Research

12 pages, 5492 KiB

Open AccessArticle

Stevia and Stevioside Attenuate Liver Steatosis through PPARα-Mediated Lipophagy in db/db Mice Hepatocytes

by Miey Park, Anshul Sharma, Hana Baek, Jin-Young Han, Junho Yu and Hae-Jeung Lee

Antioxidants 2022, 11(12), 2496; https://doi.org/10.3390/antiox11122496 - 19 Dec 2022

Cited by 3 | Viewed by 2295

Lipophagy, a type of autophagy that breaks down lipid droplets, is essential in the regulation of intracellular lipid accumulation and intracellular free fatty acid levels in numerous organisms and metabolic conditions. We investigated the effects of Stevia rebaudiana Bertoni (S), a low-calorie sweetener, [...] Read more.

Lipophagy, a type of autophagy that breaks down lipid droplets, is essential in the regulation of intracellular lipid accumulation and intracellular free fatty acid levels in numerous organisms and metabolic conditions. We investigated the effects of Stevia rebaudiana Bertoni (S), a low-calorie sweetener, and stevioside (SS) on hepatic steatosis and autophagy in hepatocytes, as well as in db/db mice. S and SS reduced the body and liver weight and levels of serum triglyceride, total cholesterol, and hepatic lipogenic proteins. In addition, S and SS increased the levels of fatty acid oxidase, peroxisome proliferator-activated receptor alpha (PPARα), and microtubule-associated protein light chain 3 B but decreased that of sequestosome 1 (p62) in the liver of db/db mice. Additionally, Beclin 1, lysosomal associated membrane protein 1, and phosphorylated adenosine monophosphate-activated protein kinase protein expression was augmented following S and SS treatment of db/db mice. Furthermore, the knockdown of PPARα blocked lipophagy in response to SS treatment in HepG2 cells. These outcomes indicate that PPARα-dependent lipophagy is involved in hepatic steatosis in the db/db mouse model and that SS, a PPARα agonist, represents a new therapeutic option for managing associated diseases. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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11 pages, 3587 KiB

Open AccessArticle

CHK2 Promotes Metabolic Stress-Induced Autophagy through ULK1 Phosphorylation

by Ran Guo, Shan-Shan Wang, Xiao-You Jiang, Ye Zhang, Yang Guo, Hong-Yan Cui, Qi-Qiang Guo, Liu Cao and Xiao-Chen Xie

Antioxidants 2022, 11(6), 1166; https://doi.org/10.3390/antiox11061166 - 14 Jun 2022

Cited by 1 | Viewed by 1787

Abstract

Reactive oxygen species (ROS) act as a signaling intermediate to promote cellular adaptation to maintain homeostasis by regulating autophagy during pathophysiological stress. However, the mechanism by which ROS promotes autophagy is still largely unknown. Here, we show that the ATM/CHK2/ULK1 axis initiates autophagy [...] Read more.

Reactive oxygen species (ROS) act as a signaling intermediate to promote cellular adaptation to maintain homeostasis by regulating autophagy during pathophysiological stress. However, the mechanism by which ROS promotes autophagy is still largely unknown. Here, we show that the ATM/CHK2/ULK1 axis initiates autophagy to maintain cellular homeostasis by sensing ROS signaling under metabolic stress. We report that ULK1 is a physiological substrate of CHK2, and that the binding of CHK2 to ULK1 depends on the ROS signal and the phosphorylation of threonine 68 of CHK2 under metabolic stress. Further, CHK2 phosphorylates ULK1 on serine 556, and this phosphorylation is dependent on the ATM/CHK2 signaling pathway. CHK2-mediated phosphorylation of ULK1 promotes autophagic flux and inhibits apoptosis induced by metabolic stress. Taken together, these results demonstrate that the ATM/CHK2/ULK1 axis initiates an autophagic adaptive response by sensing ROS, and it protects cells from metabolic stress-induced cellular damage. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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22 pages, 3983 KiB

Open AccessArticle

Apoptosis-Inducing Factor Deficiency Induces Tissue-Specific Alterations in Autophagy: Insights from a Preclinical Model of Mitochondrial Disease and Exercise Training Effects

by Sara Laine-Menéndez, Miguel Fernández-de la Torre, Carmen Fiuza-Luces, Aitor Delmiro, Joaquín Arenas, Miguel Ángel Martín, Patricia Boya, Alejandro Lucia and María Morán

Antioxidants 2022, 11(3), 510; https://doi.org/10.3390/antiox11030510 - 07 Mar 2022

Viewed by 2550

Abstract

We analyzed the effects of apoptosis-inducing factor (AIF) deficiency, as well as those of an exercise training intervention on autophagy across tissues (heart, skeletal muscle, cerebellum and brain), that are primarily affected by mitochondrial diseases, using a preclinical model of these conditions, the [...] Read more.

