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Autophagy in Health, Aging and Disease, 4th Edition
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Autophagy in Health, Aging and Disease, 4th Edition

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 July 2024) | Viewed by 6495

Special Issue Editors

Dr. Mirko Pesce

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Guest Editor
Department of Medicine and Ageing Sciences, University G. d’Annunzio, Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti, Italy
Interests: myokines; autophagy; senescence; biological bases of emotional state; cognitive performance; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Antonia Patruno

E-Mail Website
Guest Editor
Department of Medicine and Aging Science, University “G. D’Annunzio” Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti, Italy
Interests: oxidative/nitrosative stress; cell signalling; tissue repair; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Maccarone Rita

E-Mail Website
Guest Editor
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L'Aquila, Italy
Interests: retina; neurodegeneration; neuroprotection; retinal pigment epithelium; retinal function; age related macular degeneration; nanoparticles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Autophagy is an evolutionarily conserved intracellular catabolic process. It has an essential role in cellular homeostasis, facilitating lysosomal degradation and the recycling of harmful and damaged cytoplasmic components. Autophagy was first discovered as a survival mechanism in yeasts subjected to nutrient deprivation, and since then, studies in several different organisms have established its critical roles in a variety of biological processes ranging from development to aging. Interestingly, autophagy is often found perturbed in age-related disorders such as cancer, diabetes, neurodegenerative diseases, and sarcopenia. Accordingly, autophagy is important for the maintenance of organismal health, which prominently declines with aging.

This Special Issue of the International Journal of Molecular Sciences, “Autophagy in Health, Aging and Disease 4.0”, will include a selection of original articles and reviews aimed at expanding our understanding of this multifaceted process and providing support for further investigations on the role of autophagy in cellular homeostasis, aging, and disease. In particular, it will contribute to better explaining the complex machinery of autophagy and lead to further investigations on physiological and pathological fields in which the study of this process is still in its infancy. Moreover, studies on the role of autophagy in age-related processes to open new avenues for the development of novel potential anti-aging therapeutic approaches are also welcome.

Prof. Dr. Mirko Pesce
Prof. Dr. Antonia Patruno
Dr. Maccarone Rita
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • autophagy
  • aging
  • aging diseases
  • cell survival
  • inflammation
  • oxidative stress
  • signaling pathway
  • target identification

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Published Papers (5 papers)

