scholarly journals RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes

2021 ◽  
Author(s):  
Hyeon‐Ji Kim ◽  
Yong‐Hyun Han ◽  
Ju‐Yeon Kim ◽  
Mi‐Ock Lee
Keyword(s):  
Autophagic Flux ◽  
Lysosomal Acidification

scholarly journals Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity

2019 ◽  
Vol 133 (13) ◽  
pp. 1505-1521 ◽  
Author(s):  
Dong Zheng ◽  
Yi Zhang ◽  
Ming Zheng ◽  
Ting Cao ◽  
Grace Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Defense Mechanism ◽  
Myocardial Dysfunction ◽  
Cardiac Injury ◽  
Autophagic Flux ◽  
Protective Effects ◽  
Nicotinamide Riboside ◽  
And Oxidative Stress ◽  
Cultured Cardiomyocytes ◽  
Lysosomal Acidification

Abstract Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.

scholarly journals Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Qinjie Liu ◽  
Jie Wu ◽  
Xufei Zhang ◽  
Xuanheng Li ◽  
Xiuwen Wu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Organ Damage ◽  
Immune Defense ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Sepsis Induction ◽  
Sting Pathway ◽  
Lysosomal Acidification

AbstractThe STING pathway and its induction of autophagy initiate a potent immune defense response upon the recognition of pathogenic DNA. However, this protective response is minimal, as STING activation worsens organ damage, and abnormal autophagy is observed during progressive sepsis. Whether and how the STING pathway affects autophagic flux during sepsis-induced acute lung injury (sALI) are currently unknown. Here, we demonstrate that the level of circulating mtDNA and degree of STING activation are increased in sALI patients. Furthermore, STING activation was found to play a pivotal role in mtDNA-mediated lung injury by evoking an inflammatory storm and disturbing autophagy. Mechanistically, STING activation interferes with lysosomal acidification in an interferon (IFN)-dependent manner without affecting autophagosome biogenesis or fusion, aggravating sepsis. Induction of autophagy or STING deficiency alleviated lung injury. These findings provide new insights into the role of STING in the regulatory mechanisms behind extrapulmonary sALI.

scholarly journals Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification

2019 ◽  
Vol 21 (3) ◽  
pp. 384-396 ◽  
Author(s):  
Mümine Şentürk ◽  
Guang Lin ◽  
Zhongyuan Zuo ◽  
Dongxue Mao ◽  
Emma Watson ◽  
...  
Keyword(s):  
Autophagic Flux ◽  
Mtor Signalling ◽  
Lysosomal Acidification

scholarly journals Serum- and glucocorticoid- inducible kinase 2, SGK2, is a novel autophagy regulator and modulates platinum drugs response in cancer cells

Oncogene ◽  
2020 ◽  
Vol 39 (40) ◽  
pp. 6370-6386
Author(s):  
Valentina Ranzuglia ◽  
Ilaria Lorenzon ◽  
Ilenia Pellarin ◽  
Maura Sonego ◽  
Alessandra Dall’Acqua ◽  
...  
Keyword(s):  
Cancer Cells ◽  
De Novo ◽  
Acquired Resistance ◽  
Response To Treatment ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Chemical Inhibition ◽  
Tumor Types ◽  
Lysosomal Acidification

Abstract For many tumor types chemotherapy still represents the therapy of choice and many standard treatments are based on the use of platinum (PT) drugs. However, de novo or acquired resistance to platinum is frequent and leads to disease progression. In Epithelial Ovarian Cancer (EOC) patients, PT-resistant recurrences are very common and improving the response to treatment still represents an unmet clinical need. To identify new modulators of PT-sensitivity, we performed a loss-of-function screening targeting 680 genes potentially involved in the response of EOC cells to platinum. We found that SGK2 (Serum-and Glucocorticoid-inducible kinase 2) plays a key role in PT-response. We show here that EOC cells relay on the induction of autophagy to escape PT-induced death and that SGK2 inhibition increases PT sensitivity inducing a block in the autophagy cascade due to the impairment of lysosomal acidification. Mechanistically we demonstrate that SGK2 controls autophagy in a kinase-dependent manner by binding and inhibiting the V-ATPase proton pump. Accordingly, SGK2 phosphorylates the subunit V1H (ATP6V1H) of V-ATPase and silencing or chemical inhibition of SGK2, affects the normal autophagic flux and sensitizes EOC cells to platinum. Hence, we identified a new pathway that links autophagy to the survival of cancer cells under platinum treatment in which the druggable kinase SGK2 plays a central role. Our data suggest that blocking autophagy via SGK2 inhibition could represent a novel therapeutic strategy to improve patients’ response to platinum.

scholarly journals Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity

2016 ◽  
Vol 214 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Kyle M. Trudeau ◽  
Aaron H. Colby ◽  
Jialiu Zeng ◽  
Guy Las ◽  
Jiazuo H. Feng ◽  
...  
Keyword(s):  
Cell Function ◽  
Autophagic Flux ◽  
Causative Role ◽  
Cellular Functions ◽  
Β Cells ◽  
Β Cell Function ◽  
Mouse Islets ◽  
Glucose Stimulated Insulin Secretion ◽  
And Function ◽  
Lysosomal Acidification

In pancreatic β-cells, liver hepatocytes, and cardiomyocytes, chronic exposure to high levels of fatty acids (lipotoxicity) inhibits autophagic flux and concomitantly decreases lysosomal acidity. Whether impaired lysosomal acidification is causally inhibiting autophagic flux and cellular functions could not, up to the present, be determined because of the lack of an approach to modify lysosomal acidity. To address this question, lysosome-localizing nanoparticles are described that, upon UV photoactivation, enable controlled acidification of impaired lysosomes. The photoactivatable, acidifying nanoparticles (paNPs) demonstrate lysosomal uptake in INS1 and mouse β-cells. Photoactivation of paNPs in fatty acid–treated INS1 cells enhances lysosomal acidity and function while decreasing p62 and LC3-II levels, indicating rescue of autophagic flux upon acute lysosomal acidification. Furthermore, paNPs improve glucose-stimulated insulin secretion that is reduced under lipotoxicity in INS1 cells and mouse islets. These results establish a causative role for impaired lysosomal acidification in the deregulation of autophagy and β-cell function under lipotoxicity.

First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome Accumulation

2020 ◽  
Author(s):  
Daniel Herp ◽  
Johannes Ridinger ◽  
Dina Robaa ◽  
Stephen A. Shinsky ◽  
Karin Schmidtkunz ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
High Throughput Screening ◽  
Neuroblastoma Cell ◽  
Hdac Inhibitors ◽  
Anticancer Therapy ◽  
Colony Growth ◽  
Autophagic Flux ◽  
Enzymatic Conversion ◽  
Lysine Deacetylase

Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, esp. cancer. First HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement e.g. in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of the other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like spermine or spermidine. Hence, it also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin labelled acetyl spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10 mediated spermidine deacetylation in-vitro. Among those are potent inhibitors of neuroblastoma colony growth in culture that show accumulation of lysosomes, implicating disturbance of autophagic flux.

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