Heme as a Magnificent Molecule with Multiple Missions: Heme Determines Its Own Fate and Governs Cellular Homeostasis

Furuyama, Kazumichi; Kaneko, Kiriko; Vargas, D V Patrick

doi:10.1620/tjem.213.1

Cited by 172 publications

(168 citation statements)

References 114 publications

(116 reference statements)

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“…However, excess free or non-protein-bound heme damages lipid, protein, and DNA through the generation of reactive oxygen species, resulting in cellular injury and death (12). Therefore, free cellular heme levels must be tightly regulated to provide an adequate supply yet avoid heme toxicities (4,(13)(14)(15).Most studies of heme homeostasis focus on its biosynthesis and degradation. The rate of heme biosynthesis varies significantly among various cells and tissues and is especially high in hepatocytes and erythroid cells, where large amounts of heme are required for cytochrome P450 and hemoglobin, respectively (4).…”

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confidence: 99%

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Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

Yang

Philips

Doty

et al. 2010

Journal of Biological Chemistry

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The feline leukemia virus subgroup C receptor (FLVCR) is a heme export protein that is required for proerythroblast survival and facilitates macrophage heme iron recycling. However, its mechanism of heme export and substrate specificity are uncharacterized. Using [55 Fe]heme and the fluorescent heme analog zinc mesoporphyrin, we investigated whether export by FLVCR depends on the availability and avidity of extracellular heme-binding proteins. Export was 100-fold more efficient when the medium contained hemopexin (K d < 1 pM) compared with albumin (K d ‫؍‬ 5 nM) at the same concentration and was not detectable when the medium lacked heme-binding proteins. Besides heme, FLVCR could export other cyclic planar porphyrins, such as protoporphyrin IX and coproporphyrin. However, FLVCR has a narrow substrate range because unconjugated bilirubin, the primary breakdown product of heme, was not transported. As neither protoporphyrin IX nor coproporphyrin export improved with extracellular hemopexin (versus albumin), our observations further suggest that hemopexin, an abundant protein with a serum concentration (6.7-25 M) equivalent to that of the iron transport protein transferrin (22-31 M), by accepting heme from FLVCR and targeting it to the liver, might regulate macrophage heme export and heme iron recycling in vivo. Final studies show that hemopexin directly interacts with FLVCR, which also helps explain why FLVCR, in contrast to some major facilitator superfamily members, does not function as a bidirectional gradient-dependent transporter. Together, these data argue that hemopexin has a role in assuring systemic iron balance during homeostasis in addition to its established role as a scavenger during internal bleeding or hemolysis.The biological roles of heme are diverse and encompass most areas of cell metabolism and gene regulation. Heme serves as a prosthetic group in the hemeproteins, which are involved in crucial biological functions, including oxygen binding (hemoglobin and myoglobin), oxygen metabolism (oxidases, peroxidases, catalases, and hydroxylases), electron transfer (cytochromes) (4), and signal transduction (nitric-oxide synthases) (5). In addition, heme serves as a signaling molecule in erythropoiesis and other physiological systems. Because heme generally signals by binding and inactivating a transcriptional repressor (e.g. Bach1) or translational inhibitor (e.g. heme-regulated inhibitor and thus eIF␣2 kinase), its impact is immediate (6 -8). Perhaps for this reason, heme is utilized in time-sensitive processes, such as the regulation of circadian rhythm (9), N-end rule pathway/protein ubiquitination (10), and globin synthesis. Heme is also required for microRNA processing (11). However, excess free or non-protein-bound heme damages lipid, protein, and DNA through the generation of reactive oxygen species, resulting in cellular injury and death (12). Therefore, free cellular heme levels must be tightly regulated to provide an adequate supply yet avoid heme toxicities (4,(13)(14)(15).Most studies of h...

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confidence: 99%

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confidence: 99%

Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

Yang

Philips

Doty

et al. 2010

Journal of Biological Chemistry

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“…Heme oxygenase (HO) is the first and ratelimiting enzyme in an enzymatic pathway that catabolizes the degradation of heme into biliverdin, iron and carbon monoxide (CO) (reviewed in Shibahara 2003;Furuyama et al 2007). There are two isoforms of HO, i.e., HO-1 and HO-2.…”

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confidence: 99%

Hepatocyte-Specific Deletion of Heme Oxygenase-1 Disrupts Redox Homeostasis in Basal and Oxidative Environments

Mamiya

Katsuoka

Hirayama

et al. 2008

Tohoku J. Exp. Med.

