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Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Autophagy".

Deadline for manuscript submissions: closed (20 November 2022) | Viewed by 31698

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Special Issue Editors

Dr. Vladimir Trajkovic

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Guest Editor

Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
Interests: Regulation and role of intracellular energy balance-controlling signaling pathways and autophagy in neoplastic and immune diseases

Dr. Paola Maycotte

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Guest Editor

Centro de Investigacion Biomedica de Oriente, Instututo Mexicano del Seguro Social, Mexico
Interests: autophagy; cancer; metabolism; mitochondria; reactive oxygen species
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Macroautophagy (hereafter autophagy) is a process of cellular degradation through lysosomal machinery that occurs at basal levels in eukaryotic cells, serving a homeostatic function of cytoplasmic maintenance. Autophagy is upregulated in response to diverse types of stressful stimuli, functioning as a cell survival mechanism that removes damaged proteins/organelles and provides new building blocks and energy sources during metabolic, hypoxic, oxidative, proteotoxic, and drug-induced stress. In addition to regulating cellular metabolism and stress responses in both normal and cancer cells, autophagy shapes immunity through pathogen clearance, modulation of cytokine production, antigen presentation, and lymphocyte selection, homeostasis, and survival. The main intracellular signals for autophagy induction are the activation of the energy sensor AMP-activated protein kinase (AMPK) and subsequent inhibition of the mechanistic target of rapamycin (mTOR), the major repressor of catabolic processes, including autophagy. This Special Issue welcomes submissions on autophagy and AMPK/mTOR signaling in regulation of stress responses, metabolism, and immune cell function, with the purpose of outlining their roles and interaction in cellular and organismal homeostatic functions as well as in diverse pathologic settings, including metabolic and immune-system-related diseases.

Dr. Vladimir Trajkovic
Dr. Paola Maycotte
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

autophagy
AMPK
mTOR
metabolism
diabetes
hypertension
stress
immunity
cytokine
inflammation

Published Papers (12 papers)

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Research

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17 pages, 3555 KiB

Open AccessArticle

Autophagy Receptor p62 Regulates SARS-CoV-2-Induced Inflammation in COVID-19

by Verica Paunovic, Ljubica Vucicevic, Maja Misirkic Marjanovic, Vladimir Perovic, Biljana Ristic, Mihajlo Bosnjak, Milos Mandic, Danijela Stevanovic, Ljubica Harhaji-Trajkovic, Jovan Lalosevic, Milos Nikolic, Branka Bonaci-Nikolic and Vladimir Trajkovic

Cells 2023, 12(9), 1282; https://doi.org/10.3390/cells12091282 - 28 Apr 2023

Cited by 2 | Viewed by 2079

Abstract

As autophagy can promote or inhibit inflammation, we examined autophagy-inflammation interplay in COVID-19. Autophagy markers in the blood of 19 control subjects and 26 COVID-19 patients at hospital admission and one week later were measured by ELISA, while cytokine levels were examined by flow cytometric bead immunoassay. The antiviral IFN-α and proinflammatory TNF, IL-6, IL-8, IL-17, IL-33, and IFN-γ were elevated in COVID-19 patients at both time points, while IL-10 and IL-1β were increased at admission and one week later, respectively. Autophagy markers LC3 and ATG5 were unaltered in COVID-19. In contrast, the concentration of autophagic cargo receptor p62 was significantly lower and positively correlated with TNF, IL-10, IL-17, and IL-33 at hospital admission, returning to normal levels after one week. The expression of SARS-CoV-2 proteins NSP5 or ORF3a in THP-1 monocytes caused an autophagy-independent decrease or autophagy-inhibition-dependent increase, respectively, of intracellular/secreted p62, as confirmed by immunoblot/ELISA. This was associated with an NSP5-mediated decrease in TNF/IL-10 mRNA and an ORF3a-mediated increase in TNF/IL-1β/IL-6/IL-10/IL-33 mRNA levels. A genetic knockdown of p62 mimicked the immunosuppressive effect of NSP5, and a p62 increase in autophagy-deficient cells mirrored the immunostimulatory action of ORF3a. In conclusion, the proinflammatory autophagy receptor p62 is reduced inacute COVID-19, and the balance between autophagy-independent decrease and autophagy blockade-dependent increase of p62 levels could affect SARS-CoV-induced inflammation. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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28 pages, 26339 KiB

