Multi-omics Evidence for Inheritance of Energy Pathways in Red Blood Cells

Weisenhorn, Erin; Erve, Thomas J. van ‘t; Riley, Nicholas M.; Hess, John R.; Raife, Thomas J.; Coon, Joshua J.

doi:10.1074/mcp.m116.062349

Cited by 15 publications

(35 citation statements)

References 55 publications

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“…The heritability of energy metabolism in RBCs was established in the 1960s. In twin studies, we confirmed the heritability of pre‐ and poststorage RBC ATP concentrations, glutathione metabolism, hemolysis, and activity of the glycolytic pathway . Two heritable pathways affecting RBC storage have emerged: 1) inheritance of higher glycolytic activity correlates with higher ATP during storage and 2) inheritance of higher concentrations of carbonic anhydrase 1 (CA1) correlate with lower ATP during storage.…”

Section: Session 3: Methods For the Detection Of Rbc Processing And Ssupporting

confidence: 58%

“…In twin studies, we confirmed the heritability of pre-and poststorage RBC ATP concentrations, glutathione metabolism, hemolysis, and activity of the glycolytic pathway. [28][29][30] Two heritable pathways affecting RBC storage have emerged: 1) inheritance of higher glycolytic activity correlates with higher ATP during storage and 2) inheritance of higher concentrations of carbonic anhydrase 1 (CA1) correlate with lower ATP during storage. CA1 concentrations correlate negatively with pH, suggesting that the effect of CA1 may involve the production of acid, with resulting inhibition of glycolytic enzymes.…”

Section: Systems Biology Of Rbc Storage Lesions-bernhard Palsson Phdmentioning

confidence: 99%

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Proceedings of the Food and Drug Administration's public workshop on new red blood cell product regulatory science 2016

Vostal¹,

Buehler²,

Gelderman³

et al. 2017

Transfusion

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The US Food and Drug Administration (FDA) held a workshop on red blood cell (RBC) product regulatory science on October 6 and 7, 2016, at the Natcher Conference Center on the National Institutes of Health (NIH) Campus in Bethesda, Maryland. The workshop was supported by the National Heart, Lung, and Blood Institute, NIH; the Department of Defense; the Office of the Assistant Secretary for Health, Department of Health and Human Services; and the Center for Biologics Evaluation and Research, FDA. The workshop reviewed the status and scientific basis of the current regulatory framework and the available scientific tools to expand it to evaluate innovative and future RBC transfusion products. A full record of the proceedings is available on the FDA website (http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm507890.htm). The contents of the summary are the authors' opinions and do not represent agency policy.

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Section: Session 3: Methods For the Detection Of Rbc Processing And Ssupporting

confidence: 58%

Section: Systems Biology Of Rbc Storage Lesions-bernhard Palsson Phdmentioning

confidence: 99%

Proceedings of the Food and Drug Administration's public workshop on new red blood cell product regulatory science 2016

Vostal¹,

Buehler²,

Gelderman³

et al. 2017

Transfusion

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“…In the last 7 years, such large-scale studies as the Recipient Epidemiology and Donor Evaluation Study-III have addressed the issue of biological variability and found that biological variability across donors (i.e., donor ethnicity, gender, and age) affects RBC storability and stress hemolysis ( 18 ). Such observations have been supported by smaller scale laboratory studies in humans ( 19 , 20 ) that demonstrated heritability of the metabolic storage lesion ( 21 – 23 ), as well as studies performed in mice ( 24 , 25 ) showing that post-transfusion recoveries are greatly variable across donors ( 26 ). Of note, Yoshida and colleagues have recently provided preliminary evidence suggesting that hemoglobin oxygen saturation (SO 2 ) at 8 h from donation and routine processing varies significantly across donors ( 27 ), potentially contributing to the donor-dependent development of the storage lesion.…”

