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Cell Death & Disease Oct 2023Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role... (Review)
Review
Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role in cells, but disruption of autophagy mechanisms or excessive autophagic flux usually leads to cell death. Despite recent progress in the study of the regulation and underlying molecular mechanisms of autophagy, numerous questions remain to be answered. How does autophagy regulate cell death? What are the fine-tuned regulatory mechanisms underlying autophagy-dependent cell death (ADCD) and autophagy-mediated cell death (AMCD)? In this article, we highlight the different roles of autophagy in cell death and discuss six of the main autophagy-related cell death modalities, with a focus on the metabolic changes caused by excessive endoplasmic reticulum-phagy (ER-phagy)-induced cell death and the role of mitophagy in autophagy-mediated ferroptosis. Finally, we discuss autophagy enhancement in the treatment of diseases and offer a new perspective based on the use of autophagy for different functional conversions (including the conversion of autophagy and that of different autophagy-mediated cell death modalities) for the clinical treatment of tumors.
Topics: Endoplasmic Reticulum Stress; Autophagy; Endoplasmic Reticulum; Mitophagy; Cell Death
PubMed: 37794028
DOI: 10.1038/s41419-023-06154-8 -
Seminars in Cell & Developmental Biology Feb 2020Metabolic reprogramming in tumours is now recognized as a hallmark of cancer, participating both in tumour growth and cancer progression. Cancer cells develop global... (Review)
Review
Metabolic reprogramming in tumours is now recognized as a hallmark of cancer, participating both in tumour growth and cancer progression. Cancer cells develop global metabolic adaptations allowing them to survive in the low oxygen and nutrient tumour microenvironment. Among these metabolic adaptations, cancer cells use glycolysis but also mitochondrial oxidations to produce ATP and building blocks needed for their high proliferation rate. Another particular adaptation of cancer cell metabolism is the use of autophagy and specific forms of autophagy like mitophagy to recycle intracellular components in condition of metabolic stress or during anticancer treatments. The plasticity of cancer cell metabolism is a major limitation of anticancer treatments and could participate to therapy resistances. The aim of this review is to report recent advances in the understanding of the relationship between tumour metabolism and autophagy/mitophagy in order to propose new therapeutic strategies.
Topics: Animals; Autophagy; Cellular Reprogramming; Humans; Mitophagy; Neoplasms
PubMed: 31154012
DOI: 10.1016/j.semcdb.2019.05.029 -
Redox Biology Sep 2020Exercise and dietary intervention are currently available strategies to treat nonalcoholic fatty liver disease (NAFLD), while the underlying mechanism remains...
Exercise and dietary intervention are currently available strategies to treat nonalcoholic fatty liver disease (NAFLD), while the underlying mechanism remains controversial. Emerging evidence shows that lipophagy is involved in the inhibition of the lipid droplets accumulation. However, it is still unclear if exercise and dietary intervention improve NAFLD through regulating lipophagy, and how exercise of skeletal muscle can modulate lipid metabolism in liver. Moreover, NAFLD is associated with aging, and little is known about the effect of lipid accumulation on aging process. Here in vivo and in vitro models, we found that exercise and dietary intervention reduced lipid droplets formation, decreased hepatic triglyceride in the liver induced by high-fat diet. Exercise and dietary intervention enhanced the lipophagy by activating AMPK/ULK1 and inhibiting Akt/mTOR/ULK1 pathways respectively. Furthermore, exercise stimulated FGF21 production in the muscle, followed by secretion to the circulation to promote the lipophagy in the liver via an AMPK-dependent pathway. Importantly, for the first time, we demonstrated that lipid accumulation exacerbated liver aging, which was ameliorated by exercise and dietary intervention through inducing lipophagy. Our findings suggested a new mechanism of exercise and dietary intervention to improve NAFLD through promoting lipophagy. The study also provided evidence to support that muscle exercise is beneficial to other metabolic organs such as liver. The FGF21-mediated AMPK dependent lipophagy might be a potential drug target for NAFLD and aging caused by lipid metabolic dysfunction.
Topics: Aging; Autophagy; Diet, High-Fat; Humans; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease
PubMed: 32863214
DOI: 10.1016/j.redox.2020.101635 -
Annual Review of Nutrition 2015Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy.... (Review)
Review
Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy. Starvation and an acute lipid stimulus increase autophagic sequestration of lipid droplets and their degradation in lysosomes. Accordingly, liver-specific deletion of the autophagy gene Atg7 increases hepatic fat content, mimicking the human condition termed nonalcoholic fatty liver disease. In this review, we provide insights into the molecular regulation of lipophagy, discuss fundamental questions related to the mechanisms by which autophagosomes recognize lipid droplets and how ATG proteins regulate membrane curvature for lipid droplet sequestration, and comment on the possibility of cross talk between lipophagy and cytosolic lipases in lipid mobilization. Finally, we discuss the contribution of lipophagy to the pathophysiology of human fatty liver disease. Understanding how lipophagy clears hepatocellular lipid droplets could provide new ways to prevent fatty liver disease, a major epidemic in developed nations.