We analyzed the effects of apoptosis-inducing factor (AIF) deficiency, as well as those of an exercise training intervention on autophagy across tissues (heart, skeletal muscle, cerebellum and brain), that are primarily affected by mitochondrial diseases, using a preclinical model of these conditions, the Harlequin (Hq) mouse. Autophagy markers were analyzed in: (i) 2, 3 and 6 month-old male wild-type (WT) and Hq mice, and (ii) WT and Hq male mice that were allocated to an exercise training or sedentary group. The exercise training started upon onset of the first symptoms of ataxia in Hq mice and lasted for 8 weeks. Higher content of autophagy markers and free amino acids, and lower levels of sarcomeric proteins were found in the skeletal muscle and heart of Hq mice, suggesting increased protein catabolism. Leupeptin-treatment demonstrated normal autophagic flux in the Hq heart and the absence of mitophagy. In the cerebellum and brain, a lower abundance of Beclin 1 and ATG16L was detected, whereas higher levels of the autophagy substrate p62 and LAMP1 levels were observed in the cerebellum. The exercise intervention did not counteract the autophagy alterations found in any of the analyzed tissues. In conclusion, AIF deficiency induces tissue-specific alteration of autophagy in the Hq mouse, with accumulation of autophagy markers and free amino acids in the heart and skeletal muscle, but lower levels of autophagy-related proteins in the cerebellum and brain. Exercise intervention, at least if starting when muscle atrophy and neurological symptoms are already present, is not sufficient to mitigate autophagy perturbations. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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Review

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25 pages, 822 KiB

Open AccessReview

Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues

by Inmaculada Navarro-Lérida, Anna M. Aragay, Alejandro Asensio and Catalina Ribas

Antioxidants 2022, 11(8), 1599; https://doi.org/10.3390/antiox11081599 - 18 Aug 2022

Cited by 1 | Viewed by 3576

Abstract

All processes in human physiology relies on homeostatic mechanisms which require the activation of specific control circuits to adapt the changes imposed by external stimuli. One of the critical modulators of homeostatic balance is autophagy, a catabolic process that is responsible of the [...] Read more.

All processes in human physiology relies on homeostatic mechanisms which require the activation of specific control circuits to adapt the changes imposed by external stimuli. One of the critical modulators of homeostatic balance is autophagy, a catabolic process that is responsible of the destruction of long-lived proteins and organelles through a lysosome degradative pathway. Identification of the mechanism underlying autophagic flux is considered of great importance as both protective and detrimental functions are linked with deregulated autophagy. At the mechanistic and regulatory levels, autophagy is activated in response to diverse stress conditions (food deprivation, hyperthermia and hypoxia), even a novel perspective highlight the potential role of physical forces in autophagy modulation. To understand the crosstalk between all these controlling mechanisms could give us new clues about the specific contribution of autophagy in a wide range of diseases including vascular disorders, inflammation and cancer. Of note, any homeostatic control critically depends in at least two additional and poorly studied interdependent components: a receptor and its downstream effectors. Addressing the selective receptors involved in autophagy regulation is an open question and represents a new area of research in this field. G-protein coupled receptors (GPCRs) represent one of the largest and druggable targets membrane receptor protein superfamily. By exerting their action through G proteins, GPCRs play fundamental roles in the control of cellular homeostasis. Novel studies have shown Gαq, a subunit of heterotrimeric G proteins, as a core modulator of mTORC1 and autophagy, suggesting a fundamental contribution of Gαq-coupled GPCRs mechanisms in the control of this homeostatic feedback loop. To address how GPCR-G proteins machinery integrates the response to different stresses including oxidative conditions and mechanical stimuli, could provide deeper insight into new signaling pathways and open potential and novel therapeutic strategies in the modulation of different pathological conditions. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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20 pages, 2053 KiB

Open AccessReview

From Intestinal Epithelial Homeostasis to Colorectal Cancer: Autophagy Regulation in Cellular Stress

by Qiuluo Liu, Yan Chen, Li Zhou, Haining Chen and Zongguang Zhou

Antioxidants 2022, 11(7), 1308; https://doi.org/10.3390/antiox11071308 - 30 Jun 2022

Cited by 2 | Viewed by 2209

Abstract

The intestinal epithelium is continuously exposed to abundant stress stimuli, which relies on an evolutionarily conserved process, autophagy, to maintain its homeostasis by degrading and recycling unwanted and damaged intracellular substances. Otherwise, disruption of this balance will result in the development of a [...] Read more.

