotube formation. The ability to track different types of autophagy is another feature of this methodology, which could be key to expand the current understanding of autophagy regulation in regenerating the skeletal muscle.

ATG7-dependent and independent autophagy determine the type of treatment in lung cancer

Based on the role of ATG7 in the initiation of autophagy, autophagy can be divided into ATG7-dependent selective autophagy and ATG7-independent alternative autophagy. However, the detailed roles of two different types of autophagy in antitumor therapy have not been fully elucidated so far. Here, we for the first time demonstrated an investigational inducer, w09, could induce both selective autophagy and alternative autophagy in NSCLC, but the phenotypes of these two kinds of autophagy are different：(1) w09-induced selective autophagy mainly promoted cell apoptosis, while w09-triggered alternative autophagy markedly induced autophagic cell death in NSCLC；(2) w09-induced ATG7 dependent autophagy mainly promoted the accumulation of SQSTM1/p62, while w09-triggered ATG7 independent autophagy markedly accelerated the degradation of SQSTM1/p62. These above results were further confirmed by knockout ATG7 gene in A549 cells or restoration of ATG7 function in H1650 cells. Deletion of ATG7 gene markedly attenuated the effect of w09-induced autophagy or apoptosis on A549 cells, while restoration of functional ATG7 markedly enhanced the effect of w09-induced autophagy and apoptosis on H1650 cells. Mechanistically, we further revealed that w09 induced two different types of autophagy through inhibiting PI3K/AKT/mTOR signaling pathway. Notably, compared with A549WT xenograft model, the in vivo antitumor effect of w09 or Taxel on the ATG7-deficient A549 xenograft model was significantly attenuated. Therefore, a special attention must be paid to distinguish which kinds of autophagy have been induced by autophagy inducers with antitumor agents by targeting PI3K/AKT/mTOR signaling pathway.

Mechanistic and compositional studies of the autophagy-inducing areca nut ingredient

Background/purposeWe previously found that the partially purified 30–100 kDa fraction of areca-nut-extract (ANE 30–100K) induces autophagy in different types of cells including oral carcinoma OECM-1 cells. This study was to analyze the composition and possible mechanisms of ANE 30-100K-induced autophagy (AIA). Materials and methodsPhenol-sulfuric acid method and high performance anion exchange chromatography were utilized to analyze the composition of ANE 30–100K. OECM-1 and esophageal CE81T/VGH cells were taken as the experimental models. Microscope and transmission electron microscope were used to observe morphological changes. Cell viability and specific proteins were respectively measured by XTT and Western bot assay. shRNA and chemical inhibitors were applied to assess the involvement of Atg5, caveolin, and proteasome in AIA. ResultsANE 30–100K contains ∼67% carbohydrate, which is composed of fucose (5.938%), arabinose (24.631%), glucosamine (8.066%), galactose (26.820%), glucose (21.388%), and mannose (13.157%). After ANE 30–100K stimulation, CE81T/VGH cells showed intracellular vacuoles, acidic vesicles, double-membrane vacuoles, and elevated LC3-II level. ANE 30-100K-induced cytotoxicity and LC3-II accumulation were significantly inhibited by Atg5 knockdown. Furthermore, the endocytosis inhibitor (methyl-β-cyclodextrin) and two caveolin shRNAs, as well as two proteasome inhibitors (lactacystin and epoxomicin), were shown to significantly attenuate ANE 30-100K-induced cytotoxicity and LC3-II accumulation in both OECM-1 and CE81T/VGH cells. ConclusionThe major components of ANE 30–100K are carbohydrates. CE81T/VGH also exhibited autophagic responses to ANE 30–100K. Caveolin-mediated endocytosis and proteasome are involved in AIA. This study may have provided new knowledges of the action mechanisms and compositions of ANE 30–100K.

Chaperone-Mediated Autophagy after Spinal Cord Injury.