Open AccessArticle

Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy–Lysosomal Pathway

by Juan Carlos Gómora-García, Teresa Montiel, Melanie Hüttenrauch, Ashley Salcido-Gómez, Lizbeth García-Velázquez, Yazmin Ramiro-Cortés, Juan Carlos Gomora, Susana Castro-Obregón and Lourdes Massieu

Cells 2023, 12(3), 486; https://doi.org/10.3390/cells12030486 - 02 Feb 2023

Cited by 13 | Viewed by 4376

Abstract

Mitochondrial activity and quality control are essential for neuronal homeostasis as neurons rely on glucose oxidative metabolism. The ketone body, D-β-hydroxybutyrate (D-BHB), is metabolized to acetyl-CoA in brain mitochondria and used as an energy fuel alternative to glucose. We have previously reported that D-BHB sustains ATP production and stimulates the autophagic flux under glucose deprivation in neurons; however, the effects of D-BHB on mitochondrial turnover under physiological conditions are still unknown. Sirtuins (SIRTs) are NAD⁺-activated protein deacetylases involved in the regulation of mitochondrial biogenesis and mitophagy through the activation of transcription factors FOXO1, FOXO3a, TFEB and PGC1α coactivator. Here, we aimed to investigate the effect of D-BHB on mitochondrial turnover in cultured neurons and the mechanisms involved. Results show that D-BHB increased mitochondrial membrane potential and regulated the NAD⁺/NADH ratio. D-BHB enhanced FOXO1, FOXO3a and PGC1α nuclear levels in an SIRT2-dependent manner and stimulated autophagy, mitophagy and mitochondrial biogenesis. These effects increased neuronal resistance to energy stress. D-BHB also stimulated the autophagic–lysosomal pathway through AMPK activation and TFEB-mediated lysosomal biogenesis. Upregulation of SIRT2, FOXOs, PGC1α and TFEB was confirmed in the brain of ketogenic diet (KD)-treated mice. Altogether, the results identify SIRT2, for the first time, as a target of D-BHB in neurons, which is involved in the regulation of autophagy/mitophagy and mitochondrial quality control. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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19 pages, 8895 KiB

Open AccessArticle

Withaferin A Enhances Mitochondrial Biogenesis and BNIP3-Mediated Mitophagy to Promote Rapid Adaptation to Extreme Hypoxia

by Ruzhou Zhao, Yixin Xu, Xiaobo Wang, Xiang Zhou, Yanqi Liu, Shuai Jiang, Lin Zhang and Zhibin Yu

Cells 2023, 12(1), 85; https://doi.org/10.3390/cells12010085 - 25 Dec 2022

Cited by 1 | Viewed by 1492

Abstract

Rapid adaptation to extreme hypoxia is a challenging problem, and there is no effective scheme to achieve rapid adaptation to extreme hypoxia. In this study, we found that withaferin A (WA) can significantly reduce myocardial damage, maintain cardiac function, and improve survival in rats in extremely hypoxic environments. Mechanistically, WA protects against extreme hypoxia by affecting BCL2-interacting protein 3 (BNIP3)-mediated mitophagy and the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)-mediated mitochondrial biogenesis pathway among mitochondrial quality control mechanisms. On the one hand, enhanced mitophagy eliminates hypoxia-damaged mitochondria and prevents the induction of apoptosis; on the other hand, enhanced mitochondrial biogenesis can supplement functional mitochondria and maintain mitochondrial respiration to ensure mitochondrial ATP production under acute extreme hypoxia. Our study shows that WA can be used as an effective drug to improve tolerance to extreme hypoxia. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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16 pages, 3733 KiB

Open AccessArticle

A Novel TP53 Gene Mutation Sustains Non-Small Cell Lung Cancer through Mitophagy

by Yuanli Wang, Kah Yong Goh, Zhencheng Chen, Wen Xing Lee, Sze Mun Choy, Jia Xin Fong, Yun Ka Wong, Dongxia Li, Fangrong Hu and Hong-Wen Tang