Topics: Animals; Autophagy; Autophagy-Related Protein 7; Gene Deletion; Hepatocytes; Homeostasis; Humans; Lipase; Lipid Droplets; Lipid Metabolism; Liver; Liver Diseases; Non-alcoholic Fatty Liver Disease; Signal Transduction; Ubiquitin-Activating Enzymes
PubMed: 26076903
DOI: 10.1146/annurev-nutr-071813-105336 -
Molecules and Cells Aug 2020Autophagy is an intracellular degradation system that breaks down damaged organelles or damaged proteins using intracellular lysosomes. Recent studies have also revealed... (Review)
Review
Autophagy is an intracellular degradation system that breaks down damaged organelles or damaged proteins using intracellular lysosomes. Recent studies have also revealed that various forms of selective autophagy play specific physiological roles under different cellular conditions. Lipid droplets, which are mainly found in adipocytes and hepatocytes, are dynamic organelles that store triglycerides and are critical to health. Lipophagy is a type of selective autophagy that targets lipid droplets and is an essential mechanism for maintaining homeostasis of lipid droplets. However, while processes that regulate lipid droplets such as lipolysis and lipogenesis are relatively well known, the major factors that control lipophagy remain largely unknown. This review introduces the underlying mechanism by which lipophagy is induced and regulated, and the current findings on the major roles of lipophagy in physiological and pathological status. These studies will provide basic insights into the function of lipophagy and may be useful for the development of new therapies for lipophagy dysfunction-related diseases.
Topics: Autophagy; Humans; Lipid Metabolism; Metabolic Diseases
PubMed: 32624503
DOI: 10.14348/molcells.2020.0046 -
Cells Apr 2022Autophagy and apoptosis represent two fundamental pathophysiological mechanisms of cell fate regulation. However, the signaling pathways of these processes are...
Autophagy and apoptosis represent two fundamental pathophysiological mechanisms of cell fate regulation. However, the signaling pathways of these processes are significantly interconnected through various mechanisms of crosstalk. Indeed, autophagy/apoptosis crosstalk is still an emerging field, in which an increasing number of molecules are involved, including, for example, PINK1 and ERLINs. On the other hand, this crosstalk involves signal transduction pathways which are strongly dependent on Ca. Interestingly, crosstalk between autophagy and apoptosis impacts several pathologies, including multiple rheumatic diseases. The purpose of this Special Issue is also to investigate the bioactive properties of drugs with antitumor activity, focusing particularly on the role of anthraquinone derivatives in the regulation of cell death and autophagy crosstalk. This Special Issue of brings together the most recent advances in understanding the various aspects of crosstalk between autophagy and apoptosis and the interconnected signaling pathways, implying therapeutic perspectives for the utility of its modulation in an anti-cancer setting.
Topics: Apoptosis; Autophagy; Humans; Neoplasms; Signal Transduction
PubMed: 35563785
DOI: 10.3390/cells11091479 -
Cell Death and Differentiation Mar 2015Autophagy is a catabolic process aimed at recycling cellular components and damaged organelles in response to diverse conditions of stress, such as nutrient deprivation,... (Review)
Review
Autophagy is a catabolic process aimed at recycling cellular components and damaged organelles in response to diverse conditions of stress, such as nutrient deprivation, viral infection and genotoxic stress. A growing amount of evidence in recent years argues for oxidative stress acting as the converging point of these stimuli, with reactive oxygen species (ROS) and reactive nitrogen species (RNS) being among the main intracellular signal transducers sustaining autophagy. This review aims at providing novel insight into the regulatory pathways of autophagy in response to glucose and amino acid deprivation, as well as their tight interconnection with metabolic networks and redox homeostasis. The role of oxidative and nitrosative stress in autophagy is also discussed in the light of its being harmful for both cellular biomolecules and signal mediator through reversible posttranslational modifications of thiol-containing proteins. The redox-independent relationship between autophagy and antioxidant response, occurring through the p62/Keap1/Nrf2 pathway, is also addressed in order to provide a wide perspective upon the interconnection between autophagy and oxidative stress. Herein, we also attempt to afford an overview of the complex crosstalk between autophagy and DNA damage response (DDR), focusing on the main pathways activated upon ROS and RNS overproduction. Along these lines, the direct and indirect role of autophagy in DDR is dissected in depth.
Topics: Animals; Autophagy; Homeostasis; Humans; Oxidative Stress; Signal Transduction
PubMed: 25257172
DOI: 10.1038/cdd.2014.150 -
Neurobiology of Disease Feb 2019Amyotrophic lateral sclerosis (ALS) is a debilitating and incurable disease involving the loss of motor neurons and subsequent muscle atrophy. Genetic studies have... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a debilitating and incurable disease involving the loss of motor neurons and subsequent muscle atrophy. Genetic studies have implicated deficits in autophagy and/or mitophagy in the onset of the disease. Here we review recent progress in our understanding of the pathways for autophagy and mitophagy in neurons, and how these pathways may be affected by mutations in genes including DCTN1, OPTN, TBK1, VCP, and C9ORF72. We also discuss the implications of modulating autophagy in ALS, highlighting both the potential of the approach and the concerns raised by targeting this pathway as a therapeutic strategy in neurodegenerative disease.
