Do Mammalian Cells Really Need to Export and Import Heme?

Vertebrate red blood cells (RBCs) arise from erythroblasts in the human bone marrow through a process known as erythropoiesis. Iron uptake is a crucial hallmark, essential for heme biosynthesis in the differentiating erythroblasts, which are dedicated to producing hemoglobin. Erythropoiesis is facilitated by a network of intracellular transport proteins, chaperones, and circulating hormones. Intracellular iron is targeted to the mitochondria for incorporation into a porphyrin ring to form heme and cytosolic iron-sulfur proteins, including Iron Regulatory Protein 1 (IRP1). These processes are tightly regulated to prevent both excess and insufficient levels of iron and heme precursors. Crosstalk between the heme and iron-sulfur synthesizing pathways has been demonstrated to serve as a regulatory feedback mechanism. The activity of δ-aminolevulinic acid synthase (ALAS), the first and rate-limiting enzyme of heme biosynthesis, is a fundamental node of this regulation. Recently, the mitochondrial unfoldase, ClpX, has received attention as a novel key player that modulates this step in heme biogenesis, implicating a role in the pathophysiology of anemic diseases. This chapter reviews the canonical pathways in intracellular iron and heme trafficking and recent findings of iron and heme metabolism in vertebrate red cells. A discussion of the molecular approaches to studying iron and heme transport is provided to highlight opportunities for revealing therapeutic targets.

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“…59 The conditions in which heme is exported from erythroid cells by FLVCR are nicely reviewed elsewhere. 60 …”

Section: Mitochondrial Iron Metabolismmentioning

confidence: 99%

Intracellular iron and heme trafficking and metabolism in developing erythroblasts

Kafina

Paw

2017

Metallomics

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“…The very properties that make heme so potent a cofactor make free heme toxic to a living cell. The redox-active iron of heme can catalyze formation of harmful reactive oxygen species and promote oxidative stress, presenting a real danger even at low concentrations of heme, and to limit reactivity, free heme is closely regulated at many levels including biosynthesis, degradation, and transport (Furuyama et al, 2007;Chiabrando et al, 2014;Knutson, 2017;Coffey and Ganz, 2017;Ponka et al, 2017). In mammalian cells, excess free heme initiates its own catabolism by inducing transcription of heme oxidase 1 (HMOX1), the key enzyme in heme degradation.…”

Section: Introductionmentioning

confidence: 99%

G-quadruplexes Sequester Free Heme in Living Cells

Gray

Lombardi

Verga

et al. 2019

Cell Chemical Biology

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Heme is an essential cofactor for many enzymes, but free heme is toxic and its levels are tightly regulated. G-quadruplexes bind heme avidly in vitro, raising the possibility that they may sequester heme in vivo. If so, then treatment that displaces heme from quadruplexes is predicted to induce expression of genes involved in iron and heme homeostasis. Here we show that PhenDC3, a G-quadruplex ligand structurally unrelated to heme, displaces quadruplex-bound heme in vitro and alters transcription in cultured human cells, upregulating genes that support heme degradation and iron homeostasis, and most strikingly causing a 30-fold induction of heme oxidase 1, the key enzyme in heme degradation. We propose that G-quadruplexes sequester heme to protect cells from the pathophysiological consequences of free heme.

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“…The natural affinity of quadruplexes for heme suggested that quadruplexes may bind to heme in vivo , enabling use of heme as a cofactor for nucleic acid-catalyzed reactions [Poon LC et al 2011]. However, free heme is potentially toxic even at low concentrations, as its redox-active iron can catalyze formation of harmful reactive oxygen species and promoting oxidative stress [Chiabrando D et al 2014; Ponka P et al 2017]. This raised the possibility that sequestration of heme by quadruplexes might protect cells and the genome from oxidative damage by limiting free heme levels while ensuring ready availability of this key cofactor.…”

Section: Introductionmentioning

confidence: 99%

G-quadruplexes sequester free heme in living cells

Gray

Lombardi

Verga

et al. 2019

Preprint

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Heme is an essential cofactor for many enzymes, but free heme is toxic and its levels are tightly regulated. G-quadruplexes bind heme avidly in vitro, raising the possibility that they may sequester heme in vivo. If so, then treatment that displaces heme from quadruplexes is predicted to induce expression of genes involved in iron and heme homeostasis. Here we show that PhenDC3, a G-quadruplex ligand structurally unrelated to heme, displaces quadruplex-bound heme in vitro and alters transcription in cultured human cells, up-regulating genes that support heme degradation and iron homeostasis, and most strikingly causing a 30-fold induction of heme oxidase 1, the key enzyme in heme degradation. We propose that G-quadruplexes sequester heme to protect cells from the pathophysiological consequences of free heme. This identifies a new function for G-quadruplexes and a new mechanism for protection of cells from heme.

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Do Mammalian Cells Really Need to Export and Import Heme?

Cited by 59 publications

References 74 publications

Intracellular iron and heme trafficking and metabolism in developing erythroblasts

Intracellular iron and heme trafficking and metabolism in developing erythroblasts

G-quadruplexes Sequester Free Heme in Living Cells

G-quadruplexes sequester free heme in living cells

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