Iron-independent phosphorylation of iron regulatory protein 2 regulates ferritin during the cell cycle.

Iron regulatory protein 2 (IRP2) is a key iron sensor that post-transcriptionally regulates mammalian iron homeostasis by binding to iron-responsive elements (IREs) in mRNAs that encode proteins involved in iron metabolism (e.g. ferritin and transferrin receptor 1). During iron deficiency, IRP2 binds IREs to regulate mRNA translation or stability whereas during iron sufficiency IRP2 is degraded by the proteasome. Here, we identify an iron-independent IRP2 phosphorylation site that is regulated by the cell cycle. IRP2 S157 is phosphorylated by Cdk1/cyclin B1 during G2/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. S157 phosphorylation during G2/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, while S157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis. These data show that reversible phosphorylation of IRP2 during G2/M has a role in modulating the iron-independent expression of ferritin and other IRE-containing mRNAs during the cell cycle.


The Usefulness of the Serum Transferrin Receptor to Serum Ferritin Ratio for Discriminating between Iron Deficiency Anemia and Anemia of Inflammation

The incidence of iron deficiency anaemia in infants, which is caused by the increased iron demand for rapid growth during this period, is reported to range from 10 to 40%. This age group also suffers from a number of acute illnesses (urinary tract infection, pneumonia and other viral illness). The aim of this study was to evaluate the usefulness of soluble transferrin receptor (sTfR) values and the different methods of calculating the sTfR and serum ferritin (SF) ratio for differentiating anemia of inflammation (AI) from iron deficiency anemia (IDA) or a mixture of these two types of anemia.

173 infants among all the infants who visited Gyeongsang National University Hospital from 2000 to 2006 were enrolled in this study. The hemoglobin (Hb), SF and sTfR values were checked and the infants were divided into the Al subgroup (Hb <11g/dL and SF > 50microgram/L), the IDA subgroup (Hb <11g/dL and SF < 12microgram/L), the normal group (Hb > or =11g/dL and SF > or =12microgram/L), and the unclassified anemia (UCA) group (Hb <11g/dL and SF 12~50microgram/L).

The mean sTfR and sTfR/Log SF values in the AI group were 3.89 and 10.6microgram/mL, respectively (P<0.01). These values in the IDA group were 1.9 and 36.11, respectively (P<0.01). The mean Log (sTfR/SF) was statistically significant between all the subgroups (1.35 in AI, 3.29 in IDA, 1.76 in Nor and 2.35 in UCA). All the infants in the IDA group had a Log (sTfR/SF) value >2.55 whereas all the infants classified in AI group had a Log (sTfR/SF) value <2.55.

The Log (sTfR/SF) value is a useful criterion for discriminating between AI and IDA.


High Prevalence of Iron Overload in Adult Allogeneic Hematopoietic Cell Transplant Survivors

Allogeneic hematopoietic cell transplant (HCT) recipients frequently need red blood cell transfusions, and can be at risk for developing iron overload. We studied the prevalence of iron overload in 56 adult allogeneic HCT patients who had survived for a median of 28 (range: 12-151) months from transplant. Patients were initially screened with serum ferritin, and those with serum ferritin >1000 ng/mL underwent R2 magnetic resonance imaging (MRI) of the liver, a sensitive and specific noninvasive imaging technique to measure liver iron concentration (LIC). Iron overload was defined as LIC above normal (>1.8 mg/g dry weight). Nineteen patients had serum ferritin >1000 ng/mL with a median LIC of 7.0 (range: 1.8-28.3) mg/g. The overall prevalence of iron overload was 32% (95% confidence intervals, 20%-46%). The LIC on MRI was moderately correlated with serum ferritin (ρ = .47). Iron overload is a frequent complication of allogeneic transplantation. serum ferritin is a good screening test but does not reliably predict tissue iron overload, and estimation of LIC should be considered before initiating therapy. More studies are needed to determine the impact of iron overload on long-term morbidity and mortality in allogeneic transplant survivors.


