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Autophagy in Health and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 11420

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Dr. Jiahong Lu

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Guest Editor

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China
Interests: chemotherapy; autophagy and biogenesis; Alzheimer’s disease pathology; neurobiology; cell biology; pharmacology

Special Issue Information

Dear Colleagues,

Our understanding of molecular mechanisms of autophagy has greatly expanded in the past 20 years. In recent years, the main interests of the autophagy research field have gradually shifted from pure mechanistic studies to revealing the role of autophagy in various physiological and pathological conditions. By establishing the causative link between autophagy dysregulation and diseases, scientist have attempted to determine whether autophagy can be a therapeutic target against a series of diseases, including neurodegenerative diseases and cancers. Indeed, an increasing number of autophagy modulatory compounds have been identified and tested in different disease models, while dozens of clinical trials targeting autophagy inhibition through chloroquine or hydroxychloroquine for the treatment of multiple cancers are ongoing. However, challenges remain, such as poor selectivity of autophagy regulation in different tissues, and approaches to modulate autophagy in patients are limited.

This Special Issue aims to collect exciting progress in deciphering the roles of autophagy in physiological and diseases conditions. The accumulation of studies in this area may pave the way for the development of therapeutic intervention for multiple diseases by targeting autophagy.

Dr. Jiahong Lu
Guest Editor

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Keywords

autophagy
neurodegenerative disease
cancer
inflammatory diseases
autophagy modulators

Published Papers (7 papers)

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Research

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17 pages, 7180 KiB

Open AccessArticle

Effects of a N-Maleimide-derivatized Phosphatidylethanolamine on the Architecture and Properties of Lipid Bilayers

by Uxue Ballesteros, Emilio J. González-Ramirez, Igor de la Arada, Jesús Sot, Asier Etxaniz, Félix M. Goñi, Alicia Alonso and Lidia Ruth Montes

Int. J. Mol. Sci. 2023, 24(23), 16570; https://doi.org/10.3390/ijms242316570 - 21 Nov 2023

Cited by 1 | Viewed by 684

Abstract

N-maleimide-derivatized phospholipids are often used to facilitate protein anchoring to membranes. In autophagy studies, this is applied to the covalent binding of Atg8, an autophagy protein, to a phosphatidylethanolamine (PE) in the nascent autophagosome. However, the question remains on how closely the N-maleimide PE derivative (PE-mal) mimicks the native PE in the bilayer. In the present paper, spectroscopic and calorimetric techniques have been applied to vesicles containing either PE or PE-mal (together with other phospholipids) to compare the properties of the native and derivatized forms of PE. According to differential scanning calorimetry, and to infrared spectroscopy, the presence of PE-mal did not perturb the fatty acyl chains in the bilayer. Fluorescence spectroscopy and microscopy showed that PE-mal did not alter the bilayer permeability either. However, fluorescence emission polarization of the Laurdan and DPH probes indicated an increased order, or decreased fluidity, in the bilayers containing PE-mal. In addition, the infrared spectral data from the phospholipid phosphate region revealed a PE-mal-induced conformational change in the polar heads, accompanied by increased hydration. Globally considered, the results suggest that PE-mal would be a reasonable substitute for PE in model membranes containing reconstituted proteins. Full article

(This article belongs to the Special Issue Autophagy in Health and Diseases)

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13 pages, 1988 KiB

Open AccessArticle

Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus

by Matteo Zurlo, Cristina Zuccato, Lucia Carmela Cosenza, Jessica Gasparello, Maria Rita Gamberini, Alice Stievano, Monica Fortini, Marco Prosdocimi, Alessia Finotti and Roberto Gambari

Int. J. Mol. Sci. 2023, 24(20), 15049; https://doi.org/10.3390/ijms242015049 - 10 Oct 2023

Cited by 2 | Viewed by 945

Abstract

The β-thalassemias are hereditary monogenic diseases characterized by a low or absent production of adult hemoglobin and excess in the content of α-globin. This excess is cytotoxic for the erythroid cells and responsible for the β-thalassemia-associated ineffective erythropoiesis. Therefore, the decrease in excess α-globin is a relevant clinical effect for these patients and can be realized through the induction of fetal hemoglobin, autophagy, or both. The in vivo effects of sirolimus (rapamycin) and analogs on the induction of fetal hemoglobin (HbF) are of key importance for therapeutic protocols in a variety of hemoglobinopathies, including β-thalassemias. In this research communication, we report data showing that a decrease in autophagy-associated p62 protein, increased expression of ULK-1, and reduction in excess α-globin are occurring in erythroid precursors (ErPCs) stimulated in vitro with low dosages of sirolimus. In addition, increased ULK-1 mRNA content and a decrease in α-globin content were found in ErPCs isolated from β-thalassemia patients recruited for the NCT03877809 clinical trial and treated with 0.5–2 mg/day sirolimus. Our data support the concept that autophagy, ULK1 expression, and α-globin chain reduction should be considered important endpoints in sirolimus-based clinical trials for β-thalassemias. Full article