Cells 2022, 11(22), 3587; https://doi.org/10.3390/cells11223587 - 13 Nov 2022

Cited by 3 | Viewed by 2240

Abstract

Lung cancer is the leading cause of cancer death in the world. In particular, non-small-cell lung cancer (NSCLC) represents the majority of the lung cancer population. Advances in DNA sequencing technologies have significantly contributed to revealing the roles, functions and mechanisms of gene mutations. However, the driver mutations that cause cancers and their pathologies remain to be explored. Here, we performed next-generation sequencing (NGS) on tumor tissues isolated from 314 Chinese NSCLC patients and established the mutational landscape in NSCLC. Among 656 mutations, we identified TP53-p.Glu358Val as a driver mutation in lung cancer and found that it activates mitophagy to sustain cancer cell growth. In support of this finding, mice subcutaneously implanted with NSCLC cells expressing TP53-p.Glu358Val developed larger tumors compared to wild-type cells. The pharmaceutical inhibition of autophagy/mitophagy selectively suppresses the cell proliferation of TP53-null or TP53-p.Glu358Val-expressing lung cancer cells. Together, our study characterizes a new TP53 mutation identified from Chinese lung cancer patients and uncovers its roles in regulating mitophagy, providing a new insight into NSCLC treatment. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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16 pages, 1951 KiB

Open AccessFeature PaperArticle

Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain–Barre Syndrome

by Verica Paunovic, Stojan Peric, Irena Vukovic, Marina Stamenkovic, Emina Milosevic, Danijela Stevanovic, Milos Mandic, Ivana Basta, Ivana Berisavac, Mirjana Arsenijevic, Ivo Bozovic, Marko Nikolic, Zorica Stevic and Vladimir Trajkovic

Cells 2022, 11(18), 2897; https://doi.org/10.3390/cells11182897 - 16 Sep 2022

Cited by 1 | Viewed by 2211

Abstract

AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain–Barré syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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20 pages, 4857 KiB

Open AccessArticle

Autophagy in Rat Müller Glial Cells Is Modulated by the Sirtuin 4/AMPK/mTOR Pathway and Induces Apoptosis under Oxidative Stress

by Mengqi Qin, Zhi Xie, Ting Cao, Zhiruo Wang, Xiaoyu Zhang, Feifei Wang, Wei Wei, Ming Jin, Jingyuan Ma, Ling Zeng, Yanan Wang, Shaonan Pei and Xu Zhang

Cells 2022, 11(17), 2645; https://doi.org/10.3390/cells11172645 - 25 Aug 2022

Cited by 5 | Viewed by 1919

Abstract

Müller glial cells (MGCs) are a group of glial cells in the retina that provide essential support to retinal neurons; however, the understanding of MGC apoptosis and autophagy remains limited. This study was aimed at investigating the role of autophagy in MGCs under normal and oxidative conditions, and identifying the underlying mechanisms. In addition, the sirtuin 4 (SIRT4)-mediated signaling pathway was observed to regulate the autophagic process in MGCs. To assess the effect of autophagy on MGC mitochondrial function and survival, we treated rMC-1 cells—rat-derived Müller glial cells—with rapamycin and 3-methyladenine (3-MA), and found that MGC death was not induced by such treatment, while autophagic dysfunction could increase MGC apoptosis under oxidative stress, as reflected by the expression level of cleaved caspase 3 and PI staining. In addition, the downregulation of autophagy by 3-MA could influence the morphology of the mitochondrial network structure, the mitochondrial membrane potential, and generation of reactive oxygen species (ROS) under oxidative stress. Moreover, SIRT4 depletion enhanced autophagosome formation, as verified by an increase in the LC3 II/I ratio and a decrease in the expression of SQSTM1/p62, and vice versa. The inhibition of AMPK phosphorylation by compound C could reverse these changes in LC3 II/I and SQSTM1/p62 caused by SIRT4 knockdown. Our research concludes that MGCs can endure autophagic dysfunction in the absence of oxidative stress, while the downregulation of autophagy can cause MGCs to become more sensitized to oxidative stress. Simultaneous exposure to oxidative stress and autophagic dysfunction in MGCs can result in a pronounced impairment of cell survival. Mechanically, SIRT4 depletion can activate the autophagic process in MGCs by regulating the AMPK–mTOR signaling pathway. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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11 pages, 2818 KiB

Open AccessArticle

Salmonella Promotes Its Own Survival in B Cells by Inhibiting Autophagy

by Lopez-Bailon Luis, Gonzalez-Telona Ana, Galán-Enríquez Carlos, García-Gil Abraham, Estrada-García Iris, Moreno-Lafont Martha and Ortiz-Navarrete Vianney

