Abstract 17382: Jumonji-C Histone Demethylases Are Cellular Iron Sensors That Control mTORC1 and Mitophagy

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Jason S Shapiro ◽  
Hsiang-Chun Chang ◽  
Hossein Ardehali
Keyword(s):  
Mitochondrial Dynamics ◽  
Rna Stability ◽  
Cellular Growth ◽  
Histone Demethylases ◽  
Epigenetic Landscape ◽  
Selective Autophagy ◽  
Cellular Iron ◽  
Essential Nutrient ◽  
Amino Acid Homeostasis ◽  
Mtor Activity

Iron is an essential nutrient and is critical for cellular growth and metabolism. Here, we delineate a novel mechanism by which iron alters amino acid homeostasis and mTOR activity by remodeling the cellular epigenetic landscape. We find that iron deficiency inactivates Jumonji-C domain containing histone-demethylases, resulting in histone hyper-methylation and silencing of the leucine transporter LAT3 and obligatory mTORC1 cofactor RAPTOR. Additionally, we identify that mTOR-mediated regulation of RNA stability through tristetraprolin (TTP) is a novel and requisite step in selective-autophagy. In the absence of TTP, mitochondria damaged by the loss of iron cannot undergo fission, rendering the mitochondria too large for engulfment and subsequent recycling. Accumulation of damaged mitochondria leads to defective oxidative metabolism and impairs hepatic gluconeogenesis in response to fasting. These studies uncover a novel pathway that integrates iron sensing with cellular metabolism, mitochondrial dynamics and autophagy.

Role of PRAS40 in Akt and mTOR signaling in health and disease

2012 ◽  
Vol 302 (12) ◽  
pp. E1453-E1460 ◽  
Author(s):  
Claudia Wiza ◽  
Emmani B. M. Nascimento ◽  
D. Margriet Ouwens
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Cellular Growth ◽  
S6 Kinase ◽  
Binding Partners ◽  
Health And Disease ◽  
Mtor Complex 1 ◽  
Mtor Activity

The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease.

scholarly journals Hyperosmotic Stress Induces Unconventional Autophagy Independent of the Ulk1 Complex

2019 ◽  
Vol 39 (16) ◽  
Author(s):  
Naoki Tamura ◽  
Shun Kageyama ◽  
Masaaki Komatsu ◽  
Satoshi Waguri
Keyword(s):  
Hyperosmotic Stress ◽  
Adaptive Mechanism ◽  
Phosphatidylinositol 3 Kinase ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Selective Autophagy ◽  
Membrane Markers ◽  
T24 Cells ◽  
Mtor Activity ◽  
Phosphatidylinositol 3

ABSTRACT Autophagy is considered an adaptive mechanism against hyperosmotic stress. Although the process has been reported to be triggered by the inhibition of mTORC1, the precise downstream mechanisms remain elusive. Here, we demonstrate that hyperosmotic-stress-induced autophagy is different from conventional macroautophagy in mouse embryonic fibroblasts (MEFs) and human T24 cells. Our results indicated that cytoplasmic puncta for the isolation membrane markers WIPI2 and Atg16L increased after hyperosmotic stress. They were found to partially colocalize with puncta for a selective autophagy substrate, SQSTM1/p62, and were shown to be diminished by inhibitors of phosphatidylinositol 3-kinase (PI3K) or by knockdown of human Vps34 (hVps34), a component of PI3K. In addition, flux assays showed that SQSTM1/p62 and NcoA4 were degraded by the lysosomal pathway. Surprisingly, Ulk1, which is essential for starvation-induced macroautophagy, remained inactivated under hyperosmotic stress, which was partially caused by mTOR activity. Accordingly, the Ulk1 complex was not nucleated under hyperosmotic stress. Finally, autophagy proceeded even in MEFs deficient in RB1CC1/FIP200 or Atg13, which encode components of the Ulk1 complex. These data suggest that hyperosmotic-stress-induced autophagy represents an unconventional type of autophagy that bypasses Ulk1 signaling.

