Erythropoietin signaling regulates heme biosynthesis

Chung, Joon; Wittig, Johannes G.; Ghamari, Alireza; Maeda, Masako; Dailey, Tamara A.; Bergonia, Hector A.; Kafina, Martin D.; Coughlin, Emma E.; Minogue, Catherine E.; Hebert, Alexander S.; Li, Liangtao; Kaplan, Jerry; Lodish, Harvey F.; Bauer, Daniel E.; Orkin, Stuart H.; Cantor, Alan B.; Maeda, Takahiro; Phillips, John D.; Coon, Joshua J.; Pagliarini, David J.; Dailey, Harry A.; Paw, Barry H.

doi:10.7554/elife.24767

Cited by 40 publications

(42 citation statements)

References 97 publications

(80 reference statements)

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“…Studies in stem cell-derived cardiomyocytes indicate that AKAP10 (D-AKAP2) is essential in controlling the heart rate and rhythm [ 25 ]. Recently, it was shown that AKAP10 is crucial in erythropoietin signaling and heme biosynthesis at the outer mitochondrial membrane [ 26 ]. Cardiac phosphoinositide 3-kinase gamma (PI3Kγ) is an AKAP that binds phosphodiesterase3B (PDE3B) and phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) along with PKA regulating cAMP and PtdIns(3,4,5)P3 signaling.…”

Section: Role Of Akaps In Cardiovascular Physiologymentioning

confidence: 99%

Polymorphisms/Mutations in A-Kinase Anchoring Proteins (AKAPs): Role in the Cardiovascular System

Suryavanshi

Jadhav

McConnell

2018

JCDD

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A-kinase anchoring proteins (AKAPs) belong to a family of scaffolding proteins that bind to protein kinase A (PKA) by definition and a variety of crucial proteins, including kinases, phosphatases, and phosphodiesterases. By scaffolding these proteins together, AKAPs build a “signalosome” at specific subcellular locations and compartmentalize PKA signaling. Thus, AKAPs are important for signal transduction after upstream activation of receptors ensuring accuracy and precision of intracellular PKA-dependent signaling pathways. Since their discovery in the 1980s, AKAPs have been studied extensively in the heart and have been proven essential in mediating cyclic adenosine monophosphate (cAMP)-PKA signaling. Although expression of AKAPs in the heart is very low, cardiac-specific knock-outs of several AKAPs have a noteworthy cardiac phenotype. Moreover, single nucleotide polymorphisms and genetic mutations in crucial cardiac proteins play a substantial role in the pathophysiology of cardiovascular diseases (CVDs). Despite the significant role of AKAPs in the cardiovascular system, a limited amount of research has focused on the role of genetic polymorphisms and/or mutations in AKAPs in increasing the risk of CVDs. This review attempts to overview the available literature on the polymorphisms/mutations in AKAPs and their effects on human health with a special focus on CVDs.

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Section: Role Of Akaps In Cardiovascular Physiologymentioning

confidence: 99%

Polymorphisms/Mutations in A-Kinase Anchoring Proteins (AKAPs): Role in the Cardiovascular System

Suryavanshi

Jadhav

McConnell

2018

JCDD

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“…6E), suggesting that its effects on FECH activity may be mediated by the requirement for FAM210B for efficient iron delivery to FECH, and/or by playing a role in allosteric activation of the FECH enzyme. These data add to our understanding of the mechanisms by which Epo signaling regulates heme synthesis by post-translational regulation of FECH (49) and suggest mechanisms by which the activity of heme synthetic enzymes, in this case, FECH, may be rapidly modulated in response to metabolic requirements.…”

Section: Discussionmentioning

confidence: 73%

“…To determine whether FAM210B functions as a mitochondrial iron importer or whether it played a role in regulation of FECH, we carried out an in vitro heme synthesis assay to compare the amount of iron transported across the mitochondrial membrane to synthesize deuteroheme (49). 55 Fe and DP were added to isolated mitochondria from WT and Fam210b Ϫ/Ϫ MEL cells.…”

Section: Fam210b Regulates Mitochondrial Iron Import and Fech Activitmentioning

confidence: 99%

FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity

Yien

Shi

Chen

et al. 2018

Journal of Biological Chemistry

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Edited by Joel M. GottesfeldErythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur

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“…For instance, erythroid cells shift from the use of the Krebs' cycle and oxidative phosphorylation to exclusive dependence on glycolysis as they terminally differentiate mitochondria (Gasko and Danon, 1972c, 1972a, 1972b. During terminal differentiation, the main function of erythroid mitochondria shifts towards heme production for hemoglobin synthesis (Chen et al, 2013;Chung et al, 2017;Yien et al, 2014Yien et al, , 2018Zhang et al, 2003). It is therefore unsurprising, but revealing, that CLPXP regulates erythroid heme synthesis at multiple points in the pathway, but does not seem to be as essential for regulating oxidative phosphorylation proteins as it does in other cell types.…”

Section: Discussionmentioning

confidence: 99%

CLPX regulates erythroid heme synthesis by control of mitochondrial heme synthesis enzymes and iron utilization

Rondelli

Perfetto

Danoff

et al. 2020

Preprint

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Heme is a prosthetic group that plays a critical role in catalyzing life-essential redox reactions in all cells, including critical metabolic processes. Heme synthesis must be tightly co-regulated with cellular requirements in order to maximize utilization and minimize toxicity. Terminally differentiating erythroid cells have an extremely high demand for heme for hemoglobin synthesis. While the enzymatic reactions of heme synthesis are extremely well studied, the mechanisms by which the mitochondrial homeostatic machinery interacts with and regulates heme synthesis are poorly understood. Knowledge of these regulatory mechanisms are key to understanding how red cells couple heme production with heme demand. Heme synthesis is tightly regulated by the mitochondrial AAA+ unfoldase CLPX, which has been reported to promote heme synthesis by activation of yeast δ-aminolevulinate synthase (ALAS/Hem1). CLPX was also reported to mediate heme-induced turnover of ALAS1 in human cells. However, a mutation in the ATP binding domain of CLPX that abrogated ATP binding caused an increase in ALAS activity, contrary to previous predictions that CLPX activated ALAS. Using loss-of-function assays in murine cells and zebrafish, we interrogated the mechanisms by which CLPX regulates erythroid heme synthesis. We found that consistent with previous studies, CLPX is required for erythroid heme synthesis. We show that ALAS2 stability and activity were both increased in the absence of CLPX, suggesting that CLPX primarily regulates ALAS2 by control of its turnover. However, we also showed that CLPX is required for PPOX activity and maintenance of FECH levels, likely accounting for the heme deficiency in the absence of CLPX. Lastly, CLPX is required for iron metabolism during erythroid terminal differentiation. Our results show that the role of CLPX in heme synthesis is not conserved across eukaryotes. Our studies reveal a potential mechanism for the role of CLPX in anemia and porphyria, and reveal multiple nodes at which heme synthesis is regulated by the mitochondrial housekeeping machinery.

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Erythropoietin signaling regulates heme biosynthesis

Cited by 40 publications

References 97 publications

Polymorphisms/Mutations in A-Kinase Anchoring Proteins (AKAPs): Role in the Cardiovascular System

Polymorphisms/Mutations in A-Kinase Anchoring Proteins (AKAPs): Role in the Cardiovascular System

FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity

CLPX regulates erythroid heme synthesis by control of mitochondrial heme synthesis enzymes and iron utilization

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