Cells 2022, 11(13), 2061; https://doi.org/10.3390/cells11132061 - 29 Jun 2022

Cited by 5 | Viewed by 2286

Abstract

Salmonella is a Gram-negative bacterium known to be the major cause of gastrointestinal diseases and systemic infections. During infection of murine B cells, Salmonella activates the PI3K/Akt pathway through its effector, SopB. This signaling pathway induces the downregulation of NLRC4 transcription, resulting in reduced secretion of IL-1β. Thus, Salmonella-infected B cells do not progress to pyroptosis; consequently, the bacteria can survive inside these cells. However, the mechanism by which Salmonella evades the control of B cells has not yet been elucidated. In this study, we found that SopB activates mTORC1, which is necessary for bacterial survival, since B cells cultured with the mTORC1 inhibitor rapamycin and B cells lacking raptor can control Salmonella infection. A similar result was observed in B cells when they were infected with the Salmonella SopB mutant (Δsopb). Salmonella also promoted the phosphorylation of the ULK1 complex at serine 757 (Ser757) by mTORC1, resulting in decreased levels of LC3-II in infected B cells. In this study, we did not observe these results when B cells were infected with Δsopb Salmonella. Our results demonstrated that Salmonella survival within B cells depends on the inhibition of autophagy by mTORC1 activation. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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19 pages, 10850 KiB

Open AccessArticle

Transcriptome Analysis of Retinoic Acid-Inducible Gene I Overexpression Reveals the Potential Genes for Autophagy-Related Negative Regulation

by Shaotang Ye, Chen Tan, Xiaoyun Yang, Ji Wang, Qi Li, Liang Xu, Zhen Wang, Jianwei Mao, Jingyu Wang, Kui Cheng, Aolei Chen, Pei Zhou and Shoujun Li

Cells 2022, 11(13), 2009; https://doi.org/10.3390/cells11132009 - 23 Jun 2022

Cited by 2 | Viewed by 2259

Abstract

Retinoic acid-inducible gene I (RIG-I) serves as an essential viral RNA sensor for innate immune. The activation of the RIG-I-like receptors (RLRs) pathway triggers many regulations for the outcome of type I interferon, including ubiquitination, dephosphorylation, ISGylation, and autophagy. However, the autophagy-related regulation of RIG-I is still not fully understood. To investigate the potentially unknown genes related to autophagy-related regulation of RIG-I, we firstly confirm the induction of autophagy derived by overexpression of RIG-I. Furthermore, the autophagy inducer and inhibitor drugs were used in different assays. The results showed autophagy could control the activation of RLRs pathway and expression of exogenous RIG-I. In addition, we carried out the transcriptome analysis of overexpression of RIG-I in vitro. Differentially expressed genes (DEGs) in GO and KEGG signaling pathways enrichment provided a newly complex network. Finally, the validation of qPCR indicated that the DEGs PTPN22, PRKN, OTUD7B, and SIRT2 were correlated to the negative regulation of excessive expression of RIG-I. Taken together, our study contributed new insights into a more comprehensive understanding of the regulation of excessive expression of RIG-I. It provided the potential candidate genes for autophagy-related negative regulation for further investigation. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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Review

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15 pages, 579 KiB

Open AccessReview

Is Autophagy Inhibition in Combination with Temozolomide a Therapeutically Viable Strategy?

by Ahmed M. Elshazly and David A. Gewirtz

Cells 2023, 12(4), 535; https://doi.org/10.3390/cells12040535 - 07 Feb 2023

Cited by 6 | Viewed by 1662

Abstract

Temozolomide is an oral alkylating agent that is used as the first line treatment for glioblastoma multiform, and in recurrent anaplastic astrocytoma, as well as having demonstrable activity in patients with metastatic melanoma. However, as the case with other chemotherapeutic agents, the development of resistance often limits the therapeutic benefit of temozolomide, particularly in the case of glioblastoma. A number of resistance mechanisms have been proposed including the development of cytoprotective autophagy. Cytoprotective autophagy is a survival mechanism that confers upon tumor cells the ability to survive in a nutrient deficient environment as well as under external stresses, such as cancer chemotherapeutic drugs and radiation, in part through the suppression of apoptotic cell death. In this review/commentary, we explore the available literature and provide an overview of the evidence for the promotion of protective autophagy in response to temozolomide, highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of temozolomide and to overcome the development of resistance. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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12 pages, 970 KiB

