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Publications

Journal Article Ppublish 6 citations

PubMed: 39541586 DOI: 10.1182/blood.2024026109

Ferroptosis regulates hemolysis in stored murine and human red blood cells.

Blood 145(7):765-783

Authors: Angelo D'Alessandro, Gregory R Keele, Ariel Hay, Travis Nemkov, Eric J Earley, Daniel Stephenson, Matthew Vincent, Xutao Deng, Mars Stone, Monika Dzieciatkowska, Kirk C Hansen, Steven Kleinman, Steven L Spitalnik, Nareg Roubinian, Philip J Norris, Michael P Busch, Grier P Page, Brent R Stockwell, Gary A Churchill, James C Zimring

Affiliations

  • Department of Biochemistry and Molecular Genetics, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO.
  • Omix Technologies Inc, Aurora, CO.
  • The Jackson Laboratory, Bar Harbor, ME.
  • RTI International, Research Triangle Park, NC.
  • Department of Pathology, Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, VA.
  • Vitalant Research Institute, San Francisco, CA.
  • Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA.
  • Department of Pathology and Laboratory Medicine, University of British Columbia, Victoria, BC, Canada.
  • Columbia University Irving Medical Center, New York, NY.
  • Kaiser Permanente Northern California Division of Research, Oakland, CA.
  • Department of Biological Sciences, Department of Chemistry, and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.

Abstract

Red blood cell (RBC) metabolism regulates hemolysis during aging in vivo and in the blood bank. However, the genetic underpinnings of RBC metabolic heterogeneity and extravascular hemolysis at population scale are incompletely understood. On the basis of the breeding of 8 founder strains with extreme genetic diversity, the Jackson Laboratory diversity outbred population can capture the impact of genetic heterogeneity in like manner to population-based studies. RBCs from 350 outbred mice, either fresh or stored for 7 days, were tested for posttransfusion recovery, as well as metabolomics and lipidomics analyses. Metabolite and lipid quantitative trait loci (QTL) mapped >400 gene-metabolite associations, which we collated into an online interactive portal. Relevant to RBC storage, we identified a QTL hotspot on chromosome 1, mapping on the region coding for the ferrireductase 6-transmembrane epithelial antigen of the prostate 3 (Steap3), a transcriptional target to p53. Steap3 regulated posttransfusion recovery, contributing to a ferroptosis-like process of lipid peroxidation, as validated via genetic manipulation in mice. Translational validation of murine findings in humans, STEAP3 polymorphisms were associated with RBC iron content, lipid peroxidation, and in vitro hemolysis in 13 091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. QTL analyses in humans identified a network of gene products (fatty acid desaturases 1 and 2, epoxide hydrolase 2, lysophosphatidylcholine acetyl-transferase 3, solute carrier family 22 member 16, glucose 6-phosphate dehydrogenase, very long chain fatty acid elongase, and phospholipase A2 group VI) associated with altered levels of oxylipins. These polymorphisms were prevalent in donors of African descent and were linked to allele frequency of hemolysis-linked polymorphisms for Steap3 or p53. These genetic variants were also associated with lower hemoglobin increments in thousands of single-unit transfusion recipients from the vein-to-vein database.

MeSH

Cells, Genes, Hematology, Erythrocytes, Blood, Ferroptosis, Recycling, Genes, P53, Hemolysis, Blood Cells, Veins, Fatty Acids

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