The intestinal epithelium is continuously exposed to abundant stress stimuli, which relies on an evolutionarily conserved process, autophagy, to maintain its homeostasis by degrading and recycling unwanted and damaged intracellular substances. Otherwise, disruption of this balance will result in the development of a wide range of disorders, including colorectal cancer (CRC). Dysregulated autophagy is implicated in the regulation of cellular responses to stress during the development, progression, and treatment of CRC. However, experimental investigations addressing the impact of autophagy in different phases of CRC have generated conflicting results, showing that autophagy is context-dependently related to CRC. Thus, both inhibition and activation of autophagy have been proposed as therapeutic strategies against CRC. Here, we will discuss the multifaceted role of autophagy in intestinal homeostasis and CRC, which may provide insights for future research directions. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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25 pages, 2229 KiB

Open AccessReview

mTOR Signalling Pathway: A Potential Therapeutic Target for Ocular Neurodegenerative Diseases

by Yipin Wang, Nicholas Siu Kay Fung, Wai-Ching Lam and Amy Cheuk Yin Lo

Antioxidants 2022, 11(7), 1304; https://doi.org/10.3390/antiox11071304 - 29 Jun 2022

Cited by 12 | Viewed by 4773

Abstract

Recent advances in the research of the mammalian target of the rapamycin (mTOR) signalling pathway demonstrated that mTOR is a robust therapeutic target for ocular degenerative diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. Although the exact mechanisms of individual [...] Read more.

Recent advances in the research of the mammalian target of the rapamycin (mTOR) signalling pathway demonstrated that mTOR is a robust therapeutic target for ocular degenerative diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. Although the exact mechanisms of individual ocular degenerative diseases are unclear, they share several common pathological processes, increased and prolonged oxidative stress in particular, which leads to functional and morphological impairment in photoreceptors, retinal ganglion cells (RGCs), or retinal pigment epithelium (RPE). mTOR not only modulates oxidative stress but is also affected by reactive oxygen species (ROS) activation. It is essential to understand the complicated relationship between the mTOR pathway and oxidative stress before its application in the treatment of retinal degeneration. Indeed, the substantial role of mTOR-mediated autophagy in the pathogenies of ocular degenerative diseases should be noted. In reviewing the latest studies, this article summarised the application of rapamycin, an mTOR signalling pathway inhibitor, in different retinal disease models, providing insight into the mechanism of rapamycin in the treatment of retinal neurodegeneration under oxidative stress. Besides basic research, this review also summarised and updated the results of the latest clinical trials of rapamycin in ocular neurodegenerative diseases. In combining the current basic and clinical research results, we provided a more complete picture of mTOR as a potential therapeutic target for ocular neurodegenerative diseases. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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12 pages, 1052 KiB

Open AccessReview

Hydrogen Sulfide: A Key Role in Autophagy Regulation from Plants to Mammalians

by Angeles Aroca and Cecilia Gotor

Antioxidants 2022, 11(2), 327; https://doi.org/10.3390/antiox11020327 - 08 Feb 2022

Cited by 9 | Viewed by 2137

Abstract

Autophagy is a degradative conserved process in eukaryotes to recycle unwanted cellular protein aggregates and damaged organelles. Autophagy plays an important role under normal physiological conditions in multiple biological processes, but it is induced under cellular stress. Therefore, it needs to be tightly [...] Read more.

Autophagy is a degradative conserved process in eukaryotes to recycle unwanted cellular protein aggregates and damaged organelles. Autophagy plays an important role under normal physiological conditions in multiple biological processes, but it is induced under cellular stress. Therefore, it needs to be tightly regulated to respond to different cellular stimuli. In this review, the regulation of autophagy by hydrogen sulfide is described in both animal and plant systems. The underlying mechanism of action of sulfide is deciphered as the persulfidation of specific targets, regulating the pro- or anti-autophagic role of sulfide with a cell survival outcome. This review aims to highlight the importance of sulfide and persulfidation in autophagy regulation comparing the knowledge available in mammals and plants. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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31 pages, 3418 KiB

Open AccessReview

How Cells Deal with the Fluctuating Environment: Autophagy Regulation under Stress in Yeast and Mammalian Systems

by Yuchen Lei, Yuxiang Huang, Xin Wen, Zhangyuan Yin, Zhihai Zhang and Daniel J. Klionsky

Antioxidants 2022, 11(2), 304; https://doi.org/10.3390/antiox11020304 - 02 Feb 2022

Cited by 13 | Viewed by 3438

Abstract

Eukaryotic cells frequently experience fluctuations of the external and internal environments, such as changes in nutrient, energy and oxygen sources, and protein folding status, which, after reaching a particular threshold, become a type of stress. Cells develop several ways to deal with these [...] Read more.