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Research

26 pages, 11651 KiB  
Article
The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts
by Laura Patricia Perez-Abshana, Miguel Mendivil-Perez, Marlene Jimenez-Del-Rio and Carlos Velez-Pardo
Int. J. Mol. Sci. 2024, 25(17), 9220; https://doi.org/10.3390/ijms25179220 - 25 Aug 2024
Viewed by 790
Abstract
Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as a result of the loss of dopaminergic (DAergic) neurons of the pars compacta in the substantia nigra and protein aggregates of alpha synuclein (α-Syn). Although its etiopathology agent [...] Read more.
Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as a result of the loss of dopaminergic (DAergic) neurons of the pars compacta in the substantia nigra and protein aggregates of alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental and genetic factors have been suggested as the major contributors to the disease. Mutations in the glucosidase beta acid 1 (GBA1) gene, which encodes the lysosomal glucosylceramidase (GCase) enzyme, are one of the major genetic risks for PD. We found that the GBA1 K198E fibroblasts but not WT fibroblasts showed reduced catalytic activity of heterozygous mutant GCase by −70% but its expression levels increased by 3.68-fold; increased the acidification of autophagy vacuoles (e.g., autophagosomes, lysosomes, and autolysosomes) by +1600%; augmented the expression of autophagosome protein Beclin-1 (+133%) and LC3-II (+750%), and lysosomal–autophagosome fusion protein LAMP-2 (+107%); increased the accumulation of lysosomes (+400%); decreased the mitochondrial membrane potential (∆Ψm) by −19% but the expression of Parkin protein remained unperturbed; increased the oxidized DJ-1Cys106-SOH by +900%, as evidence of oxidative stress; increased phosphorylated LRRK2 at Ser935 (+1050%) along with phosphorylated α-synuclein (α-Syn) at pathological residue Ser129 (+1200%); increased the executer apoptotic protein caspase 3 (cleaved caspase 3) by +733%. Although exposure of WT fibroblasts to environmental neutoxin rotenone (ROT, 1 μM) exacerbated the autophagy–lysosomal system, oxidative stress, and apoptosis markers, ROT moderately increased those markers in GBA1 K198E fibroblasts. We concluded that the K198E mutation endogenously primes skin fibroblasts toward autophagy dysfunction, OS, and apoptosis. Our findings suggest that the GBA1 K198E fibroblasts are biochemically and molecularly equivalent to the response of WT GBA1 fibroblasts exposed to ROT. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease, 4th Edition)
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17 pages, 3555 KiB  
Article
Bafilomycin 1A Affects p62/SQSTM1 Autophagy Marker Protein Level and Autophagosome Puncta Formation Oppositely under Various Inflammatory Conditions in Cultured Rat Microglial Cells
by István Pesti, Gábor Barczánfalvi, Karolina Dulka, Diana Kata, Eszter Farkas and Karoly Gulya
Int. J. Mol. Sci. 2024, 25(15), 8265; https://doi.org/10.3390/ijms25158265 - 29 Jul 2024
Viewed by 607
Abstract
Regulation of autophagy through the 62 kDa ubiquitin-binding protein/autophagosome cargo protein sequestosome 1 (p62/SQSTM1), whose level is generally inversely proportional to autophagy, is crucial in microglial functions. Since autophagy is involved in inflammatory mechanisms, we investigated the actions of pro-inflammatory lipopolysaccharide (LPS) and [...] Read more.
Regulation of autophagy through the 62 kDa ubiquitin-binding protein/autophagosome cargo protein sequestosome 1 (p62/SQSTM1), whose level is generally inversely proportional to autophagy, is crucial in microglial functions. Since autophagy is involved in inflammatory mechanisms, we investigated the actions of pro-inflammatory lipopolysaccharide (LPS) and anti-inflammatory rosuvastatin (RST) in secondary microglial cultures with or without bafilomycin A1 (BAF) pretreatment, an antibiotic that potently inhibits autophagosome fusion with lysosomes. The levels of the microglia marker protein Iba1 and the autophagosome marker protein p62/SQSTM1 were quantified by Western blots, while the number of p62/SQSTM1 immunoreactive puncta was quantitatively analyzed using fluorescent immunocytochemistry. BAF pretreatment hampered microglial survival and decreased Iba1 protein level under all culturing conditions. Cytoplasmic p62/SQSTM1 level was increased in cultures treated with LPS+RST but reversed markedly when BAF+LPS+RST were applied together. Furthermore, the number of p62/SQSTM1 immunoreactive autophagosome puncta was significantly reduced when RST was used but increased significantly in BAF+RST-treated cultures, indicating a modulation of autophagic flux through reduction in p62/SQSTM1 degradation. These findings collectively indicate that the cytoplasmic level of p62/SQSTM1 protein and autophagocytotic flux are differentially regulated, regardless of pro- or anti-inflammatory state, and provide context for understanding the role of autophagy in microglial function in various inflammatory settings. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease, 4th Edition)
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16 pages, 6873 KiB  
Article
Cisplatin Nephrotoxicity Is Critically Mediated by the Availability of BECLIN1
by Tillmann Bork, Camila Hernando-Erhard, Wei Liang, Zhejia Tian, Kosuke Yamahara and Tobias B. Huber
Int. J. Mol. Sci. 2024, 25(5), 2560; https://doi.org/10.3390/ijms25052560 - 22 Feb 2024
Cited by 1 | Viewed by 1406
Abstract
Cisplatin nephrotoxicity is a critical limitation of solid cancer treatment. Until now, the complex interplay of various pathophysiological mechanisms leading to proximal tubular cell apoptosis after cisplatin exposure has not been fully understood. In our study, we assessed the role of the autophagy-related [...] Read more.