scholarly journals Nifedipine Potentiates Susceptibility of Salmonella Typhimurium to Different Classes of Antibiotics

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1200
Author(s):  
David Haschka ◽  
Manuel Grander ◽  
Johannes Eibensteiner ◽  
Stefanie Dichtl ◽  
Sabine Koppelstätter ◽  
...  
Keyword(s):  
Salmonella Typhimurium ◽  
Bacterial Resistance ◽  
Additive Effect ◽  
Lipocalin 2 ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Cellular Iron ◽  
Essential Nutrient ◽  
Conventional Antibiotics ◽  
Significant Additive Effect

The calcium channel blocker nifedipine induces cellular iron export, thereby limiting the availability of the essential nutrient iron for intracellular pathogens, resulting in bacteriostatic activity. To study if nifedipine may exert a synergistic anti-microbial activity when combined with antibiotics, we used the mouse macrophage cell line RAW267.4, infected with the intracellular bacterium Salmonella Typhimurium, and exposed the cells to varying concentrations of nifedipine and/or ampicillin, azithromycin and ceftriaxone. We observed a significant additive effect of nifedipine in combination with various antibiotics, which was not observed when using Salmonella, with defects in iron uptake. Of interest, increasing intracellular iron levels increased the bacterial resistance to treatment with antibiotics or nifedipine or their combination. We further showed that nifedipine increases the expression of the siderophore-binding peptide lipocalin-2 and promotes iron storage within ferritin, where the metal is less accessible for bacteria. Our data provide evidence for an additive effect of nifedipine with conventional antibiotics against Salmonella, which is partly linked to reduced bacterial access to iron.

scholarly journals TRMT2B is responsible for both tRNA and rRNA m5U-methylation in human mitochondria

2019 ◽  
Author(s):  
Christopher A. Powell ◽  
Michal Minczuk
Keyword(s):  
Rna Stability ◽  
Human Cells ◽  
Cellular Growth ◽  
12S Rrna ◽  
Mitochondrial Translation ◽  
Ribosomal Rnas

AbstractRNA species play host to a plethora of post-transcriptional modifications which together make up the epitranscriptome. 5-methyluridine (m5U) is one of the most common modifications made to cellular RNA, where it is found almost ubiquitously in bacterial and eukaryotic cytosolic tRNAs at position 54. Here, we demonstrate that m5U54 in human mitochondrial tRNAs is catalysed by the nuclear-encoded enzyme TRMT2B, and that its repertoire of substrates is expanded to ribosomal RNAs, catalysing m5U429 in 12S rRNA. We show that TRMT2B is not essential for viability in human cells and that knocking-out the gene shows no obvious phenotype with regards to RNA stability, mitochondrial translation, or cellular growth.

scholarly journals TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Ser877

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ricardo J. Antonia ◽  
Johnny Castillo ◽  
Laura E. Herring ◽  
D. Stephen Serafin ◽  
Pengda Liu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Innate Immune System ◽  
Innate Immune ◽  
Cellular Growth ◽  
Phosphorylation Sites ◽  
Cell Type ◽  
Mechanistic Target Of Rapamycin ◽  
Mtor Complex 1 ◽  
Mtor Activity

Abstract While best known for its role in the innate immune system, the TANK-binding kinase 1 (TBK1) is now known to play a role in modulating cellular growth and autophagy. One of the major ways that TBK1 accomplishes this task is by modulating the mechanistic Target of Rapamycin (mTOR), a master regulator that when activated promotes cell growth and inhibits autophagy. However, whether TBK1 promotes or inhibits mTOR activity is highly cell type and context dependent. To further understand the mechanism whereby TBK1 regulates mTOR, we tested the hypothesis that TBK1 phosphorylates a key component of the mTOR complex 1 (mTORC1), Raptor. Using kinase assays coupled with mass spectrometry, we mapped the position of the TBK1 dependent phosphorylation sites on Raptor in vitro. Among the sites identified in vitro, we found that TBK1 promotes Raptor Ser877 phosphorylation in cells both basally and in response to pathogen-associated molecules known to induce TBK1 activity. The levels of Raptor Ser877 phosphorylation were inversely correlated with the levels of mTOR activity. Expression of a mutant Raptor that could not be phosphorylated at Ser877 led to an increase in mTORC1 activity. We conclude that TBK1 limits mTORC1 activity by promoting Raptor Ser877 phosphorylation.

