The ins and outs of erythroid heme transport

Cao, Chang; Fleming, Mark D.

doi:10.3324/haematol.2015.127886

Cited by 4 publications

(3 citation statements)

References 7 publications

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“…As far as we know, the regulatory genes and pathways of heme biosynthesis, degradation and transport are largely conserved between mammals and zebrafish in general. 20 , 23 , 35 , 36 , 43 Vertebrates contain two ALAS isozymes encoded by 2 distinct genes located on different chromosomes; ALAS2 is expressed in erythrocytes, whereas ALAS1 is ubiquitously expressed. 11 By searching the integrated RNA-seq database on BloodSpot, 44 we found that, in humans and mice, ALAS1 is highly expressed in myeloid cells, which is consistent with our zebrafish data and partly explains the importance of alas1 for neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Alas1 is essential for neutrophil maturation in zebrafish

et al. 2018

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Neutrophils play essential roles in innate immunity and are the first responders to kill foreign micro-organisms, a function that partially depends on their granule content. The complicated regulatory network of neutrophil development and maturation remains largely unknown. Here we utilized neutrophil-deficient zebrafish to identify a novel role of Alas1, a heme biosynthesis pathway enzyme, in neutrophil development. We showed that Alas1-deficient zebrafish exhibited proper neutrophil initiation, but further neutrophil maturation was blocked due to heme deficiency, with lipid storage and granule formation deficiencies, and loss of heme-dependent granule protein activities. Consequently, Alas1-deficient zebrafish showed impaired bactericidal ability and augmented inflammatory responses when challenged with Escherichia coli. These findings demonstrate the important role of Alas1 in regulating neutrophil maturation and physiological function through the heme. Our study provides an in vivo model of Alas1 deficiency and may be useful to evaluate the progression of heme-related disorders in order to facilitate the development of drugs and treatment strategies for these diseases.

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Section: Discussionmentioning

confidence: 99%

Alas1 is essential for neutrophil maturation in zebrafish

et al. 2018

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“…Heme, an iron-containing molecule, plays an essential role in mitochondrial electron transport as a cofactor of cytochromes. Heme can enter cell through FLVCR2 (feline leukemia virus subgroup C receptor-related protein 2), SLC48A1, and SCL46A1 in the cell membrane ( Cao and Fleming, 2015 ). Its degradation is regulated by HO-1, which is also an Nrf2-regulated gene.…”

Section: The Regulatory Role Of Nrf2 In Iron Homeostasismentioning

confidence: 99%

Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells

Zhang

Jin

et al. 2021

Front. Cell Dev. Biol.

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Iron is an essential trace mineral element in almost all living cells and organisms. However, cellular iron metabolism pathways are disturbed in most cancer cell types. Cancer cells have a high demand of iron. To maintain rapid growth and proliferation, cancer cells absorb large amounts of iron by altering expression of iron metabolism related proteins. However, iron can catalyze the production of reactive oxygen species (ROS) through Fenton reaction. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important player in the resistance to oxidative damage by inducing the transcription of antioxidant genes. Aberrant activation of Nrf2 is observed in most cancer cell types. It has been revealed that the over-activation of Nrf2 promotes cell proliferation, suppresses cell apoptosis, enhances the self-renewal capability of cancer stem cells, and even increases the chemoresistance and radioresistance of cancer cells. Recently, several genes involving cellular iron homeostasis are identified under the control of Nrf2. Since cancer cells require amounts of iron and Nrf2 plays pivotal roles in oxidative defense and iron metabolism, it is highly probable that Nrf2 is a potential modulator orchestrating iron homeostasis and redox balance in cancer cells. In this hypothesis, we summarize the recent findings of the role of iron and Nrf2 in cancer cells and demonstrate how Nrf2 balances the oxidative stress induced by iron through regulating antioxidant enzymes and iron metabolism. This hypothesis provides new insights into the role of Nrf2 in cancer progression. Since ferroptosis is dependent on lipid peroxide and iron accumulation, Nrf2 inhibition may dramatically increase sensitivity to ferroptosis. The combination of Nrf2 inhibitors with ferroptosis inducers may exert greater efficacy on cancer therapy.

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“…[31][32][33][34][35] The details of intracellular heme trafficking are not completely understood, but molecules like glyceraldehyde-3-phosphate dehydrogenase (GAPDH) have been proposed to be involved, and such trafficking would play a role in signal amplification. 5,36,37 With the discovery of ubiquitous heme transporters found on the membranes of many cells, including red blood cells, [1][2][3]38,39 we hypothesized that a labile NOferroheme could transduce NO bioactivity in the vasculature. This hypothesis is supported by the observation that in humans, iron-nitrosylated hemoglobinmeasured selectively by both chemiluminescence and by electron paramagnetic resonance (EPR) spectroscopyforms in human blood endogenously during artery-to-vein physiological deoxygenation of blood, as nitrite is reduced to NO by deoxyhemoglobin and auto-captured as iron-nitrosylhemoglobin.…”

Section: Introductionmentioning

confidence: 99%

Thiol catalyzed formation of NO-ferroheme regulates canonical intravascular NO signaling

DeMartino

Poudel

Dent

et al. 2023

Preprint

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Nitric oxide (NO) is an endogenously produced physiological signaling molecule that regulates blood flow and platelet activation. However, both the intracellular and intravascular diffusion of NO is severely limited by scavenging reactions with hemoglobin, myoglobin, and other hemoproteins, raising unanswered questions as to how free NO can signal in hemoprotein-rich environments, like blood and cardiomyocytes. We explored the hypothesis that NO could be stabilized as a ferrous heme-nitrosyl complex (Fe2+-NO, NO-ferroheme) either in solution within membranes or bound to albumin. Unexpectedly, we observed a rapid reaction of NO with free ferric heme (Fe3+) and a reduced thiol under physiological conditions to yield NO-ferroheme and a thiyl radical. This thiol-catalyzed reductive nitrosylation reaction occurs readily when the hemin is solubilized in lipophilic environments, such as red blood cell membranes, or bound to serum albumin. NO-ferroheme albumin is stable, even in the presence of excess oxyhemoglobin, and potently inhibits platelet activation. NO-ferroheme-albumin administered intravenously to mice dose-dependently vasodilates at low- to mid-nanomolar concentrations. In conclusion, we report the fastest rate of reductive nitrosylation observed to date to generate a NO-ferroheme molecule that resists oxidative inactivation, is soluble in cell membranes, and is transported intravascularly by albumin to promote potent vasodilation.

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The ins and outs of erythroid heme transport

Cited by 4 publications

References 7 publications

Alas1 is essential for neutrophil maturation in zebrafish

Alas1 is essential for neutrophil maturation in zebrafish

Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells

Thiol catalyzed formation of NO-ferroheme regulates canonical intravascular NO signaling

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