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Crosstalk between Autophagy and Oxidative Stress

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (10 April 2025) | Viewed by 14000

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Dr. Marina Garcia-Macia

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Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, 37007 Salamanca, Spain
Interests: oxidative stress; autophagy; lipophagy; metabolism; neuroscience; liver; metabolic diseases
Special Issues, Collections and Topics in MDPI journals

Dr. Álvaro F. Fernández

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1. Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
2. Departamento de Biología Funcional, Universidad de Oviedo, 33011 Oviedo, Spain
Interests: autophagy; aging; animal models; metabolism; cell death
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Autophagy, a fundamental cellular mechanism, plays a pivotal role in maintaining cellular homeostasis by facilitating the removal of damaged organelles and proteins. Autophagy can be activated in response to various stressors, such as nutrient deprivation, hypoxia, drugs, and virus-mediated infections. More and more evidence in recent years indicates that autophagy is a crucial mediator in the regulation of oxidative stress response.

This Special Issue aims to provide a comprehensive platform for researchers to delve into the cross-regulation between autophagy and oxidative stress. Topics will encompass the molecular mechanisms governing this crosstalk, its impact on cellular functions, and the implications for various diseases, including neurodegenerative disorders, cancer, and metabolic diseases.

We invite contributions from experts across disciplines to explore the latest advancements in understanding how autophagy and oxidative stress communicate within cellular environments. By fostering collaborative discussions, this Special Issue seeks to deepen our insights into these interconnected processes, paving the way for innovative therapeutic strategies and unveiling novel targets for intervention.

Dr. Marina Garcia-Macia
Dr. Álvaro F. Fernández
Guest Editors

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Keywords

autophagy
oxidative stress
reactive oxygen species
aging
cellular homeostasis

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Published Papers (8 papers)

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Research

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19 pages, 4688 KiB

Open AccessArticle

The Probiotic Yeast, Milmed, Promotes Autophagy and Antioxidant Pathways in BV-2 Microglia Cells and C. elegans

by Federica Armeli, Beatrice Mengoni, Emily Schifano, Thomas Lenz, Trevor Archer, Daniela Uccelletti and Rita Businaro

Antioxidants 2025, 14(4), 393; https://doi.org/10.3390/antiox14040393 - 27 Mar 2025

Viewed by 472

Abstract

Background: Autophagy, a catabolic process essential for maintaining cellular homeostasis, declines with age and unhealthy lifestyles, contributing to neurodegenerative diseases. Probiotics, including Milmed yeast, have demonstrated anti-inflammatory and antioxidant properties. This study evaluated the activity of Milmed on BV-2 microglial cells in vitro and in the in vivo model of Caenorhabditis elegans (C. elegans) in restoring autophagic processes. Methods: BV-2 microglial cells were incubated with S. cerevisiae (Milmed treated yeast or untreated yeast) and then stimulated with lipopolysaccharide (LPS). mRNAs of the autophagic factors and antioxidant enzymes were assessed by qPCR; mTOR and NRF2 were evaluated by ELISA. pNRF2 compared with cytosolic NRF2 was evaluated by immunofluorescence. The longevity, body size, and reactive oxygen species (ROS) levels of C. elegans were measured by fluorescence microscopy. Results: Treatment with Milmed YPD cultured yeast or the dried powder obtained from it promoted autophagic flux, as shown by the increased expression of the Beclin-1, ATG7, LC3, and p62 mRNAs and the inhibition of mTOR, as evaluated by ELISA. It also enhanced the antioxidant response by increasing the expression of NRF2, SOD1, and GPX; moreover, pNRF2 expression compared with cytosolic NRF2 expression was enhanced, as shown by immunofluorescence. Milmed dietary supplementation prolonged the survival of C. elegans and reduced the age-related ROS accumulation without changing the expression of gst-4. The pro-longevity effect was found to be dependent on SKN-1/Nrf2 activation, as shown by the absence of benefit in skn-1 mutants. Conclusions: Milmed yeast demonstrates significant pro-autophagy and antioxidant activity with significant pro-longevity effects in C. elegans, thereby extending the lifespan and improving stress resistance, which, together with the previously demonstrated anti-inflammatory activity, highlights its role as a highly effective probiotic for its beneficial health effects. Activation of the SKN-1/NRF2 pathway and the modulation of autophagy support the therapeutic potential of Milmed in neuroprotection and healthy aging. Full article

