Author
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CHENG, NINGHUI - Children'S Nutrition Research Center (CNRC) |
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ZHAO, FAN - Children'S Nutrition Research Center (CNRC) |
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DONELSON, JIMMONIQUE - Children'S Nutrition Research Center (CNRC) |
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YU, HAN - Children'S Nutrition Research Center (CNRC) |
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MO, QIANXING - Baylor College Of Medicine |
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MARINI, JUAN - Children'S Nutrition Research Center (CNRC) |
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NGUYEN, TRUNG - Children'S Nutrition Research Center (CNRC) |
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LI, CHUNBAO - Nanjing Agricultural University |
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HIRSCHI, KENDAL - Children'S Nutrition Research Center (CNRC) |
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CHAN, LAWRENCE - Children'S Nutrition Research Center (CNRC) |
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WANG, JIN - Baylor College Of Medicine |
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Nakata, Paul |
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Submitted to: Meeting Abstract
Publication Type: Abstract Only Publication Acceptance Date: 2/15/2018 Publication Date: 3/3/2018 Citation: Cheng, N., Zhao, F., Donelson, J., Yu, H., Mo, Q., Marini, J.C., Nguyen, T.C., Li, C., Hirschi, K.D., Chan, L., Wang, J., Nakata, P.A. 2018. Role of glutaredoxin 3 in iron homeostsis. 9th Annual Frontiers in Digestive Diseases Symposium, March 3, 2018, Houston, Texas. p. 15. Available at: https://www.bcm.edu/research/centers/digestive-disease. Interpretive Summary: Technical Abstract: Iron is an essential mineral nutrient that is tightly regulated through mechanisms involving iron regulatory genes, intracellular storage, and iron recycling. Dysregulation of these mechanisms often results in either excess tissue iron accumulation (overload) or iron deficiency (anemia). Many biochemical reactions associated with energy production, biosynthesis, replication, locomotion, and gene regulation utilize iron in some form. At the core of hundreds of enzymes, which are mostly involved in primary metabolism in the cell, iron is often found complexed with cysteine or sulphide as in the iron-sulfur (Fe-S) cluster. In vitro and in vivo biochemical analysis has established the role of monothiol glutaredoxins (Grxs) in Fe-S cluster biogenesis in both prokaryotes and eukaryotes. In both classes of organisms monothiol Grx dimers function and serve as carriers delivering intact Fe–S clusters to apoproteins and/or form [2Fe–2S] cluster–ligand complexes that mediate signaling events in the cell. In addition, recent studies have suggested that mammalian Grx3 may play a crucial role in iron homeostasis and hemoglobin maturation, but the underlying mechanism is still largely unknown. To study the function of Grx3 in iron regulation in vivo, a mouse Grx3 conditional allele with two LoxP sites flanking exon2 was created and a liver specific Grx3 deficient (LKO) mouse strain was generated by crossing it with an Albumin-cre mouse strain. RNA-seq analysis was conducted to profile gene expression and western blot analysis was performed to study signaling pathways. Grx3 expression was found to increase in the livers of mice during development. Mice with liver specific deletion of Grx3 were viable and grew indistinguishably from their wild type littermates. Although measurements showed no differences in total body weight between the LKO and WT mice, the LKO mice were found to have livers larger than controls with higher concentrations of iron. Grx3 LKO mice also displayed impaired liver function at the age of 8 months. RNA-seq and q-PCR analysis revealed increased expression of iron homeostasis genes in LKO compared to controls. Disruption of Grx3 in the LKO mice was found to result in altered mitochondrial and nuclear Fe-S cluster assembly. Among the many iron regulatory proteins present in the liver, ferritin H accumulation was increased in the LKO mice compared to controls. Interestingly, the accumulation of hepatic ferritin H was correlated to a down-regulation of the autophagy pathway (Ferritinophagy). Furthermore, our data suggests that Grx3-mediated ferritinophagy may be dependent on cellular iron status. These findings support the hypothesis that Grx3 is an important factor in regulating iron homeostasis in hepatocytes by controlling cellular storage protein turnover through a mechanism related to the autophagy pathway. |