scholarly journals Modulation of Energy Metabolism and Epigenetic Landscape in Rainbow Trout Fry by a Parental Low Protein/High Carbohydrate Diet

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 585
Author(s):  
Thérèse Callet ◽  
Hongyan Li ◽  
Pascale Coste ◽  
Stéphane Glise ◽  
Cécile Heraud ◽  
...  
Keyword(s):  
Rainbow Trout ◽  
Energy Metabolism ◽  
Mitochondrial Dynamics ◽  
Control Diet ◽  
Epigenetic Landscape ◽  
Carbohydrate Diet ◽  
High Carbohydrate ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
First Feeding ◽  
Low Protein

It is now recognized that parental diets could highly affect offspring metabolism and growth. Studies in fish are, however, lacking. In particular, the effect of a parental diet high in carbohydrate (HC) and low in protein (LP) on progeny has never been examined in higher trophic level teleost fish. Thus, two-year old male and female rainbow trout (Oncorhynchus mykiss) were fed either a control diet (0% carbohydrate and 63.89% protein) or a diet containing 35% carbohydrate and 42.96% protein (HC/LP) for a complete reproductive cycle for females and over a 5-month period for males. Cross-fertilizations were then carried out. To evaluate the effect of the parental diet on their offspring, different phenotypic and metabolic traits were recorded for offspring before their first feeding and again three weeks later. When considering the paternal and maternal HC/LP nutrition independently, fry phenotypes and transcriptomes were only slightly affected. The combination of the maternal and paternal HC/LP diets altered the energy metabolism and mitochondrial dynamics of their progeny, demonstrating the existence of a synergistic effect. The global DNA methylation of whole fry was also highly affected by the HC/LP parental diet, indicating that it could be one of the fundamental mechanisms responsible for the effects of nutritional programming.

scholarly journals Mitochondrial Dynamics and VMP1-Related Selective Mitophagy in Experimental Acute Pancreatitis

2021 ◽  
Vol 9 ◽  
Author(s):  
Virginia Vanasco ◽  
Alejandro Ropolo ◽  
Daniel Grasso ◽  
Diego S. Ojeda ◽  
María Noé García ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Pancreatic Acinar Cells ◽  
Atp Production ◽  
Selective Autophagy ◽  
Mild Disease

Mitophagy and zymophagy are selective autophagy pathways early induced in acute pancreatitis that may explain the mild, auto limited, and more frequent clinical presentation of this disease. Adequate mitochondrial bioenergetics is necessary for cellular restoration mechanisms that are triggered during the mild disease. However, mitochondria and zymogen contents are direct targets of damage in acute pancreatitis. Cellular survival depends on the recovering possibility of mitochondrial function and efficient clearance of damaged mitochondria. This work aimed to analyze mitochondrial dynamics and function during selective autophagy in pancreatic acinar cells during mild experimental pancreatitis in rats. Also, using a cell model under the hyperstimulation of the G-coupled receptor for CCK (CCK-R), we aimed to investigate the mechanisms involved in these processes in the context of zymophagy. We found that during acute pancreatitis, mitochondrial O2consumption and ATP production significantly decreased early after induction of acute pancreatitis, with a consequent decrease in the ATP/O ratio. Mitochondrial dysfunction was accompanied by changes in mitochondrial dynamics evidenced by optic atrophy 1 (OPA-1) and dynamin-related protein 1 (DRP-1) differential expression and ultrastructural features of mitochondrial fission, mitochondrial elongation, and mitophagy during the acute phase of experimental mild pancreatitis in rats. Mitophagy was also evaluated by confocal assay after transfection with the pMITO-RFP-GFP plasmid that specifically labels autophagic degradation of mitochondria and the expression and redistribution of the ubiquitin ligase Parkin1. Moreover, we report for the first time that vacuole membrane protein-1 (VMP1) is involved and required in the mitophagy process during acute pancreatitis, observable not only by repositioning around specific mitochondrial populations, but also by detection of mitochondria in autophagosomes specifically isolated with anti-VMP1 antibodies as well. Also, VMP1 downregulation avoided mitochondrial degradation confirming that VMP1 expression is required for mitophagy during acute pancreatitis. In conclusion, we identified a novel DRP1-Parkin1-VMP1 selective autophagy pathway, which mediates the selective degradation of damaged mitochondria by mitophagy in acute pancreatitis. The understanding of the molecular mechanisms involved to restore mitochondrial function, such as mitochondrial dynamics and mitophagy, could be relevant in the development of novel therapeutic strategies in acute pancreatitis.