(This article belongs to the Special Issue Crosstalk between Autophagy and Oxidative Stress)

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22 pages, 11880 KiB

Open AccessArticle

Procyanidin A1 from Peanut Skin Exerts Anti-Aging Effects and Attenuates Senescence via Antioxidative Stress and Autophagy Induction

by Yajing Li, Lan Xiang and Jianhua Qi

Antioxidants 2025, 14(3), 322; https://doi.org/10.3390/antiox14030322 - 7 Mar 2025

Viewed by 789

Abstract

The aging population is steadily increasing, with aging and age-related diseases serving as major risk factors for morbidity, mortality, and economic burden. Peanuts, known as the “longevity nut” in China, have been shown to offer various health benefits, with peanut skin extract (PSE) emerging as a key compound of interest. This study investigates the bioactive compound in PSE with anti-aging potential and explores its underlying mechanisms of action. Procyanidin A1 (PC A1) was isolated from PSE, guided by the K6001 yeast replicative lifespan model. PC A1 prolonged the replicative lifespan of yeast and the yeast-like chronological lifespan of PC12 cells. To further confirm its anti-aging effect, cellular senescence, a hallmark of aging, was assessed. In senescent cells induced by etoposide (Etop), PC A1 alleviated senescence by reducing ROS levels, decreasing the percentage of senescent cells, and restoring proliferative capacity. Transcriptomics analysis revealed that PC A1 induced apoptosis, reduced senescence-associated secretory phenotype (SASP) factors, and modulated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. The antioxidative capacity of PC A1 was also evaluated, showing enhanced resistance to oxidative stress in PC12 cells by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD) activity. Moreover, PC A1 induced autophagy, as evidenced by an increase in fluorescence-labeled autophagic compartments and confirmation via Western blot analysis of autophagy-related proteins. In addition, the treatment of an autophagy inhibitor abolished the antioxidative stress and senescence-alleviating effects of PC A1. These findings reveal that PC A1 extended lifespans and alleviated cellular senescence by enhancing oxidative stress resistance and inducing autophagy, positioning it as a promising candidate for further exploration as a geroprotective agent. Full article

(This article belongs to the Special Issue Crosstalk between Autophagy and Oxidative Stress)

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18 pages, 5324 KiB

Open AccessArticle

The Survival of Human Intervertebral Disc Nucleus Pulposus Cells under Oxidative Stress Relies on the Autophagy Triggered by Delphinidin

by Md Entaz Bahar, Jin Seok Hwang, Trang Huyen Lai, June-Ho Byun, Dong-Hee Kim and Deok Ryong Kim

Antioxidants 2024, 13(7), 759; https://doi.org/10.3390/antiox13070759 - 23 Jun 2024

Cited by 1 | Viewed by 1595

Abstract

Delphinidin (Delp), a natural antioxidant, has shown promise in treating age-related ailments such as osteoarthritis (OA). This study investigates the impact of delphinidin on intervertebral disc degeneration (IVDD) using human nucleus pulposus cells (hNPCs) subjected to hydrogen peroxide. Various molecular and cellular assays were employed to assess senescence, extracellular matrix (ECM) degradation markers, and the activation of AMPK and autophagy pathways. Initially, oxidative stress (OS)-induced hNPCs exhibited notably elevated levels of senescence markers like p53 and p21, which were mitigated by Delp treatment. Additionally, Delp attenuated IVDD characteristics including apoptosis and ECM degradation markers in OS-induced senescence (OSIS) hNPCs by downregulating MMP-13 and ADAMTS-5 while upregulating COL2A1 and aggrecans. Furthermore, Delp reversed the increased ROS production and reduced autophagy activation observed in OSIS hNPCs. Interestingly, the ability of Delp to regulate cellular senescence and ECM balance in OSIS hNPCs was hindered by autophagy inhibition using CQ. Remarkably, Delp upregulated SIRT1 and phosphorylated AMPK expression while downregulating mTOR phosphorylation in the presence of AICAR (AMPK activator), and this effect was reversed by Compound C, AMPK inhibitor. In summary, our findings suggest that Delp can safeguard hNPCs from oxidative stress by promoting autophagy through the SIRT1/AMPK/mTOR pathway. Full article