Section: Introductionmentioning

confidence: 81%

Metabolism of Citrate and Other Carboxylic Acids in Erythrocytes As a Function of Oxygen Saturation and Refrigerated Storage

et al. 2017

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State-of-the-art proteomics technologies have recently helped to elucidate the unanticipated complexity of red blood cell metabolism. One recent example is citrate metabolism, which is catalyzed by cytosolic isoforms of Krebs cycle enzymes that are present and active in mature erythrocytes and was determined using quantitative metabolic flux analysis. In previous studies, we reported significant increases in glycolytic fluxes in red blood cells exposed to hypoxia in vitro or in vivo, an observation relevant to transfusion medicine owing to the potential benefits associated with hypoxic storage of packed red blood cells. Here, using a combination of steady state and quantitative tracing metabolomics experiments with 13C1,2,3-glucose, 13C6-citrate, 13C515N2-glutamine, and 13C1-aspartate via ultra-high performance liquid chromatography coupled on line with mass spectrometry, we observed that hypoxia in vivo and in vitro promotes consumption of citrate and other carboxylates. These metabolic reactions are theoretically explained by the activity of cytosolic malate dehydrogenase 1 and isocitrate dehydrogenase 1 (abundantly represented in the red blood cell proteome), though moonlighting functions of additional enzymes cannot be ruled out. These observations enhance understanding of red blood cell metabolic responses to hypoxia, which could be relevant to understand systemic physiological and pathological responses to high altitude, ischemia, hemorrhage, sepsis, pulmonary hypertension, or hemoglobinopathies. Results from this study will also inform the design and testing of novel additive solutions that optimize red blood cell storage under oxygen-controlled conditions.

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“…Indeed, it has been documented that RBC units from a significant percentage of donors have 24‐hour recoveries of less than 75%, and for a small percentage of donors, 24‐hour recoveries are very poor (in the range of 20%‐30%) . The basis for donor‐to‐donor variability is poorly understood, but there is good evidence that it has a strong genetic component, at least at the metabolic level . Using tractable animal models of RBC storage, we have documented that both hemolysis and decreased 24‐hour recoveries vary in genetically distinct strains of inbred mice .…”

mentioning

confidence: 94%

“…2 The basis for donor-to-donor variability is poorly understood, but there is good evidence that it has a strong genetic component, at least at the metabolic level. [3][4][5][6][7] Using tractable animal models of RBC storage, we have documented that both hemolysis and decreased 24-hour recoveries vary in genetically distinct strains of inbred mice. 8,9 These strains serve as a platform to study basic mechanisms of variant RBC storage.…”

mentioning

confidence: 99%

Murine red blood cells from genetically distinct donors cross‐regulate when stored together

et al. 2017

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BACKGROUND Donor variability of red blood cell (RBC) storage has been observed in both humans and animal models. We utilized a strain of mice with RBCs known to store well (B6) and a strain known to store poorly (FVB) to test the hypothesis that RBCs affected the storage of other RBCs. STUDY DESIGN AND METHODS Five strains of mice were used: 1) transgenic B6 mice expressing green fluorescent protein (GFP) in their RBCs (GFP.B6), 2) wild‐type B6 mice, 3) wild‐type FVB mice, 4) F1 crosses between GFP.B6 and FVB mice (GFP.F1), and 5) the analogous wild‐type (B6xFVB) F1 cross. GFP.B6 or GFP.F1 RBCs were mixed with wild‐type (non‐GFP) RBCs from B6 or FVB strains before storage. Twenty‐four–hour RBC recoveries were determined for stored RBCs by enumerating circulating GFP+ RBCs by flow cytometry. RESULTS Twenty‐four–hour recoveries of GFP.F1 RBCs was increased by co‐storage with B6 RBCs but decreased by co‐storage with FVB RBCs. This effect was dose dependent when tested with GFP.B6 RBCs; the more FVB blood added, the worse the 24‐hour recoveries became. RBC cross‐regulation did not occur when B6 and FVB RBCs were separated by a semipermeable membrane with a 0.4‐µm size cutoff. CONCLUSION These findings demonstrate that RBCs affect the storage of other RBCs, in both positive and negative directions, indicating not only that RBC storage is intrinsic to the RBC but that RBC–RBC communication occurs. Additional studies will be required to determine the nature of this effect and if these findings translate into human RBC storage.

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Multi-omics Evidence for Inheritance of Energy Pathways in Red Blood Cells

Cited by 15 publications

References 55 publications

Proceedings of the Food and Drug Administration's public workshop on new red blood cell product regulatory science 2016

Proceedings of the Food and Drug Administration's public workshop on new red blood cell product regulatory science 2016

Metabolism of Citrate and Other Carboxylic Acids in Erythrocytes As a Function of Oxygen Saturation and Refrigerated Storage

Murine red blood cells from genetically distinct donors cross‐regulate when stored together

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