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

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2024 Jul 4

PMID 38964323

Authors

Travis Nemkov

Daniel Stephenson

Eric J Earley

Gregory R Keele

Ariel Hay

Alicia Key

Zachary B Haiman

Christopher Erickson

Monika Dzieciatkowska

Julie A Reisz

Amy Moore

Mars Stone

Xutao Deng

Steven Kleinman

Steven L Spitalnik

Eldad A Hod

Krystalyn E Hudson

Kirk C Hansen

Bernhard O Palsson

Gary A Churchill

Nareg Roubinian

Philip J Norris

Michael P Busch

James C Zimring

Grier P Page

Angelo DAlessandro

Affiliations

Soon will be listed here.

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 blood banks. Here, we leveraged 13,029 volunteers from the Recipient Epidemiology and Donor Evaluation Study to identify associations 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 (HK1); 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 and hypoxanthine (HYPX) 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.

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