(This article belongs to the Special Issue Autophagy in Health and Diseases)

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17 pages, 3845 KiB

Open AccessArticle

Transcriptome Sequencing Reveals Autophagy Networks in Rat Livers during the Development of NAFLD and Identifies Autophagy Hub Genes

by Jian Xie, Qiuyi Chen, Yongxia Zhao, Mingxia Luo, Xin Zeng, Lin Qin, Daopeng Tan and Yuqi He

Int. J. Mol. Sci. 2023, 24(7), 6437; https://doi.org/10.3390/ijms24076437 - 29 Mar 2023

Cited by 1 | Viewed by 1832

Abstract

(1) Autophagy is an important biological process in cells and is closely associated with the development and progression of non-alcoholic fatty liver disease (NAFLD). Therefore, this study aims to investigate the biological function of the autophagy hub genes, which could be used as a potential therapeutic target and diagnostic markers for NAFLD. (2) Male C57BL/6J mice were sacrificed after 16 and 38 weeks of a high-fat diet, serum biochemical indexes were detected, and liver lobules were collected for pathological observation and transcriptome sequencing. The R software was used to identify differentially expressed autophagy genes (DEGs) from the transcriptome sequencing data of mice fed with a normal diet for 38 weeks (ND38) and a high-fat diet for 38 weeks (HFD38). Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed on the DEGs, a protein–protein interaction (PPI) network of the DEGs was established using the STRING data website, and the results were visualized through Cytoscape. (3) After 16 weeks and 38 weeks of a high-fat diet, there was a significant increase in body weight, serum total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and triglycerides (TG) in mice, along with lipid accumulation in the liver, which was more severe at 38 weeks than at 16 weeks. The transcriptome data showed significant changes in the expression profile of autophagy genes in the livers of NAFLD mice following a long-term high-fat diet. Among the 31 differentially expressed autophagy-related genes, 13 were upregulated and 18 were downregulated. GO and KEGG pathway analysis revealed that these DEGs were primarily involved in autophagy, cholesterol transport, triglyceride metabolism, apoptosis, the FoxO signaling pathway, the p53 signaling pathway and the IL-17 signaling pathway. Four hub genes were identified by the PPI network analysis, of which Irs2, Pnpla2 and Plin2 were significantly downregulated, while Srebf2 was significantly upregulated by the 38-week high-fat diet. (4) The hub genes Irs2, Pnpla2, Srebf2 and Plin2 may serve as key therapeutic targets and early diagnostic markers in the progression of NAFLD. Full article

(This article belongs to the Special Issue Autophagy in Health and Diseases)

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21 pages, 18623 KiB

Open AccessArticle

Autophagy Is Required to Sustain Increased Intestinal Cell Proliferation during Phenotypic Plasticity Changes in Honey Bee (Apis mellifera)

by Yueqin Guo, Ruoyang Hu, Naikang Li, Nannan Li, Jiangli Wu, Huimin Yu, Jing Tan, Zhouhua Li and Shufa Xu

Int. J. Mol. Sci. 2023, 24(3), 1926; https://doi.org/10.3390/ijms24031926 - 18 Jan 2023

Cited by 2 | Viewed by 1831

Abstract

Tissue phenotypic plasticity facilitates rapid adaptation of organisms to biotic and/or abiotic pressure. The reproductive capacity of honey bee workers (Apis mellifera) is plastic and responsive to pheromones produced by broods and the queen. Egg laying workers (ELWs), which could reactivate their ovaries and lay haploid eggs upon queen lost, have been commonly discussed from many aspects. However, it remains unclear whether midgut homeostasis in ELWs is affected during plastic changes. Here, we found that the expression of nutrition- and autophagy-related genes was up-regulated in the midguts of ELWs, compared with that in nurse workers (NWs) by RNA-sequencing. Furthermore, the area and number of autophagosomes were increased, along with significantly increased cell death in the midguts of ELWs. Moreover, cell cycle progression in the midguts of ELWs was increased compared with that in NWs. Consistent with the up-regulation of nutrition-related genes, the body and midgut sizes, and the number of intestinal proliferation cells of larvae reared with royal jelly (RJ) obviously increased more than those reared without RJ in vitro. Finally, cell proliferation was dramatically suppressed in the midguts of ELWs when autophagy was inhibited. Altogether, our data suggested that autophagy was induced and required to sustain cell proliferation in ELWs’ midguts, thereby revealing the critical role of autophagy played in the intestines during phenotypic plasticity changes. Full article

(This article belongs to the Special Issue Autophagy in Health and Diseases)

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Review

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28 pages, 835 KiB

Open AccessReview

The Molecular Mechanism and Therapeutic Application of Autophagy for Urological Disease

by Kuang-Shun Chueh, Jian-He Lu, Tai-Jui Juan, Shu-Mien Chuang and Yung-Shun Juan