Relation Between Iron-Overload Indices, Cardiac Echo-Doppler, and Biochemical Markers in Thalassemia Intermedia

Cardiovascular impairment is a major cause of morbidity and mortality in patients with thalassemia intermedia. In this study, echocardiographic assessment of left heart condition was performed in patients with thalassemia intermedia, and its relation to hematologic variables—amino terminal pro-brain natriuretic peptide (NT-proBNP), ferritin, hemoglobin—and liver iron concentration (LIC) was investigated. Echocardiographic assessment was performed using pulse-wave Doppler and tissue Doppler imaging. Data from 74 patients with thalassemia intermedia—35 men, 39 women, mean age 26.5 years (8 to 63) —were randomly selected and evaluated. Blood samples were collected for NT-proBNP levels in a random subgroup of 19 patients. Mean baseline values were hemoglobin 8.4 g/dl (4.9 to 13.1), serum ferritin 902.6 ng/ml (15 to 4,140), LIC 9.0 mg Fe/g (0.5 to 32.1), and NT-proBNP 113.5 pg/ml (16.4 to 371). Correlation between LIC and pulmonary artery systolic pressure was significant, suggesting that iron loading in the liver is indicative of cardiovascular sequelae. NT-proBNP was significantly correlated with the ratio of the left ventricular early rapid filling wave to early diastolic velocity at the mitral annulus (r = 0.50, p = 0.04) and hemoglobin (r = −0.49, p = 0.03), but not with other characteristics assessed. In conclusion, this study has highlighted the importance of using tissue Doppler imaging rather than pulse-wave Doppler to characterize left ventricular diastolic dysfunction in patients with thalassemia intermedia. Demonstration of the correlation of LIC and pulmonary artery systolic pressure independent of left ventricular filling pressures supports our hypothesis that left ventricular diastolic dysfunction does not contribute to the increased pulmonary artery systolic pressure in patients with thalassemia intermedia.



Serum Bilirubin and Ferritin Levels Link Between Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic

Objective: Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeat in the promoter of human HO-1 gene has been shown to modulate gene transcription. This study aims to assess the association of the length of (GT)n repeats in HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD).

Research design and methods: We screened the allelic frequencies of (GT)n repeats in the HO-1 gene promoter in 986 unrelated individuals that underwent coronary angiography. Serum bilirubin. and markers of iron status were evaluated.

Results: The distribution of numbers of (GT)n repeats was divided into 2 subclasses: class S included shorter (<27) repeats, and class L included longer (27) repeats. Among those with diabetes, subjects with L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70±0.22 vs. 0.81±0.24 mg/dL, P=0.001) and higher serum ferritin values (4.76±0.72 vs. 4.28±1.05 µg/L for log-ferritin, P=0.001). Compared with those carrying S allele, diabetic subjects with L/L genotype had an almost three-fold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, 95% confidence interval [CI] 1.22 to 6.47, P=0.015). Adjusting for both serum bilirubin and ferritin, the effect of HO-1 promoter polymorphism on susceptibility to CAD disappeared.

Conclusions: Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients and such effect might be conveyed through its influence on serum bilirubin and ferritin.

The effect of iron substrate on mitochondrial haem synthesis in copper deficiency.

Studies of iron utilization and haem synthesis were carried out with hepatic mitochondria obtained from copper-deficient and pair-fed control rats. Ferric chloride can be used as Fe substrate for mitochondrial haem synthesis in the presence of succinate. Utilization is further enhanced by the addition of FMN. Ferritin does not support haem synthesis in the presence of succinate alone, but does support haem synthesis when FMN is added. Mitochondrial haem synthesis is impaired in Cu deficiency when either FeCl3 or homologous ferritin is used as Fe substrate. The results of the present study suggest that impaired haem synthesis in Cu deficiency occurs at a step following the chemical reduction of Fe substrate.