(This article belongs to the Special Issue Crosstalk between Autophagy and Oxidative Stress)

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21 pages, 18370 KiB

Open AccessArticle

Luteolin Alleviates Cadmium-Induced Kidney Injury by Inhibiting Oxidative DNA Damage and Repairing Autophagic Flux Blockade in Chickens

by Kanglei Zhang, Jiahui Li, Wenxuan Dong, Qing Huang, Xueru Wang, Kai Deng, Waseem Ali, Ruilong Song, Hui Zou, Di Ran, Gang Liu and Zongping Liu

Antioxidants 2024, 13(5), 525; https://doi.org/10.3390/antiox13050525 - 26 Apr 2024

Cited by 10 | Viewed by 2135

Abstract

Chickens are a major source of meat and eggs in human food and have significant economic value. Cadmium (Cd) is a common environmental pollutant that can contaminate feed and drinking water, leading to kidney injury in livestock and poultry, primarily by inducing the generation of free radicals. It is necessary to develop potential medicines to prevent and treat Cd-induced nephrotoxicity in poultry. Luteolin (Lut) is a natural flavonoid compound mainly extracted from peanut shells and has a variety of biological functions to defend against oxidative damage. In this study, we aimed to demonstrate whether Lut can alleviate kidney injury under Cd exposure and elucidate the underlying molecular mechanisms. Renal histopathology and cell morphology were observed. The indicators of renal function, oxidative stress, DNA damage and repair, NAD⁺ content, SIRT1 activity, and autophagy were analyzed. In vitro data showed that Cd exposure increased ROS levels and induced oxidative DNA damage and repair, as indicated by increased 8-OHdG content, increased γ-H2AX protein expression, and the over-activation of the DNA repair enzyme PARP-1. Cd exposure decreased NAD⁺ content and SIRT1 activity and increased LC3 II, ATG5, and particularly p62 protein expression. In addition, Cd-induced oxidative DNA damage resulted in PARP-1 over-activation, reduced SIRT1 activity, and autophagic flux blockade, as evidenced by reactive oxygen species scavenger NAC application. The inhibition of PARP-1 activation with the pharmacological inhibitor PJ34 restored NAD⁺ content and SIRT1 activity. The activation of SIRT1 with the pharmacological activator RSV reversed Cd-induced autophagic flux blockade and cell injury. In vivo data demonstrated that Cd treatment caused the microstructural disruption of renal tissues, reduced creatinine, and urea nitrogen clearance, raised MDA content, and decreased the activities or contents of antioxidants (GSH, T-SOD, CAT, and T-AOC). Cd treatment caused oxidative DNA damage and PARP-1 activation, decreased NAD⁺ content, decreased SIRT1 activity, and impaired autophagic flux. Notably, the dietary Lut supplement observably alleviated these alterations in chicken kidney tissues induced by Cd. In conclusion, the dietary Lut supplement alleviated Cd-induced chicken kidney injury through its potent antioxidant properties by relieving the oxidative DNA damage-activated PARP-1-mediated reduction in SIRT1 activity and repairing autophagic flux blockade. Full article

(This article belongs to the Special Issue Crosstalk between Autophagy and Oxidative Stress)

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19 pages, 12143 KiB

Open AccessArticle

Antioxidative Sirt1 and the Keap1-Nrf2 Signaling Pathway Impair Inflammation and Positively Regulate Autophagy in Murine Mammary Epithelial Cells or Mammary Glands Infected with Streptococcus uberis

by Sohrab Khan, Tian Wang, Eduardo R. Cobo, Bingchun Liang, Muhammad Asfandyar Khan, Maolin Xu, Weijie Qu, Jian Gao, Herman W. Barkema, John P. Kastelic, Gang Liu and Bo Han