scholarly journals Modulating Wine Aromatic Amino Acid Catabolites by Using Torulaspora delbrueckii in Sequentially Inoculated Fermentations or Saccharomyces cerevisiae Alone

2020 ◽  
Vol 8 (9) ◽  
pp. 1349
Author(s):  
M. Antonia Álvarez-Fernández ◽  
Ilaria Carafa ◽  
Urska Vrhovsek ◽  
Panagiotis Arapitsas
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Aromatic Amino Acids ◽  
Grape Juice ◽  
Cellular Growth ◽  
Wine Quality ◽  
Torulaspora Delbrueckii ◽  
Sequential Inoculation ◽  
Essential Nutrient ◽  
Key Microorganisms ◽  
Indole Carboxylic Acid

Yeasts are the key microorganisms that transform grape juice into wine, and nitrogen is an essential nutrient able to affect yeast cell growth, fermentation kinetics and wine quality. In this work, we focused on the intra- and extracellular metabolomic changes of three aromatic amino acids (tryptophan, tyrosine, and phenylalanine) during alcoholic fermentation of two grape musts by two Saccharomyces cerevisiae strains and the sequential inoculation of Torulaspora delbrueckii with Saccharomyces cerevisiae. An UPLC-MS/MS method was used to monitor 33 metabolites, and 26 of them were detected in the extracellular samples and 8 were detected in the intracellular ones. The results indicate that the most intensive metabolomic changes occurred during the logarithm cellular growth phase and that pure S. cerevisiae fermentations produced higher amounts of N-acetyl derivatives of tryptophan and tyrosine and the off-odour molecule 2-aminoacetophenone. The sequentially inoculated fermentations showed a slower evolution and a higher production of metabolites linked to the well-known plant hormone indole acetic acid (auxin). Finally, the production of sulfonated tryptophol during must fermentation was confirmed, which also may explain the bitter taste of wines produced by Torulaspora delbrueckii co-fermentations, while sulfonated indole carboxylic acid was detected for the first time in such an experimental design.

The emerging roles for histone demethylases in the modulation of signaling pathways

2013 ◽  
Vol 4 (1) ◽  
pp. 13-27 ◽  
Author(s):  
Luisa Di Stefano ◽  
Nicholas J. Dyson
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathways ◽  
Biological Processes ◽  
Epigenetic Alterations ◽  
Histone Demethylases ◽  
Epigenetic Landscape ◽  
Environmental Signals ◽  
Cellular Processes ◽  
A Cell ◽  
Uncontrolled Cell Proliferation

AbstractSince their discovery in 2004, histone demethylases have emerged as key regulators of chromatin. Recent studies have started to reveal the interconnections between histone demethylases and signaling pathways, suggesting that this interplay drives fundamental biological processes. Here, we summarize the different families and subfamilies of histone demethylases and the insights into the biological roles of these enzymes that have been provided by the analysis of mutant animals. We then review recent work linking demethylases and signaling pathways. These studies suggest that demethylase activities are a component of the critical connections that enable environmental signals to modulate the epigenetic landscape of a cell. A greater mechanistic understanding of the network of signals that control chromatin states during normal cellular processes, together with a better understanding of the ways that epigenetic alterations lead to uncontrolled cell proliferation, might help in the design of effective tools for cancer therapy.

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