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

Yien, Yvette Y.; Shi, Jiahai; Chen, Caiyong; Cheung, Jesmine T. M.; Grillo, Anthony S.; Shrestha, Rishna; Li, Liangtao; Zhang, Xuedi; Kafina, Martin D.; Kingsley, Paul D.; King, Matthew; Ablain, Julien; Li, Hojun; Zon, Leonard I.; Palis, James; Burke, Martin D.; Bauer, Daniel E.; Orkin, Stuart H.; Koehler, Carla M.; Phillips, John D.; Kaplan, Jerry; Ward, Diane McVey; Lodish, Harvey F.; Paw, Barry H.

doi:10.1074/jbc.ra118.002742

Cited by 38 publications

(58 citation statements)

References 82 publications

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“…Stabilization of FECH protein caused by the binding of iron-sulfur clusters [32] or the increased transcription of FECH mRNA [33] lead to ferrochelatase protein expression increased during erythropoiesis. FAM210B can effectively transport iron to FECH, and / or affect the allosteric activation of the FECH enzyme [31]. The possible mechanisms behind APOE -CNTNAP2 and RTF2 -CNTNAP2 warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…The impact of CNTNAP2 on cellular migration of neurons, synapse development, and synaptic communication indicate that it plays a key role in the brain function. FAM210B can promote the transfer of protoporphyrinogen IX (PPIX) to FECH, and promote the introduction of iron and the synthesis of heme by forming oligomers with PPOX and FECH to enhance the introduction of mitochondrial iron and the synthesis of heme [31]. Stabilization of FECH protein caused by the binding of iron-sulfur clusters [32] or the increased transcription of FECH mRNA [33] lead to ferrochelatase protein expression increased during erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide Variant-based Study of Genetic Effects with the Largest Neuroanatomic Coverage

Liu

et al. 2020

Preprint

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Background: Brain image genetics provides enormous opportunities for examining the effects of genetic variations on the brain. Many studies have shown that the structure, function, and abnormality (e.g., those related to Alzheimer's disease) of the brain are heritable. However, which genetic variations contribute to these phenotypic changes is not completely clear. Advances in neuroimaging and genetics have led us to obtain detailed brain anatomy and genome-wide information. These data offer us new opportunities to identify genetic variations such as single nucleotide polymorphisms ( SNPs ) that affect brain structure. In this paper, we perform a genome-wide variant-based study, and aim to identify top SNPs or SNP sets which have genetic effects with the largest neuroanotomic coverage at both voxel and region-of-interest ( ROI ) levels. Based on the voxelwise genome-wide association study ( GWAS ) results, we used the exhaustive search to find the top SNPs or SNP sets that have the largest voxel -based or ROI -based neuroanatomic coverage. For SNP sets with > 2 SNPs , we proposed an efficient genetic algorithm to identify top SNP sets that can cover all ROIs or a specific ROI . Results: We identified an ensemble of top SNPs , SNP -pairs and SNP -sets, whose effects have the largest neuroanatomic coverage. Experimental results on real imaging genetics data show that the proposed genetic algorithm is superior to the exhaustive search in terms of computational time for identifying top SNP -sets. Conclusions: We proposed and applied an informatics strategy to identify top SNPs , SNP -pairs and SNP -sets that have genetic effects with the largest neuroanatomic coverage. The proposed genetic algorithm offers an efficient solution to accomplish the task, especially for identifying top SNP -sets.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-wide Variant-based Study of Genetic Effects with the Largest Neuroanatomic Coverage

Liu

et al. 2020

Preprint

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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%

“…CRISPR/Cas9 constructs were co-electroporated with pEF1a at a 9:1 ratio. Cell selection was carried out as previously described (Yien et al, 2018). Clones were screened for loss of CLPX or CLPP protein by western analysis and qRT PCR.…”

Section: Generation Of Crispr Cell Linesmentioning

confidence: 99%

“…Less is known about how the "housekeeping" mitochondrial homeostatic machinery may regulate the activities of heme synthesis enzymes and mitochondrial iron transport. A few studies have demonstrated that proteins which regulate mitochondrial metabolism also play essential roles in facilitating high rates of heme synthesis in developing erythroid cells (Hildick-Smith et al, 2013;Shah et al, 2012;Sun et al, 2017;Yien et al, 2018). However, the functional interactions between mitochondrial homeostasis and heme synthesis, and the extent to which these regulatory mechanisms are tissuespecific, are not well understood.…”

Section: Introductionmentioning

confidence: 99%

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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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Mendelian randomization study on causal association of FAM210B with drug-induced lupus

Xu,

Gao,

Zhang

et al. 2024

Clin Rheumatol

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

Cited by 38 publications

References 82 publications

Genome-wide Variant-based Study of Genetic Effects with the Largest Neuroanatomic Coverage

Genome-wide Variant-based Study of Genetic Effects with the Largest Neuroanatomic Coverage

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

Mendelian randomization study on causal association of FAM210B with drug-induced lupus

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