Int. J. Mol. Sci. 2023, 24(19), 14887; https://doi.org/10.3390/ijms241914887 - 04 Oct 2023

Cited by 1 | Viewed by 2267

Abstract

Autophagy is a lysosomal degradation process known as autophagic flux, involving the engulfment of damaged proteins and organelles by double-membrane autophagosomes. It comprises microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy. Macroautophagy consists of three stages: induction, autophagosome formation, and autolysosome formation. Atg8-family proteins are valuable for tracking autophagic structures and have been widely utilized for monitoring autophagy. The conversion of LC3 to its lipidated form, LC3-II, served as an indicator of autophagy. Autophagy is implicated in human pathophysiology, such as neurodegeneration, cancer, and immune disorders. Moreover, autophagy impacts urological diseases, such as interstitial cystitis /bladder pain syndrome (IC/BPS), ketamine-induced ulcerative cystitis (KIC), chemotherapy-induced cystitis (CIC), radiation cystitis (RC), erectile dysfunction (ED), bladder outlet obstruction (BOO), prostate cancer, bladder cancer, renal cancer, testicular cancer, and penile cancer. Autophagy plays a dual role in the management of urologic diseases, and the identification of potential biomarkers associated with autophagy is a crucial step towards a deeper understanding of its role in these diseases. Methods for monitoring autophagy include TEM, Western blot, immunofluorescence, flow cytometry, and genetic tools. Autophagosome and autolysosome structures are discerned via TEM. Western blot, immunofluorescence, northern blot, and RT-PCR assess protein/mRNA levels. Luciferase assay tracks flux; GFP-LC3 transgenic mice aid study. Knockdown methods (miRNA and RNAi) offer insights. This article extensively examines autophagy’s molecular mechanism, pharmacological regulation, and therapeutic application involvement in urological diseases. Full article

(This article belongs to the Special Issue Autophagy in Health and Diseases)

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17 pages, 719 KiB

Open AccessReview

Roles of Stress Response in Autophagy Processes and Aging-Related Diseases

by Yoshihisa Watanabe, Katsutoshi Taguchi and Masaki Tanaka

Int. J. Mol. Sci. 2023, 24(18), 13804; https://doi.org/10.3390/ijms241813804 - 07 Sep 2023

Cited by 3 | Viewed by 1317

Abstract

The heat shock factor 1 (HSF1)-mediated stress response pathway and autophagy processes play important roles in the maintenance of proteostasis. Autophagy processes are subdivided into three subtypes: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Recently, molecular chaperones and co-factors were shown to be involved in the selective degradation of substrates by these three autophagy processes. This evidence suggests that autophagy processes are regulated in a coordinated manner by the HSF1-mediated stress response pathway. Recently, various studies have demonstrated that proteostasis pathways including HSF1 and autophagy are implicated in longevity. Furthermore, they serve as therapeutic targets for aging-related diseases such as cancer and neurodegenerative diseases. In the future, these studies will underpin the development of therapies against various diseases. Full article

(This article belongs to the Special Issue Autophagy in Health and Diseases)

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23 pages, 1323 KiB

Open AccessReview

Autophagy and SARS-CoV-2-Old Players in New Games

by Tsvetomira Ivanova, Yuliia Mariienko, Nikolay Mehterov, Maria Kazakova, Yordan Sbirkov, Krassimira Todorova, Soren Hayrabedyan and Victoria Sarafian

Int. J. Mol. Sci. 2023, 24(9), 7734; https://doi.org/10.3390/ijms24097734 - 23 Apr 2023

Cited by 2 | Viewed by 1898

Abstract

At present it is well-defined that autophagy is a fundamental process essential for cell life but its pro-viral and anti-viral role has been stated out with the COVID pandemic. However, viruses in turn have evolved diverse adaptive strategies to cope with autophagy driven host defense, either by blocking or hijacking the autophagy machinery for their own benefit. The mechanisms underlying autophagy modulation are presented in the current review which summarizes the accumulated knowledge on the crosstalk between autophagy and viral infections, with a particular emphasizes on SARS-CoV-2. The different types of autophagy related to infections and their molecular mechanisms are focused in the context of inflammation. In particular, SARS-CoV-2 entry, replication and disease pathogenesis are discussed. Models to study autophagy and to formulate novel treatment approaches and pharmacological modulation to fight COVID-19 are debated. The SARS-CoV-2—autophagy interplay is presented, revealing the complex dynamics and the molecular machinery of autophagy. The new molecular targets and strategies to treat COVID-19 effectively are envisaged. In conclusion, our finding underline the importance of development new treatment strategies and pharmacological modulation of autophagy to fight COVID-19. Full article

(This article belongs to the Special Issue Autophagy in Health and Diseases)

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