Iron is a transition metal whose physicochemical properties make it the focus of vital biologic processes in virtually all living organisms. Among numerous roles, iron is essential for oxygen transport, cellular respiration, and DNA synthesis. Paradoxically, the same characteristics that biochemistry exploits make iron a potentially lethal substance. In the presence of oxygen, ferrous iron (Fe 2؉ ) will catalyze the production of toxic hydroxyl radicals from hydrogen peroxide. In addition, Fe 3؉ is virtually insoluble at physiologic pH. To protect tissues from deleterious effects of Fe, mammalian physiology has evolved specialized mechanisms for extracellular, intercellular, and intracellular iron handling. Here we show that developing erythroid cells, which are taking up vast amounts of Fe, deliver the metal directly from transferrin-containing endosomes to mitochondria (the site of heme biosynthesis), bypassing the oxygen-rich cytosol. Besides describing a new means of intracellular transport, our finding is important for developing therapies for patients with iron loading disorders. IntroductionAlthough its requirement for life in almost all known organisms has been recognized for decades, some of the most fundamental cell biologic processes of iron (Fe) still elude modern science. Mammalian physiology demands a constant source of bioavailible Fe, which is a functional component of hemoproteins, iron-sulfur cluster containing proteins, and other iron proteins. However, in its reduced form (Fe 2ϩ ), iron catalyzes the production of toxic hydroxyl radicals through Fenton chemistry, while the ferric version (Fe 3ϩ ) is virtually insoluble at physiologic pH. [1][2][3] Nevertheless, the adult human body contains approximately 4 g of Fe, more than 80% of which is in hemoglobin (Hb). 4 Under normal conditions, around 2 million red blood cells (RBCs) are produced per second. Hence, erythropoiesis requires approximately 25 mg of iron, daily, all of which is delivered via transferrin (Tf). The plasma contains approximately 3 M diferric Tf, the Fe of which is concentrated in maturing erythroid tissue to the equivalent of 20 mM iron, in the form of Hb. This exceptionally rapid utilization of the potentially toxic metal requires stringent regulation mechanisms that permit efficient production of hemoglobin, while protecting developing red blood cells and other tissues from iron's harmful properties. 5 Virtually every tissue acquires its iron by receptor mediated endocytosis of Tf (for review, see Richardson and Ponka 6 and Hentze et al 7 ): Diferric Tf binds to its cognate receptor on the cell surface; this binding is succeeded by internalization of the receptorligand complex. The release of Fe from Tf is achieved within the endosome by a lowering of the vesicular pH through the activity of the v-ATPase proton pump. After its liberation from Tf in the acidified endosome, Fe must be reduced (possibly by the recently identified Steap3 8 ) before it is transported across the vesicular membrane by the divalent metal transp...

Background: Matriptase-2 (MT2) is essential for iron homeostasis. The mechanism for its regulation is controversial. Results: The cytoplasmic domain of MT2 is necessary for its stabilization by iron depletion. MT2 expression is not regulated at either the transcriptional mRNA or translational level by iron. Conclusion: Depletion of cellular iron stabilizes MT2. Significance: Low iron levels in hepatocytes stabilize MT2 to suppress hepcidin expression.

Iron (Fe) is a transition metal whose physicochemical properties make it the focus of vital biological processes in virtually all living organisms. Paradoxically, the same characteristics that biochemistry exploits make Fe a potentially lethal substance. Differentiating erythroid cells acquire vast amounts of Fe at a breakneck rate. After cells acquire Fe via receptor‐mediated endocytosis, it is transferred from the endosome to the mitochondrial matrix where ferrochelatase catalyzes the insertion of the metal into protoporphyrin IX to form heme. Using both biochemical and microscopic strategies, we show that developing erythroid cells deliver the metal directly from endosome to mitochondrion, bypassing the cytosol. Reticulocytes whose cytosol was loaded with a membrane‐impermeant Fe chelator elicited no decrease in Fe incorporation into heme when Fe was delivered to the cells by the physiological chelate, transferrin (Tf). Additionally live‐cell imaging revealed a movement of Tf‐containing structures to mitochondria which was associated with an increase in mitochondrial iron. Using electron microscopy we observed an interorganellar association of a tubular, Tf‐containing network with mitochondria.

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Half maximal (50%) effective concentration (EC50) values are widely used to express fungicide potency and sensitivity of plant pathogens. This study explored the necessity of logarithmic transformation for statistical analysis of EC50 values. The results demonstrated that without logarithmic transformation, none of the five sets of epoxiconazole EC50 data (n = 26–33) against Sclerotinia sclerotiorum fitted a normal distribution. But after logarithmic transformation, four of the five datasets became normally distributed. Of the five sets of pyraclostrobin EC50 data (n = 29–32), only one dataset fitted a normal distribution. After logarithmic transformation, four datasets became normally distributed. Logarithmic transformation transformed the heterogeneity of variance across the five sets of epoxiconazole EC50 data to homogeneity but failed to improve the heterogeneity of variance across the five sets of pyraclostrobin EC50 data. For 150 isolates' EC50 values to epoxiconazole and 153 isolates' EC50 values to pyraclostrobin, the intervals of arithmetic means ± standard deviations (SD) covered 85.3% and 90.2% of data points, respectively, whereas the intervals of geometric means (X*) multiplied/divided by the multiplicative SD (S*) covered 69.3% and 70.9% of data points, respectively, which approximated the theoretical value of 68.3%. Distribution normality and homogeneity of variance are prerequisites for analysis of variance (anova) and the two parameters could be improved by logarithmic transformation, therefore, power and efficiency of statistical tests on EC50 data will be greatly enhanced by this kind of transformation.

Transferrin receptor 2 (TFR2) is a transmembrane protein expressed mainly in hepatocytes and in developing erythroid cells and is an important focal point in systemic iron regulation. Loss of TFR2 function results in a rare form of the iron-overload disease hereditary hemochromatosis. Although TFR2 in the liver has been shown to be important for regulating iron homeostasis in the body, TFR2's function in erythroid progenitors remains controversial. In this report, we analyzed TFR2-deficient mice in the presence or absence of iron overload to distinguish between the effects caused by a high iron load and those caused by loss of TFR2 function. Analysis of bone marrow from TFR2-deficient mice revealed a reduction in the early burst-forming unit–erythroid and an expansion of late-stage erythroblasts that was independent of iron overload. Spleens of TFR2-deficient mice displayed an increase in colony-forming unit–erythroid progenitors and in all erythroblast populations regardless of iron overload. This expansion of the erythroid compartment coincided with increased erythroferrone (ERFE) expression and serum erythropoietin (EPO) levels. Rescue of hepatic TFR2 expression normalized hepcidin expression and the total cell count of the bone marrow and spleen, but it had no effect on erythroid progenitor frequency. On the basis of these results, we propose a model of TFR2's function in murine erythropoiesis, indicating that deficiency in this receptor is associated with increased erythroid development and expression of EPO and ERFE in extrahepatic tissues independent of TFR's role in the liver.

BioOne Complete (complete.BioOne.org) is a full-text database of 200 subscribed and open-access titles in the biological, ecological, and environmental sciences published by nonprofit societies, associations, museums, institutions, and presses.

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