Topics: Amyotrophic Lateral Sclerosis; Animals; Autophagy; Humans; Mitophagy; Neurons
PubMed: 29981842
DOI: 10.1016/j.nbd.2018.07.005 -
Cancer Aug 2018Autophagy is a conserved, self-degradation system that is critical for maintaining cellular homeostasis during stress conditions. Dysregulated autophagy has implications... (Review)
Review
Autophagy is a conserved, self-degradation system that is critical for maintaining cellular homeostasis during stress conditions. Dysregulated autophagy has implications in health and disease. Specifically, in cancer, autophagy plays a dichotomous role by inhibiting tumor initiation but supporting tumor progression. Early results from clinical trials that repurposed hydroxychloroquine for cancer have suggested that autophagy inhibition may be a promising approach for advanced cancers. In this review of the literature, the authors present fundamental advances in the biology of autophagy, approaches to targeting autophagy, the preclinical rationale and clinical experience with hydroxychloroquine in cancer clinical trials, the potential role of autophagy in tumor immunity, and recent developments in next-generation autophagy inhibitors that have clinical potential. Autophagy is a promising target for drug development in cancer. Cancer 2018. © 2018 American Cancer Society.
Topics: Autophagy; Carcinogenesis; Drug Development; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 29671878
DOI: 10.1002/cncr.31335 -
Autophagy Dec 2021Zinc oxide nanoparticles (ZnONPs) hold great promise for biomedical applications. Previous studies have revealed that ZnONPs exposure can induce toxicity in endothelial...
Zinc oxide nanoparticles (ZnONPs) hold great promise for biomedical applications. Previous studies have revealed that ZnONPs exposure can induce toxicity in endothelial cells, but the underlying mechanisms have not been fully elucidated. In this study, we report that ZnONPs can induce ferroptosis of both HUVECs and EA.hy926 cells, as evidenced by the elevation of intracellular iron levels, lipid peroxidation and cell death in a dose- and time-dependent manner. In addition, both the lipid reactive oxygen species (ROS) scavenger ferrostatin-1 and the iron chelator deferiprone attenuated ZnONPs-induced cell death. Intriguingly, we found that ZnONPs-induced ferroptosis is macroautophagy/autophagy-dependent, because the inhibition of autophagy with a pharmacological inhibitor or by gene knockout profoundly mitigated ZnONPs-induced ferroptosis. We further demonstrated that NCOA4 (nuclear receptor coactivator 4)-mediated ferritinophagy (autophagic degradation of the major intracellular iron storage protein ferritin) was required for the ferroptosis induced by ZnONPs, by showing that knockdown can reduce the intracellular iron level and lipid peroxidation, and subsequently alleviate ZnONPs-induced cell death. Furthermore, we showed that ROS originating from mitochondria (mtROS) probably activated the AMPK-ULK1 axis to trigger ferritinophagy. Most importantly, pulmonary ZnONPs exposure caused vascular inflammation and ferritinophagy in mice, and ferrostatin-1 supplementation significantly reversed the vascular injury induced by pulmonary ZnONPs exposure. Overall, our study indicates that ferroptosis is a novel mechanism for ZnONPs-induced endothelial cytotoxicity, and that NCOA4-mediated ferritinophagy is required for ZnONPs-induced ferroptotic cell death. 3-MA: 3-methyladenine; ACTB: Actin beta; AMPK: AMP-activated protein kinase; ATG: Autophagy-related; BafA1: Bafilomycin A1; CQ: Choloroquine; DFP: Deferiprone; FACS: Fluorescence-activated cell sorting; Fer-1: Ferrostatin-1; FTH1: Ferritin heavy chain 1; GPX4: Glutathione peroxidase 4; GSH: Glutathione; IREB2/IRP2: Iron responsive element binding protein 2; LIP: Labile iron pool; MAP1LC3B/LC3B: Microtubule associated protein 1 light chain 3 beta; MTOR: Mechanistic target of rapamycin kinase; NCOA4: Nuclear receptor coactivator 4; NFE2L2/NRF2: Nuclear factor, erythroid 2 like 2; PGSK: Phen Green™ SK; ROS: Reactive oxygen species; siRNA: Small interfering RNA; SQSTM1/p62: Sequestosome 1; TEM: Transmission electron microscopy; ULK1: Unc-51 like autophagy activating kinase 1; ZnONPs: Zinc oxide nanoparticles.
Topics: Animals; Autophagy; Endothelial Cells; Ferroptosis; Mice; Nanoparticles; Zinc Oxide
PubMed: 33843441
DOI: 10.1080/15548627.2021.1911016