Biological and Genetic Determinants of Glycolysis: Phosphofructokinase Isoforms Boost Energy Status of Stored Red Blood Cells and Transfusion Outcomes

Abstract

Mature red blood cells (RBCs) lack mitochondria, and thus exclusively rely on glycolysis to generate adenosine triphosphate (ATP) during aging in vivo or storage in the blood bank. Here we leveraged 13,029 volunteers from the Recipient Epidemiology and Donor Evaluation Study to identify an association between end-of-storage levels of glycolytic metabolites and donor age, sex, and ancestry-specific genetic polymorphisms in regions encoding phosphofructokinase 1, platelet (detected in mature RBCs), hexokinase 1, ADP-ribosyl cyclase 1 and 2 (CD38/BST1). Gene-metabolite associations were validated in fresh and stored RBCs from 525 Diversity Outbred mice, and via multi-omics characterization of 1,929 samples from 643 human RBC units during storage. ATP and hypoxanthine levels - and the genetic traits linked to them - were associated with hemolysis in vitro and in vivo, both in healthy autologous transfusion recipients and in 5,816 critically ill patients receiving heterologous transfusions, suggesting their potential as markers to improve transfusion outcomes. eTOC and Highlights O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/557250v4_ufig1.gif" ALT="Figure 1"> View larger version (87K): org.highwire.dtl.DTLVardef@1a556b7org.highwire.dtl.DTLVardef@1e02b13org.highwire.dtl.DTLVardef@2bfab1org.highwire.dtl.DTLVardef@15787e3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBlood donor age and sex affect glycolysis in stored RBCs from 13,029 volunteers; C_LIO_LIAncestry, genetic polymorphisms in PFKP, HK1, CD38/BST1 influence RBC glycolysis; C_LIO_LIModeled PFKP effects relate to preventing loss of the total AXP pool in stored RBCs; C_LIO_LIATP and hypoxanthine are biomarkers of hemolysis in vitro and in vivo. C_LI