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Heme oxygenase-1 (HO-1) is the rate-limiting enzyme of heme catabolism and has been assumed to be important in cellular response against oxidative stress through modification of the pro-oxidant heme into less toxic catabolites that behave as antioxidants. However, the precise mechanisms involved and the physiological significance of such activity remain to be clarified. To elucidate roles HO-1 plays in vivo, hepatocyte-specific conditional knockout (CKO) mice of HO-1 gene were generated by site-specific recombination using albumin-promoter-driven Cre-loxP system. In livers of HO-1 CKO mice HO-1 protein level decreased to approximately 30% of control mouse livers. The HO-1 CKO mice are viable, exhibit normal growth curves over six months, and show no histological and serological abnormalities. We found that several cytoprotective genes, such as NAD(P)H dehydrogenase quinone 1 and glutathione S-transferase P1, showed markedly elevated expression, suggesting the increase of oxidative stress in HO-1 CKO mice even under quiescent conditions. In vivo electron paramagnetic resonance studies demonstrated that signal decay times of nitroxyl radicals were significantly longer in livers of HO-1 CKO mice than that of control mice, indicating that radical scavenging activity was significantly compromised in the mutant liver. HO-1 CKO mice were susceptible to carbon tetrachloride hepatotoxicity. These results provide the first in vivo evidence that HO-1 acts to protect cells against the oxidative stress in both basal conditions and upon chemical insult.heme oxygenase-1; oxidative stress; reactive oxygen species; in vivo EPR; carbon tetrachloride. Tohoku

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“…Cui et al (2008) also demonstrated that the accumulation of iron, but not heme, was found in dHO-deficient tissues, which was similar to that seen in liver and spleen of HO-1-deficient humans and mice Yachie et al 1999;Yet et al 2003). In iron-heme metabolically active tissues, the generation of heme was reduced substantially by a decrease in the expression of 5-aminolevulinic acid synthase-1 (Furuyama et al 2007), which contributes to a lack of utilization of iron, and then the accumulation of iron. Cui et al (2008) demonstrated that knockdown of dHO in transgenic fly lines induced either lethality or abnormal morphology in adult eyes, indicating that the recycling of heme-iron by dHO is indispensable for the normal development of cells.…”

Section: Discussionmentioning

confidence: 52%

Genetic Link between Heme Oxygenase and the Signaling Pathway of DNA Damage in<i> Drosophila</i> <i>Melanogaster</i>

Ida

Suyari

Shimamura

et al. 2013

Tohoku J. Exp. Med.

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Heme oxygenase (HO) is a rate-limiting step of heme degradation, which catalyzes the conversion of heme into biliverdin, iron, and CO. HO has been characterized in microorganisms, insects, plants, and mammals. The mammalian enzyme participates in adaptive and protective responses to oxidative stress and various inflammatory stimuli. The present study reports that eye imaginal disc-specific knockdown of the Drosophila HO homologue (dHO) conferred serious abnormal eye morphology in adults, resulting in the generation of reactive oxygen species and apoptosis in third-instar larvae. Oxidative stress frequently induces DNA lesions that are recognized by damage sensors, including ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3-related (ATR) proteins. The knockdown of dHO took place in G0/ G1-arrested cells posterior to the morphogenetic furrow and thus prevented these cells from entering S-phase, with an increase in the level of histone H2A.V, a DNA damage marker. Moreover, the knockdown of dHO resulted in the enhancement of the rough eye phenotype in ATM-deficient flies or was lethal in ATR-deficient flies. These results indicate that dHO functions in control of the signal pathway of DNA damage. On the other hand, genetic crosses with a collection of Drosophila deficiency stocks allowed us to identify eight genomic regions, each deletion of which caused suppression of the rough eye phenotype induced by dHO knockdown. This information should facilitate the identification of HO regulators in Drosophila and clarification of the roles of HO in eye development.

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Heme as a Magnificent Molecule with Multiple Missions: Heme Determines Its Own Fate and Governs Cellular Homeostasis

Cited by 172 publications

References 114 publications

Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

Hepatocyte-Specific Deletion of Heme Oxygenase-1 Disrupts Redox Homeostasis in Basal and Oxidative Environments

Genetic Link between Heme Oxygenase and the Signaling Pathway of DNA Damage in<i> Drosophila</i> <i>Melanogaster</i>

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