Biological and genetic determinants of glycolysis: Phosphofructokinase isoforms boost energy status of stored red blood cells and transfusion outcomes.

Pubmed ID: 38964323

Pubmed Central ID: PMC11374506

Journal: Cell metabolism

Publication Date: Sept. 3, 2024

MeSH Terms: Humans, Male, Adult, Female, Aged, Middle Aged, Isoenzymes, Blood Transfusion, Animals, Blood Preservation, Hemolysis, Energy Metabolism, Mice, Erythrocytes, Glycolysis, Phosphofructokinases, Adenosine Triphosphate, Hexokinase

Grants: HHSN268201100001C, HHSN268201100001I, R01 HL126130, R01 HL146442, R01 HL161004, R21 HL150032, R01 HL149714, R01 HL133049, 75N92019D00033, R01 HL148151

Authors: Busch MP, Kleinman S, Moore A, Deng X, Norris PJ, Page GP, Spitalnik SL, Hod EA, Reisz JA, Earley EJ, Nemkov T, Key A, Stephenson D, Keele GR, Dzieciatkowska M, Hansen KC, Zimring JC, Churchill GA, D'Alessandro A, Hay A, Haiman ZB, Erickson C, Stone M, Hudson KE, Palsson BO, Roubinian N

Cite As: Nemkov T, Stephenson D, Earley EJ, Keele GR, Hay A, Key A, Haiman ZB, Erickson C, Dzieciatkowska M, Reisz JA, Moore A, Stone M, Deng X, Kleinman S, Spitalnik SL, Hod EA, Hudson KE, Hansen KC, Palsson BO, Churchill GA, Roubinian N, Norris PJ, Busch MP, Zimring JC, Page GP, D'Alessandro A. Biological and genetic determinants of glycolysis: Phosphofructokinase isoforms boost energy status of stored red blood cells and transfusion outcomes. Cell Metab 2024 Sep 3;36(9):1979-1997.e13. Epub 2024 Jul 3.

Studies:

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.