Red Blood Cell Metabolism In Vivo and In Vitro

Abstract

Red blood cells (RBC) are the most abundant cell in the human body, with a central role in oxygen transport and its delivery to tissues. However, omics technologies recently revealed the unanticipated complexity of the RBC proteome and metabolome, paving the way for a reinterpretation of the mechanisms by which RBC metabolism regulates systems biology beyond oxygen transport. The new data and analytical tools also informed the dissection of the changes that RBCs undergo during refrigerated storage under blood bank conditions, a logistic necessity that makes >100 million units available for life-saving transfusions every year worldwide. In this narrative review, we summarize the last decade of advances in the field of RBC metabolism in vivo and in the blood bank in vitro, a narrative largely influenced by the authors’ own journeys in this field. We hope that this review will stimulate further research in this interesting and medically important area or, at least, serve as a testament to our fascination with this simple, yet complex, cell.

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

“…RBC storage is not only a clinically relevant manipulation of the erythrocyte, but also a form of stress (especially, oxidative stress 12 ) that at least partially recapitulates other biologically-relevant stressors, such as exercise, 39 exposure to drugs (e.g., chemotherapeutic anthracyclines like doxorubicin 40 ), irradiation, or disease (e.g., hemoglobinopathies like sickle cell disease 41 or chronic kidney disease). 3 By leveraging a massive vein-to-vein database, 42 our findings corroborate real-world clinical data generated from decades of studies suggesting a role for ATP levels in the regulation of RBC hemolytic propensity, especially extravascular hemolysis upon transfusion. 43 Similarly, it had been recently reported that hypoxanthine accumulation as a function of adenosine or AMP deaminase activation during storage is a marker of the metabolic storage lesion that predicts extravascular hemolysis in mice and humans.…”

“…Given their lack of de novo protein synthesis capacity, RBCs rely on dynamic metabolic reprogramming in response to environmental stimuli, including hypoxia or oxidant stress (e.g., at altitude or during exercise). 3 For example, small molecule metabolites such as ATP play critical roles in hemoglobin allostery by stabilizing the tense deoxygenated state and promoting oxygen release to tissues. 2 Relevant to biology at large, mitochondria-devoid RBCs represent a simplified model of eukaryotic cell metabolism, a cell type that exclusively relies on glycolysis as the main source of energy for the synthesis of ATP.…”

“…These efforts underlie the foundation of modern day clinical chemistry, especially the focus on inborn errors of metabolism, such as those linked to hemolytic disorders (e.g., pyruvate kinase deficiency or glucose 6-phosphate dehydrogenase deficiency). 3 Despite the importance of metabolism and glycolysis in health and disease, and decades of research on the biochemical determinants of glycolytic fluxes in mammals, 1 the genetic and non-genetic underpinnings of the biochemical heterogeneity in humans and mice are incompletely understood.…”

“… Abstract Glycolysis is a central metabolic pathway in health and disease, 1 an essential one in mature red blood cells (RBCs), which rely on the Embden-Meyerhof-Parnas pathway, i.e., glycolysis, as the sole source of energy generation. 2 During aging in vivo and in vitro under blood bank conditions, 3 the adenosine triphosphate (ATP) generated via glycolysis in mitochondria-devoid mature RBCs is essential for the modulation of oxygen kinetics, 4 deformability 2 and, ultimately, intra- and extra-vascular hemolysis. 3 Here we draw upon a cohort of 13,029 volunteers from the Recipient Epidemiology and Donor Evaluation Study (REDS) to identify biological and genetic traits associated with heterogeneity in glycolytic phenotypes.…”

“…2 During aging in vivo and in vitro under blood bank conditions, 3 the adenosine triphosphate (ATP) generated via glycolysis in mitochondria-devoid mature RBCs is essential for the modulation of oxygen kinetics, 4 deformability 2 and, ultimately, intra- and extra-vascular hemolysis. 3 Here we draw upon a cohort of 13,029 volunteers from the Recipient Epidemiology and Donor Evaluation Study (REDS) to identify biological and genetic traits associated with heterogeneity in glycolytic phenotypes. Age, sex and ethnicity influenced glycolysis, with additional effects due to genetic polymorphisms in regions coding for rate-limiting enzymes of glycolysis, 1 phosphofructokinase 1 (PFKP) and hexokinase 1 (HK1), and for the ADP-ribosyl cyclase CD38.…”