Biology of Heme in Mammalian Erythroid Cells and Related Disorders

Fujiwara, Tohru; Harigae, Hideo

doi:10.1155/2015/278536

Cited by 37 publications

(27 citation statements)

References 94 publications

(125 reference statements)

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“…Tetrapyrroles are involved in metabolism in all kingdoms of living organisms. In the animal kingdom, well-known tetrapyrroles are porphyrins that are part of the heme synthesis pathway [ 48 ]. In plants, tetrapyrroles are part of the pathways leading to heme formation and chlorophyll [ 49 ].…”

Section: Tetrapyrroles Including Protoporphyrins Such As Ppix Asmentioning

confidence: 99%

Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

Veenman

Vainshtein

Yasin

et al. 2016

IJMS

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The 18 kDa translocator protein (TSPO) is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO’s importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles’ membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships.

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Section: Tetrapyrroles Including Protoporphyrins Such As Ppix Asmentioning

confidence: 99%

Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

Veenman

Vainshtein

Yasin

et al. 2016

IJMS

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“…55 In addition to being a critical component of hemoglobin, heme is essential for various processes during erythroid differentiation. 56 Both erythroid and non-erythroid cells can acquire extracellular heme, but the mechanisms of cellular heme influx are poorly understood. Although heme uptake by erythroblasts appears to be dispensable for physiological erythropoiesis, exogenous heme could be necessary for recovery from erythropoietic stresses, such as hemolytic anemia or acute blood loss.…”

Section: Discussionmentioning

confidence: 99%

Genetic screens reveal CCDC115 as a modulator of erythroid iron and heme trafficking

et al. 2020

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Transferrin‐bound iron (TBI), the physiological circulating iron form, is acquired by cells through the transferrin receptor (TfR1) by endocytosis. In erythroid cells, most of the acquired iron is incorporated into heme in the mitochondria. Cellular trafficking of heme is indispensable for erythropoiesis and many other essential biological processes. Comprehensive elucidation of molecular pathways governing and regulating cellular iron acquisition and heme trafficking is required to better understand physiological and pathological processes affecting erythropoiesis. Here, we report the first genome‐wide clustered regularly interspaced short palindromic repeats (CRISPR) screens in human erythroid cells to identify determinants of iron and heme uptake, as well as heme‐mediated erythroid differentiation. We identified several candidate modulators of TBI acquisition including TfR1, indicating that our approach effectively revealed players mechanistically relevant to the process. Interestingly, components of the endocytic pathway were also revealed as potential determinants of transferrin acquisition. We deciphered a role for the vacuolar‐type H+ − ATPase (V‐ ATPase) assembly factor coiled‐coil domain containing 115 (CCDC115) in TBI uptake and validated this role in CCDC115 deficient K562 cells. Our screen in hemin‐treated cells revealed perturbations leading to cellular adaptation to heme, including those corresponding to trafficking mechanisms and transcription factors potentiating erythroid differentiation. Pathway analysis indicated that endocytosis and vesicle acidification are key processes for heme trafficking in erythroid precursors. Furthermore, we provided evidence that CCDC115, which we identified as required for TBI uptake, is also involved in cellular heme distribution. This work demonstrates a previously unappreciated common intersection in trafficking of transferrin iron and heme in the endocytic pathway of erythroid cells.

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“…Heme, a complex of protoporphyrin IX with iron, is a prosthetic group of various hemoproteins and an essential cofactor in many biological processes [19,20]. It is well known that heme biosynthesis is one of the most important metabolic pathways in mammals, and defective heme biosynthesis will give rise to severe metabolic disorders, such as erythropoietic porphyria and sideroblastic anemia [21]. SCD is a group of genetic blood disorders, and patients with SCD possess sickle hemoglobin, an oxygen-transport protein in the red blood cells [22,23].…”

Section: Changed Percentage Of Disturbed Pathwaysmentioning

confidence: 99%

Individualized identification of disturbed pathways in sickle cell disease

Wang

Huang

et al. 2017

Open Life Sciences

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Abstract:Background: Sickle cell disease (SCD) is one of the most common genetic blood disorders. Identifying pathway aberrance in an individual SCD contributes to the understanding of disease pathogenesis and the promotion of personalized therapy. Here we proposed an individualized pathway aberrance method to identify the disturbed pathways in SCD. Methods: Based on the transcriptome data and pathway data, an individualized pathway aberrance method was implemented to identify the altered pathways in SCD, which contained four steps: data preprocessing, gene-level statistics, pathway-level statistics, and significant analysis. The changed percentage of altered pathways in SCD individuals was calculated, and a differentially expressed gene (DEG)-based pathway enrichment analysis was performed to validate the results. Results: We identified 618 disturbed pathways between normal and SCD conditions. Among them, 6 pathways were altered in > 80% SCD individuals. Meanwhile, forty-six DEGs were identified between normal and SCD conditions, and were enriched in heme biosynthesis. Relative to DEGbased pathway analysis, the new method presented richer results and more extensive application. Conclusion: This study predicted several disturbed pathways via detecting pathway aberrance on a personalized basis. The results might provide new sights into the pathogenesis of SCD and facilitate the application of custom treatment for SCD.

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Biology of Heme in Mammalian Erythroid Cells and Related Disorders

Cited by 37 publications

References 94 publications

Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

Genetic screens reveal CCDC115 as a modulator of erythroid iron and heme trafficking

Individualized identification of disturbed pathways in sickle cell disease

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