A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice

Lim, Jackie E.; Jin, Ou; Bennett, Carolyn M.; Morgan, Kelly; Wang, Fudi; Trenor, Cameron C.; Fleming, Mark D.; Andrews, Nancy C.

doi:10.1038/ng1659

Cited by 86 publications

(74 citation statements)

References 25 publications

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“…These transient contacts are very likely to be dependent on the activity of both molecular motors and docking complexes. The recent discovery of the genetic mutation in the hemoglobin deficit (hbd) mouse, 44,45 whose reticulocytes demonstrate reduced transferrin cycling, 46,47 further supports the notion that endosomal motility is necessary because the yeast homologue of the gene in question, Sec15l1, is known to be involved in vesicular docking. We expect that myosin Vb is a major contributor to this movement, based on recent findings by Provance et al 48 Previously, one could envisage a mechanism whereby the vesicle would only have to form in order to allow the acidification of the microenvironment surrounding the Fe 2 -Tf complex and the reduction of the metal to Fe 2ϩ .…”

Section: Discussionmentioning

confidence: 91%

Direct interorganellar transfer of iron from endosome to mitochondrion

Sheftel

Zhang

Brown

et al. 2007

Blood

237

178

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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...

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Section: Discussionmentioning

confidence: 91%

Direct interorganellar transfer of iron from endosome to mitochondrion

Sheftel

Zhang

Brown

et al. 2007

Blood

237

178

View full text Add to dashboard Cite

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“…2) were significantly (P Ͻ .05) up-regulated. The exocyst complex component Sec15l1 has been implicated in assisting transferrin (Tf) Tfr1-containing endosome uptake (29,30). Thus, the alterations in these 2 molecules indicate increased iron uptake and mitochondrial iron import.…”

Section: Frataxin Deficiency Alters the Expression Of Genes Involved mentioning

confidence: 99%

Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant

Huang

Becker

Whitnall

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

183

230

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We used the muscle creatine kinase (MCK) conditional frataxin knockout mouse to elucidate how frataxin deficiency alters iron metabolism. This is of significance because frataxin deficiency leads to Friedreich's ataxia, a disease marked by neurologic and cardiologic degeneration. Using cardiac tissues, we demonstrate that frataxin deficiency leads to down-regulation of key molecules involved in 3 mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase Nfs1), mitochondrial iron storage (mitochondrial ferritin), and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase, and ferrochelatase). This marked decrease in mitochondrial iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excessive mitochondrial iron observed. This effect is compounded by increased iron availability for mitochondrial uptake through (i) transferrin receptor1 up-regulation, increasing iron uptake from transferrin; (ii) decreased ferroportin1 expression, limiting iron export; (iii) increased expression of the heme catabolism enzyme heme oxygenase1 and down-regulation of ferritin-H and -L, both likely leading to increased ''free iron'' for mitochondrial uptake; and (iv) increased expression of the mammalian exocyst protein Sec15l1 and the mitochondrial iron importer mitoferrin-2 (Mfrn2), which facilitate cellular iron uptake and mitochondrial iron influx, respectively. Our results enable the construction of a model explaining the cytosolic iron deficiency and mitochondrial iron loading in the absence of frataxin, which is important for understanding the pathogenesis of Friedreich's ataxia.heme synthesis ͉ iron ͉ transferrin ͉ frataxin

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“…TfR1 is returned to the plasma membrane, where it can participate in another round of Tf-mediated iron uptake. A protein involved in TfR1 recycling in RBCs, Sec15l1, was identified from the hemoglobin-deficit (hbd) mouse, which shows microcytic hypochromic anemia (11). It was demonstrated that Mon1a plays a role in trafficking FPN1 to the cell surface of M⌽ in mice (12).…”

mentioning

confidence: 99%

Iron and Porphyrin Trafficking in Heme Biogenesis

Schultz

Chen

Paw

et al. 2010

Journal of Biological Chemistry

123

104

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Iron is an essential element for diverse biological functions. In mammals, the majority of iron is enclosed within a single prosthetic group: heme. In metazoans, heme is synthesized via a highly conserved and coordinated pathway within the mitochondria. However, iron is acquired from the environment and subsequently assimilated into various cellular pathways, including heme synthesis. Both iron and heme are toxic but essential cofactors. How is iron transported from the extracellular milieu to the mitochondria? How are heme and heme intermediates coordinated with iron transport? Although recent studies have answered some questions, several pieces of this intriguing puzzle remain unsolved.

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A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice

Cited by 86 publications

References 25 publications

Direct interorganellar transfer of iron from endosome to mitochondrion

Direct interorganellar transfer of iron from endosome to mitochondrion

Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant

Iron and Porphyrin Trafficking in Heme Biogenesis

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