Antioxidants 2024, 13(2), 171; https://doi.org/10.3390/antiox13020171 - 29 Jan 2024

Cited by 4 | Viewed by 2173

Abstract

Streptococcus uberis mastitis in cattle infects mammary epithelial cells. Although oxidative responses often remove intracellular microbes, S. uberis survives, but the mechanisms are not well understood. Herein, we aimed to elucidate antioxidative mechanisms during pathogenesis of S. uberis after isolation from clinical bovine mastitis milk samples. S. uberis’s in vitro pathomorphology, oxidative stress biological activities, transcription of antioxidative factors, inflammatory response cytokines, autophagosome and autophagy functions were evaluated, and in vivo S. uberis was injected into the fourth mammary gland nipple of each mouse to assess the infectiousness of S. uberis potential molecular mechanisms. The results showed that infection with S. uberis induced early oxidative stress and increased reactive oxygen species (ROS). However, over time, ROS concentrations decreased due to increased antioxidative activity, including total superoxide dismutase (T-SOD) and malondialdehyde (MDA) enzymes, plus transcription of antioxidative factors (Sirt1, Keap1, Nrf2, HO-1). Treatment with a ROS scavenger (N-acetyl cysteine, NAC) before infection with S. uberis reduced antioxidative responses and the inflammatory response, including the cytokines IL-6 and TNF-α, and the formation of the Atg5-LC3II/LC3I autophagosome. Synthesis of antioxidants determined autophagy functions, with Sirt1/Nrf2 activating autophagy in the presence of S. uberis. This study demonstrated the evasive mechanisms of S. uberis in mastitis, including suppressing inflammatory and ROS defenses by stimulating antioxidative pathways. Full article

(This article belongs to the Special Issue Crosstalk between Autophagy and Oxidative Stress)

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Review

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29 pages, 1408 KiB

Open AccessReview

Roles of Oxidative Stress and Autophagy in Alcohol-Mediated Brain Damage

by Leon Ruiter-Lopez, Mohammed A. S. Khan, Xin Wang and Byoung-Joon Song

Antioxidants 2025, 14(3), 302; https://doi.org/10.3390/antiox14030302 - 28 Feb 2025

Viewed by 2668

Abstract

Excessive alcohol consumption significantly impacts human health, particularly the brain, due to its susceptibility to oxidative stress, which contributes to neurodegenerative conditions. Alcohol metabolism in the brain occurs primarily via catalase, followed by CYP2E1 pathways. Excess alcohol metabolized by CYP2E1 generates reactive oxygen/nitrogen species (ROS/RNS), leading to cell injury via altering many different pathways. Elevated oxidative stress impairs autophagic processes, increasing post-translational modifications and further exacerbating mitochondrial dysfunction and ER stress, leading to cell death. The literature highlights that alcohol-induced oxidative stress disrupts autophagy and mitophagy, contributing to neuronal damage. Key mechanisms include mitochondrial dysfunction, ER stress, epigenetics, and the accumulation of oxidatively modified proteins, which lead to neuroinflammation and impaired cellular quality control. These processes are exacerbated by chronic alcohol exposure, resulting in the suppression of protective pathways like NRF2-mediated antioxidant responses and increased susceptibility to neurodegenerative changes in the brain. Alcohol-mediated neurotoxicity involves complex interactions between alcohol metabolism, oxidative stress, and autophagy regulation, which are influenced by various factors such as drinking patterns, nutritional status, and genetic/environmental factors, highlighting the need for further molecular studies to unravel these mechanisms and develop targeted interventions. Full article

(This article belongs to the Special Issue Crosstalk between Autophagy and Oxidative Stress)

