scholarly journals Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis

2019 ◽  
Vol 216 (4) ◽  
pp. 950-965 ◽  
Author(s):  
Yoshiharu Muto ◽  
Toshiro Moroishi ◽  
Kazuya Ichihara ◽  
Masaaki Nishiyama ◽  
Hideyuki Shimizu ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Genetically Engineered ◽  
Liver Carcinogenesis ◽  
Cellular Iron ◽  
Hepatic Iron Overload ◽  
Genetically Engineered Mouse Model ◽  
Compensatory Proliferation ◽  
Cellular Iron Homeostasis

Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload elicited by FBXL5 ablation gave rise to oxidative stress, tissue damage, inflammation, and compensatory proliferation of hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting outcome of FBXL5 deficiency in the liver was also found to be effective in a model of virus-induced HCC. FBXL5-deficient mice thus constitute the first genetically engineered mouse model of liver carcinogenesis promoted by iron overload. In addition, dysregulation of FBXL5-mediated cellular iron homeostasis was found to be associated with poor prognosis in human HCC, suggesting that FBXL5 plays a key role in defense against hepatocarcinogenesis.

scholarly journals Iron Overload Is Associated With Accelerated Progression of Osteoarthritis: The Role of DMT1 Mediated Iron Homeostasis

2021 ◽  
Vol 8 ◽  
Author(s):  
Xingzhi Jing ◽  
Jiamin Lin ◽  
Ting Du ◽  
Zhensong Jiang ◽  
Tao Li ◽  
...  
Keyword(s):  
Iron Overload ◽  
Inflammatory Cytokines ◽  
Iron Homeostasis ◽  
Cartilage Destruction ◽  
Mice Model ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis ◽  
Pro Inflammatory Cytokines

Objective: Iron overload is common in elderly people which is associated with an increased prevalence of osteoarthritis (OA), but the exact role of iron in the development of OA has not been established. The aim of the present study is to elucidate the connection between iron overload and OA using an iron overloaded mice model, as well as to explore the role of iron homeostasis, iron transporters dependent iron influx in OA pathogenesis.Methods: The iron overloaded mice model was established and OA was surgically induced. OA progression was assessed at 8 weeks after surgery. Next, primary chondrocytes were treated with pro-inflammatory cytokines and iron regulators mediated iron homeostasis were evaluated. Involvement of iron transporters was analyzed using chondrocytes mimicking an osteoarthritis-related phenotype in vitro.Results: Iron overloaded mice exhibited greater cartilage destruction and elevated ADAMTS5 as well as MMP13 expression along with increased iron accumulation and dysregulated iron regulators. Pro-inflammatory cytokines could disturb cellular iron homeostasis via upregulating iron import proteins, TFR1 and DMT1, downregulating iron efflux protein FPN, thus result in cellular iron overload. Among iron transporters, DMT1 was found to play pivotal roles in iron overload induced OA progress. Inhibition of DMT1 suppressed IL-1β induced inflammatory response and ECM degradation via blockade of MAPK and PI3K/AKT/NF-κB pathways.Conclusions: Our results suggest that iron takes parts in the development of OA and cutting iron influx via inhibiting DMT1 activity could be an attractive new target for OA treatment.

Cellular Iron Homeostasis and Therapeutic Implications of Iron Chelators in Cancer

2014 ◽  
Vol 15 (12) ◽  
pp. 1125-1140 ◽  
Author(s):  
Mohsin Raza ◽  
Sankalpa Chakraborty ◽  
Monjoy Choudhury ◽  
Prahlad Ghosh ◽  
Alo Nag
Keyword(s):  
Iron Homeostasis ◽  
Iron Chelators ◽  
Therapeutic Implications ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

scholarly journals IRONOMYCIN KILLS DIFFUSE LARGE B‐CELL LYMPHOMA CELLS BY TARGETING CELLULAR IRON HOMEOSTASIS

2021 ◽  
Vol 39 (S2) ◽  
Author(s):  
J. Devin ◽  
T. Cañeque ◽  
Y.‐L. Lin ◽  
L. Mondoulet ◽  
J.‐L. Veyrune ◽  
...  
Keyword(s):  
B Cell ◽  
Iron Homeostasis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cells ◽  
Cellular Iron ◽  
Large B Cell Lymphoma ◽  
Cellular Iron Homeostasis ◽  
Large B Cell

Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2161-2167 ◽  
Author(s):  
Guangjun Nie ◽  
Alex D. Sheftel ◽  
Sangwon F. Kim ◽  
Prem Ponka
Keyword(s):  
Iron Homeostasis ◽  
Rna Binding ◽  
Binding Activity ◽  
Intracellular Iron ◽  
Free Radical Damage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Cellular Iron Uptake ◽  
A Cell ◽  
Cellular Iron Homeostasis

AbstractCytosolic ferritin sequesters and stores iron and, consequently, protects cells against iron-mediated free radical damage. However, the function of the newly discovered mitochondrial ferritin (MtFt) is unknown. To examine the role of MtFt in cellular iron metabolism, we established a cell line that stably overexpresses mouse MtFt under the control of a tetracycline-responsive promoter. The overexpression of MtFt caused a dose-dependent iron deficiency in the cytosol that was revealed by increased RNA-binding activity of iron regulatory proteins (IRPs) along with an increase in transferrin receptor levels and decrease in cytosolic ferritin. Consequently, the induction of MtFt resulted in a dramatic increase in cellular iron uptake from transferrin, most of which was incorporated into MtFt. The induction of MtFt caused a shift of iron from cytosolic ferritin to MtFt. In addition, iron inserted into MtFt was less available for chelation than that in cytosolic ferritin and the expression of MtFt was associated with decreased mitochondrial and cytosolic aconitase activities, the latter being consistent with the increase in IRP-binding activity. In conclusion, our results indicate that overexpression of MtFt causes a dramatic change in intracellular iron homeostasis and that shunting iron to MtFt likely limits its availability for active iron proteins.

scholarly journals Nitric oxide and frataxin: two players contributing to maintain cellular iron homeostasis

2009 ◽  
Vol 105 (5) ◽  
pp. 801-810 ◽  
Author(s):  
Leonor Ramirez ◽  
Eduardo Julián Zabaleta ◽  
Lorenzo Lamattina
Keyword(s):  
Nitric Oxide ◽  
Iron Homeostasis ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

scholarly journals Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: Implications for cellular iron homeostasis

1999 ◽  
Vol 96 (10) ◽  
pp. 5434-5439 ◽  
Author(s):  
L. Salter-Cid ◽  
A. Brunmark ◽  
Y. Li ◽  
D. Leturcq ◽  
P. A. Peterson ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

scholarly journals Loss of Cardiolipin Leads to Perturbation of Mitochondrial and Cellular Iron Homeostasis

2012 ◽  
Vol 288 (3) ◽  
pp. 1696-1705 ◽  
Author(s):  
Vinay A. Patil ◽  
Jennifer L. Fox ◽  
Vishal M. Gohil ◽  
Dennis R. Winge ◽  
Miriam L. Greenberg
Keyword(s):  
Iron Homeostasis ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis
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