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

Mature red blood cells (RBCs) lack mitochondria, and thus exclusively rely on glycolysis to generate adenosine triphosphate (ATP) during aging in vivo and during storage in vitro in the blood bank. Here we identify an association between blood donor age, sex, ethnicity and end-of-storage levels of glycolytic metabolites in 13,029 volunteers from the Recipient Epidemiology and Donor Evaluation Study. Associations were also observed to ancestry-specific genetic polymorphisms in regions encoding phosphofructokinase 1, platelet (which we detected in mature RBCs), hexokinase 1, and 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 levels, breakdown, and deamination into hypoxanthine 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. Highlights ![Figure][1] ### Competing Interest Statement The authors declare that AD, KCH, TN are founders of Omix Technologies Inc and Altis Biosciences LLC. AD, SLS and TN are Scientific Advisory Board (SAB) members for Hemanext Inc. AD is SAB member for Macopharma Inc. SLS is an SAB member for Alcor, Inc, a consultant for Team Conveyer Intellectual Properties, executive director for Worldwide Initiative for Rh Disease Eradication (WIRhE), and CEO for Ferrous Wheel Consultants, LLC. JCZ is a founder of Svalinn Therapeutics. All the other authors have no conflicts to disclose in relation to this study. [1]: pending:yes