Eukaryotic cells frequently experience fluctuations of the external and internal environments, such as changes in nutrient, energy and oxygen sources, and protein folding status, which, after reaching a particular threshold, become a type of stress. Cells develop several ways to deal with these various types of stress to maintain homeostasis and survival. Among the cellular survival mechanisms, autophagy is one of the most critical ways to mediate metabolic adaptation and clearance of damaged organelles. Autophagy is maintained at a basal level under normal growing conditions and gets stimulated by stress through different but connected mechanisms. In this review, we summarize the advances in understanding the autophagy regulation mechanisms under multiple types of stress including nutrient, energy, oxidative, and ER stress in both yeast and mammalian systems. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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23 pages, 1508 KiB

Open AccessReview

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

by Naveed Ur Rehman, Peichun Zeng, Zulong Mo, Shaoying Guo, Yunfeng Liu, Yifeng Huang and Qingjun Xie

Antioxidants 2021, 10(11), 1736; https://doi.org/10.3390/antiox10111736 - 29 Oct 2021

Cited by 10 | Viewed by 2710

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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25 pages, 1087 KiB

Open AccessEditor’s ChoiceReview

Mitophagy and Oxidative Stress: The Role of Aging

by Anna De Gaetano, Lara Gibellini, Giada Zanini, Milena Nasi, Andrea Cossarizza and Marcello Pinti

Antioxidants 2021, 10(5), 794; https://doi.org/10.3390/antiox10050794 - 17 May 2021

Cited by 59 | Viewed by 5948

Abstract

Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species [...] Read more.

Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer’s and Parkinson’s diseases. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, or an alteration in the regulation of mitophagy leading to the excessive production of ROS by damaged mitochondria. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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Other

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11 pages, 2033 KiB

Open AccessBrief Report

Melatonin Ameliorates Autophagy Impairment in a Metabolic Syndrome Model

by Adrián Santos-Ledo, Beatriz de Luxán-Delgado, Beatriz Caballero, Yaiza Potes, Susana Rodríguez-González, José Antonio Boga, Ana Coto-Montes and Marina García-Macia

Antioxidants 2021, 10(5), 796; https://doi.org/10.3390/antiox10050796 - 18 May 2021

Cited by 14 | Viewed by 2861

Abstract

Metabolic syndrome is a global health problem in adults and its prevalence among children and adolescents is rising. It is strongly linked to a lifestyle with high-caloric food, which causes obesity and lipid metabolism anomalies. Molecular damage due to excessive oxidative stress plays [...] Read more.

Metabolic syndrome is a global health problem in adults and its prevalence among children and adolescents is rising. It is strongly linked to a lifestyle with high-caloric food, which causes obesity and lipid metabolism anomalies. Molecular damage due to excessive oxidative stress plays a major role during the development of metabolic syndrome complications. Among the different hormones, melatonin presents strong antioxidant properties, and it is used to treat metabolic diseases. However, there is not a consensus about its use as a metabolic syndrome treatment. The aim of this study was to identify melatonin effects in a metabolic syndrome model. Golden hamsters were fed with 60% fructose-enriched food to induce metabolic syndrome and were compared to hamsters fed with regular chow diet. Both groups were also treated with melatonin. Fructose-fed hamsters showed altered blood lipid levels (increased cholesterol and LDL) and phenotypes restored with the melatonin treatment. The Harderian gland (HG), which is an ideal model to study autophagy modulation through oxidative stress, was the organ that was most affected by a fructose diet. Redox balance was altered in fructose-fed HG, inducing autophagic activation. However, since LC3-II was not increased, the impairment must be in the last steps of autophagy. Lipophagy HG markers were also disturbed, contributing to the dyslipidemia. Melatonin treatment improved possible oxidative homeostasis through autophagic induction. All these results point to melatonin as a possible treatment of the metabolic syndrome. Full article

(This article belongs to the Special Issue Regulation of Autophagy under Stress)

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