Activation of Autophagy, Observed in Liver Tissues From Patients With Wilson Disease and From ATP7B-Deficient Animals, Protects Hepatocytes From Copper-Induced Apoptosis

Polishchuk, Elena; Merolla, Assunta; Lichtmannegger, Josef; Romano, Alessia; Indrieri, Alessia; Ilyechova, Ekaterina Y.; Concilli, Mafalda; Cegli, Rossella De; Crispino, Roberta; Mariniello, Marta; Petruzzelli, Raffaella; Ranucci, Giusy; Iorio, Raffaele; Pietrocola, Federico; Einer, Claudia; Borchard, Sabine; Zibert, Andree; Schmidt, Hartmut; Schiavi, Elia Di; Puchkova, L. V.; Bazzoli, Franco; Kroemer, Guido; Zischka, Hans; Polishchuk, Roman

doi:10.1053/j.gastro.2018.11.032

Cited by 168 publications

(158 citation statements)

References 51 publications

Supporting

Mentioning

154

Contrasting

Order By: Relevance

“…Recent data highlight the protective role of autophagy against copper toxicity during Wilson's disease. 80 Interestingly, autophagy is increased both in the liver of patients with Wilson's disease, in mice bearing a deletion in Atp7b and in hepatoma cells silenced for ATP7B and exposed to CuCl 2 . In vitro or in vivo inhibition of autophagy with spautin-1 accelerates hepatocyte death, mitochondrial damage and oxidative stress, whereas activation of autophagy by starvation or TFEB overexpression promotes hepatocyte survival.…”

Section: Autophagy and Inherited Liver Diseasesmentioning

confidence: 99%

“…In vitro or in vivo inhibition of autophagy with spautin-1 accelerates hepatocyte death, mitochondrial damage and oxidative stress, whereas activation of autophagy by starvation or TFEB overexpression promotes hepatocyte survival. 80 The potential for activators of autophagy to counteract copper toxicity in the context of Wilson's disease needs to be further explored and extended to other metalrelated liver disorders, such as haemochromatosis.…”

Section: Autophagy and Inherited Liver Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

Autophagy in liver diseases: Time for translation?

Allaire

Rautou

Codogno

et al. 2019

Journal of Hepatology

278

222

View full text Add to dashboard Cite

Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role in energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy. Indeed, enhancing autophagy may prevent the progression of a number of liver diseases, including storage disorders (alpha-1 antitrypsin deficiency, Wilson's disease), acute liver injury, non-alcoholic steatohepatitis and chronic alcohol-related liver disease. Nevertheless, in some situations such as fibrosis, targeting specific liver cells must be considered, as autophagy displays opposing functions depending on the cell type. In addition, an optimal therapeutic time-window should be identified, since autophagy might be beneficial in the initial stages of disease, but detrimental at more advanced stages, as in the case of hepatocellular carcinoma. Finally, identifying biomarkers of autophagy and methods to monitor autophagic flux in vivo are important steps for the future development of personalized autophagy-targeting strategies. In this review, we provide an update on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagy and discussing the potential to modulate autophagy as a therapeutic strategy in the context of liver diseases.

show abstract

Section: Autophagy and Inherited Liver Diseasesmentioning

confidence: 99%

Section: Autophagy and Inherited Liver Diseasesmentioning

confidence: 99%

Autophagy in liver diseases: Time for translation?

Allaire

Rautou

Codogno

et al. 2019

Journal of Hepatology

278

222

View full text Add to dashboard Cite

show abstract

“…These hydrolases are responsible for degradation and recycling of macromolecules or even whole organelles thereby regulating endocytosis and autophagy [2]. Lysosome function or malfunction was found to play an important role in different diseases including cancer [3]. Interestingly, tumor cells often have an increased lysosomal activity and autophagy level as compared to non-malignant cells strengthening the hypothesis of the importance of lysosomes in resisting energetic stress conditions [4].…”

Section: Introductionmentioning

confidence: 99%

Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death

et al. 2019

Self Cite

View full text Add to dashboard Cite

Background The understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood. Methods LC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements. Results Our data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1α and PPARα expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells. Conclusion This study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors. Graphical Abstract Electronic supplementary material The online version of this article (10.1186/s12964-019-0399-2) contains supplementary material, which is available to authorized users.

show abstract

“…Autophagy inhibition is emerging as an effective approach for tumor therapy, particularly in cancers with increased levels of basal autophagy [153]. Different lines of evidence suggest that increased copper content activates a series of autophagy-related genes [154]. Accordingly, copper chelation using TM has been shown to inhibit the Unc-51-like autophagy activating kinase 1 and 2 (Ulk1/2) in lung adenocarcinoma cells [155].…”

Section: Copper Depletion and Autophagy Inhibitionmentioning

confidence: 99%

Current Biomedical Use of Copper Chelation Therapy

Baldari

Rocco

Toietta

2020

IJMS

104

105

View full text Add to dashboard Cite

Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.

show abstract

Activation of Autophagy, Observed in Liver Tissues From Patients With Wilson Disease and From ATP7B-Deficient Animals, Protects Hepatocytes From Copper-Induced Apoptosis

Cited by 168 publications

References 51 publications

Autophagy in liver diseases: Time for translation?

Autophagy in liver diseases: Time for translation?

Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death

Current Biomedical Use of Copper Chelation Therapy

Contact Info

Product

Resources

About