Autophagy is the degradation process of dysfunctional intracellular components and has a crucial function in various human diseases. There are three different types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). CMA is a major route for the elimination of cellular aberrant proteins and can provide a cytoprotective effect. The present study investigated the expression of lysosome-associated membrane protein type 2A (LAMP2A), which is the hallmark of CMA activity, in damaged neural tissue after spinal cord injury (SCI) in mice. The number of LAMP2A-expressing cells was significantly increased at the lesion following SCI. The increased number of LAMP2A-positive cells was observed from 24 h and peaked at 3 days after injury. A western blot analysis confirmed that the level of LAMP2A protein was significantly increased in the injured spinal cord compared with the uninjured cord. On double staining for LAMP2A and different neural cell type markers, the increased expression of LAMP2A was observed in neurons, astrocytes, oligodendrocytes, and microglia/macrophages following injury. An electron microscopic analysis showed that secondary lysosomes were increased in damaged neurons at the lesion site. Immunoelectron microscopy revealed that the gold particles with anti-LAMP2A antibody were frequently localized at the secondary lysosomes in the injured site. These findings indicated that CMA was clearly activated in damaged neural tissue after SCI. The activation of CMA may contribute to the elimination of intracellular aberrant proteins and exert a neuroprotective effect following SCI.

Role of Autophagy in Breast Cancer Development and Progression: Opposite Sides of theSame Coin.

The term "autophagy", which means "self (auto) - eating (phagy)", describes a catabolic process that is evolutionarially conserved among all eukaryotes. Although autophagy is mainly accepted as a cell survival mechanism, it also modulates the process known as "type II cell death". AKT/mTOR pathway is an upstream activator of autophagy and it is tightly regulated by the ATG (autophagy-related genes) signaling cascade. In addition, wide ranging cell signaling pathways and non-coding RNAs played essential roles in the control of autophagy. Autophagy is closely related to pathological processes such as neurodegenerative diseases and cancer as well as physiological conditions. After the Nobel Prize in Physiology or Medicine 2016 was awarded to Yoshinori Ohsumi "for his discoveries of mechanisms for autophagy", there was an explosion in the field of autophagy and molecular biologists started to pay considerable attention to the mechanistic insights related to autophagy in different diseases. Since autophagy behaved dualistically, both as a cell death and a cell survival mechanism, it opened new horizons for a deeper analysis of cell type and context dependent behavior of autophagy in different types of cancers. There are numerous studies showing that the induction of autophagy mechanism will promote survival of cancer cells. Since autophagy is mainly a mechanism to keep the cells alive, it may protect breast cancer cells against stress conditions such as starvation and hypoxia. For these reasons, autophagy was noted to be instrumental in metastasis and drug resistance. In this chapter we have emphasized on role of role of autophagy in breast cancer. Additionally we have partitioned this chapter into exciting role of microRNAs in modulation of autophagy in breast cancer. We have also comprehensively summarized how TRAIL-mediated signaling and autophagy operated in breast cancer cells.

The Chick Chorioallantoic Membrane (CAM) Assay as a Three-dimensional Model to Study Autophagy in Cancer Cells.

The chick chorioallantoic membrane (CAM) is an extra-embryonic organ and thus well accessible for seeding and harvesting 3D cell cultures. Samples from CAM assays are suitable for protein and gene expression analysis as well as for immuno-histochemical studies. Here we present the CAM assay as a possible model to study autophagy in different types of cancer using immunohistochemistry. Compared with other 3D and xenograft models, the CAM assay displays several advantages such as lower costs, shorter experimental times, physiological environment and reproducibility. Macroautophagy hereafter simply referred to as "autophagy" is a conserved cellular catabolic process that degrades and recycles cellular components. Under basal conditions, autophagy contributes to the maintenance of cellular homeostasis whereas under cellular stress, such as starvation or hypoxia, autophagy is activated as a survival mechanism. Dysregulation of autophagy has been described in many diseases. In cancer, autophagy has been suggested to play a dual role. Whereas autophagy has been reported to play a tumor suppressive role in early stages, it seems to be rather tumor supportive in later stages. Here we provide a method to study autophagy in 3D microtumors of cancer cells grown on the CAM.