Open AccessReview

Interplays of AMPK and TOR in Autophagy Regulation in Yeast

by John-Patrick Alao, Luc Legon, Aleksandra Dabrowska, Anne-Marie Tricolici, Juhi Kumar and Charalampos Rallis

Cells 2023, 12(4), 519; https://doi.org/10.3390/cells12040519 - 04 Feb 2023

Cited by 10 | Viewed by 2774

Abstract

Cells survey their environment and need to balance growth and anabolism with stress programmes and catabolism towards maximum cellular bioenergetics economy and survival. Nutrient-responsive pathways, such as the mechanistic target of rapamycin (mTOR) interact and cross-talk, continuously, with stress-responsive hubs such as the AMP-activated protein kinase (AMPK) to regulate fundamental cellular processes such as transcription, protein translation, lipid and carbohydrate homeostasis. Especially in nutrient stresses or deprivations, cells tune their metabolism accordingly and, crucially, recycle materials through autophagy mechanisms. It has now become apparent that autophagy is pivotal in lifespan, health and cell survival as it is a gatekeeper of clearing damaged macromolecules and organelles and serving as quality assurance mechanism within cells. Autophagy is hard-wired with energy and nutrient levels as well as with damage-response, and yeasts have been instrumental in elucidating such connectivities. In this review, we briefly outline cross-talks and feedback loops that link growth and stress, mainly, in the fission yeast Schizosaccharomyces pombe, a favourite model in cell and molecular biology. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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24 pages, 3167 KiB

Open AccessFeature PaperReview

Adipokines as Regulators of Autophagy in Obesity-Linked Cancer

by Alin García-Miranda, Alejandra Garcia-Hernandez, Eduardo Castañeda-Saucedo, Napoleon Navarro-Tito and Paola Maycotte

Cells 2022, 11(20), 3230; https://doi.org/10.3390/cells11203230 - 14 Oct 2022

Cited by 7 | Viewed by 3685

Abstract

Excess body weight and obesity have become significant risk factors for cancer development. During obesity, adipose tissue alters its biological function, deregulating the secretion of bioactive factors such as hormones, cytokines, and adipokines that promote an inflammatory microenvironment conducive to carcinogenesis and tumor progression. Adipokines regulate tumor processes such as apoptosis, proliferation, migration, angiogenesis, and invasion. Additionally, it has been found that they can modulate autophagy, a process implicated in tumor suppression in healthy tissue and cancer progression in established tumors. Since the tumor-promoting role of autophagy has been well described, the process has been suggested as a therapeutic target in cancer. However, the effects of targeting autophagy might depend on the tumor type and microenvironmental conditions, where circulating adipokines could influence the role of autophagy in cancer. Here, we review recent evidence related to the role of adipokines in cancer cell autophagy in an effort to understand the tumor response in the context of obesity under the assumption of an autophagy-targeting treatment. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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14 pages, 1261 KiB

Open AccessReview

Shining Light on Autophagy in Skin Pigmentation and Pigmentary Disorders

by Daniela Kovacs, Giorgia Cardinali, Mauro Picardo and Emanuela Bastonini

Cells 2022, 11(19), 2999; https://doi.org/10.3390/cells11192999 - 26 Sep 2022

Cited by 8 | Viewed by 2973

Abstract

Autophagy is a vital process for cell survival and it preserves homeostasis by recycling or disassembling unnecessary or dysfunctional cellular constituents. Autophagy ameliorates skin integrity, regulating epidermal differentiation and constitutive pigmentation. It induces melanogenesis and contributes to skin color through melanosome turnover. Autophagy activity is involved in skin phenotypic plasticity and cell function maintenance and, if altered, it concurs to the onset and/or progression of hypopigmentary and hyperpigmentary disorders. Overexpression of autophagy exerts a protective role against the intrinsic metabolic stress occurring in vitiligo skin, while its dysfunction has been linked to the tuberous sclerosis complex hypopigmentation. Again, autophagy impairment reduces melanosome degradation by concurring to pigment accumulation characterizing senile lentigo and melasma. Here we provide an updated review that describes recent findings on the crucial role of autophagy in skin pigmentation, thus revealing the complex interplay among melanocyte biology, skin environment and autophagy. Hence, targeting this process may also represent a promising strategy for treating pigmentary disorders. Full article

(This article belongs to the Special Issue Autophagy and AMPK/mTOR Signaling Regulate Stress Responses, Metabolism, and Immunity)

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