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55 pages, 3547 KiB

Open AccessReview

Crosstalk Between Autophagy and Oxidative Stress in Hematological Malignancies: Mechanisms, Implications, and Therapeutic Potential

by Antonio José Cabrera-Serrano, José Manuel Sánchez-Maldonado, Carmen González-Olmedo, María Carretero-Fernández, Leticia Díaz-Beltrán, Juan Francisco Gutiérrez-Bautista, Francisco José García-Verdejo, Fernando Gálvez-Montosa, José Antonio López-López, Paloma García-Martín, Eva María Pérez, Pedro Sánchez-Rovira, Fernando Jesús Reyes-Zurita and Juan Sainz

Antioxidants 2025, 14(3), 264; https://doi.org/10.3390/antiox14030264 - 25 Feb 2025

Cited by 1 | Viewed by 1222

Abstract

Autophagy is a fundamental cellular process that maintains homeostasis by degrading damaged components and regulating stress responses. It plays a crucial role in cancer biology, including tumor progression, metastasis, and therapeutic resistance. Oxidative stress, similarly, is key to maintaining cellular balance by regulating oxidants and antioxidants, with its disruption leading to molecular damage. The interplay between autophagy and oxidative stress is particularly significant, as reactive oxygen species (ROS) act as both inducers and by-products of autophagy. While autophagy can function as a tumor suppressor in early cancer stages, it often shifts to a pro-tumorigenic role in advanced disease, aiding cancer cell survival under adverse conditions such as hypoxia and nutrient deprivation. This dual role is mediated by several signaling pathways, including PI3K/AKT/mTOR, AMPK, and HIF-1α, which coordinate the balance between autophagic activity and ROS production. In this review, we explore the mechanisms by which autophagy and oxidative stress interact across different hematological malignancies. We discuss how oxidative stress triggers autophagy, creating a feedback loop that promotes tumor survival, and how autophagic dysregulation leads to increased ROS accumulation, exacerbating tumorigenesis. We also examine the therapeutic implications of targeting the autophagy–oxidative stress axis in cancer. Current strategies involve modulating autophagy through specific inhibitors, enhancing ROS levels with pro-oxidant compounds, and combining these approaches with conventional therapies to overcome drug resistance. Understanding the complex relationship between autophagy and oxidative stress provides critical insights into novel therapeutic strategies aimed at improving cancer treatment outcomes. Full article

(This article belongs to the Special Issue Crosstalk between Autophagy and Oxidative Stress)

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15 pages, 1079 KiB

Open AccessReview

Pexophagy and Oxidative Stress: Focus on Peroxisomal Proteins and Reactive Oxygen Species (ROS) Signaling Pathways

by Xiaofan Wei, Laxman Manandhar, Hyunsoo Kim, Arun Chhetri, Jaetaek Hwang, Gyuho Jang, Channy Park and Raekil Park

Antioxidants 2025, 14(2), 126; https://doi.org/10.3390/antiox14020126 - 23 Jan 2025

Cited by 1 | Viewed by 1421

Abstract

Peroxisomes generate reactive oxygen species (ROS) and also play a role in protecting cells from the damaging effects of such radicals. Dysfunctional peroxisomes are recognized by receptors and degraded by a selective type of macroautophagy called pexophagy. Oxidative stress is one of the signals that activates pexophagy through multiple signaling pathways. Conversely, impaired pexophagy results in the accumulation of damaged peroxisomes, which in turn leads to elevated ROS levels and oxidative stress, resulting as cellular dysfunction and the progression of diseases such as neurodegeneration, cancer, and metabolic disorders. This review explores the molecular mechanisms driving pexophagy and its regulation by oxidative stress with a particular focus on ROS. This highlights the role of peroxisomal proteins and ROS-mediated signaling pathways in regulating pexophagy. In addition, emerging evidence suggests that the dysregulation of pexophagy is closely linked to neurological disorders, underscoring its potential as a therapeutic target. Understanding the intricate crosstalk between pexophagy and oxidative stress provides new insights into the maintenance of cellular homeostasis and offers promising directions for addressing neurological disorders that are tightly associated with pexophagy and oxidative stress. Full article

(This article belongs to the Special Issue Crosstalk between Autophagy and Oxidative Stress)

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