Cisplatin nephrotoxicity is a critical limitation of solid cancer treatment. Until now, the complex interplay of various pathophysiological mechanisms leading to proximal tubular cell apoptosis after cisplatin exposure has not been fully understood. In our study, we assessed the role of the autophagy-related protein BECLIN1 (ATG6) in cisplatin-induced acute renal injury (AKI)—a candidate protein involved in autophagy and with putative impact on apoptosis by harboring a B-cell lymphoma 2 (BCL2) interaction site of unknown significance. By using mice with heterozygous deletion of Becn1, we demonstrate that reduced intracellular content of BECLIN1 does not impact renal function or autophagy within 12 months. However, these mice were significantly sensitized towards cisplatin-induced AKI, and by using Becn1+/−;Sglt2-Cre;Tomato/EGFP mice with subsequent primary cell analysis, we confirmed that nephrotoxicity depends on proximal tubular BECLIN1 content. Mechanistically, BECLIN1 did not impact autophagy or primarily the apoptotic pathway. In fact, a lack of BECLIN1 sensitized mice towards cisplatin-induced ER stress. Accordingly, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blunted cisplatin-induced cell death in Becn1 heterozygosity. In conclusion, our data first highlight a novel role of BECLIN1 in protecting against cellular ER stress independent from autophagy. These novel findings open new therapeutic avenues to intervene in this important intracellular stress response pathway with a promising impact on future AKI management. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease, 4th Edition)
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13 pages, 2497 KiB  
Article
THSD1 Suppresses Autophagy-Mediated Focal Adhesion Turnover by Modulating the FAK-Beclin 1 Pathway
by Zhen Xu, Jiayi Lu, Song Gao and Yan-Ning Rui
Int. J. Mol. Sci. 2024, 25(4), 2139; https://doi.org/10.3390/ijms25042139 - 10 Feb 2024
Viewed by 1093
Abstract
Focal adhesions (FAs) play a crucial role in cell spreading and adhesion, and their autophagic degradation is an emerging area of interest. This study investigates the role of Thrombospondin Type 1 Domain-Containing Protein 1 (THSD1) in regulating autophagy and FA stability in brain [...] Read more.
Focal adhesions (FAs) play a crucial role in cell spreading and adhesion, and their autophagic degradation is an emerging area of interest. This study investigates the role of Thrombospondin Type 1 Domain-Containing Protein 1 (THSD1) in regulating autophagy and FA stability in brain endothelial cells, shedding light on its potential implications for cerebrovascular diseases. Our research reveals a physical interaction between THSD1 and FAs. Depletion of THSD1 significantly reduces FA numbers, impairing cell spreading and adhesion. The loss of THSD1 also induces autophagy independently of changes in mTOR and AMPK activation, implying that THSD1 primarily governs FA dynamics rather than serving as a global regulator of nutrient and energy status. Mechanistically, THSD1 negatively regulates Beclin 1, a central autophagy regulator, at FAs through interactions with focal adhesion kinase (FAK). THSD1 inactivation diminishes FAK activity and relieves its inhibitory phosphorylation on Beclin 1. This, in turn, promotes the complex formation between Beclin 1 and ATG14, a critical event for the activation of the autophagy cascade. In summary, our findings identify THSD1 as a novel regulator of autophagy that degrades FAs in brain endothelial cells. This underscores the distinctive nature of THSD1-mediated, cargo-directed autophagy and its potential relevance to vascular diseases due to the loss of endothelial FAs. Investigating the underlying mechanisms of THSD1-mediated pathways holds promise for discovering novel therapeutic targets in vascular diseases. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease, 4th Edition)
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17 pages, 10681 KiB  
Article
Altered Expression of Autophagy Biomarkers in Hippocampal Neurons in a Multiple Sclerosis Animal Model
by Sabrina Ceccariglia, Diego Sibilia, Ornella Parolini, Fabrizio Michetti and Gabriele Di Sante
Int. J. Mol. Sci. 2023, 24(17), 13225; https://doi.org/10.3390/ijms241713225 - 25 Aug 2023
Cited by 4 | Viewed by 1596
Abstract
Multiple Sclerosis (MS) is a chronic inflammatory disease that affects the brain and spinal cord. Inflammation, demyelination, synaptic alteration, and neuronal loss are hallmarks detectable in MS. Experimental autoimmune encephalomyelitis (EAE) is an animal model widely used to study pathogenic aspects of MS. [...] Read more.
Multiple Sclerosis (MS) is a chronic inflammatory disease that affects the brain and spinal cord. Inflammation, demyelination, synaptic alteration, and neuronal loss are hallmarks detectable in MS. Experimental autoimmune encephalomyelitis (EAE) is an animal model widely used to study pathogenic aspects of MS. Autophagy is a process that maintains cell homeostasis by removing abnormal organelles and damaged proteins and is involved both in protective and detrimental effects that have been seen in a variety of human diseases, such as cancer, neurodegenerative diseases, inflammation, and metabolic disorders. This study is aimed at investigating the autophagy signaling pathway through the analysis of the main autophagic proteins including Beclin-1, microtubule-associated protein light chain (LC3, autophagosome marker), and p62 also called sequestosome1 (SQSTM1, substrate of autophagy-mediated degradation) in the hippocampus of EAE-affected mice. The expression levels of Beclin-1, LC3, and p62 and the Akt/mTOR pathway were examined by Western blot experiments. In EAE mice, compared to control animals, significant reductions of expression levels were detectable for Beclin-1 and LC3 II (indicating the reduction of autophagosomes), and p62 (suggesting that autophagic flux increased). In parallel, molecular analysis detected the deregulation of the Akt/mTOR signaling. Immunofluorescence double-labeling images showed co-localization of NeuN (neuronal nuclear marker) and Beclin-1, LC3, and p62 throughout the CA1 and CA3 hippocampal subfields. Taken together, these data demonstrate that activation of autophagy occurs in the neurons of the hippocampus in this experimental model. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease, 4th Edition)
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