Genetic regulation of carnitine metabolism controls lipid damage repair and aging RBC hemolysis in vivo and in vitro.

Autor:	Nemkov T; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO.; Omix Technologies Inc, Aurora, CO., Key A; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO., Stephenson D; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO., Earley EJ; Genomics and Translational Research Center, RTI International, Research Triangle Park, NC., Keele GR; Genomics and Translational Research Center, RTI International, Research Triangle Park, NC.; The Jackson Laboratory, Bar Harbor, ME., Hay A; Department of Pathology, University of Virginia, Charlottesville, VA., Amireault P; Université Paris Cité et Université des Antilles, INSERM, Biologie Intégrée du Globule Rouge, Paris, France.; Université Paris Cité, Institut Imagine, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM, Paris, France., Casimir M; Université Paris Cité et Université des Antilles, INSERM, Biologie Intégrée du Globule Rouge, Paris, France.; Université Paris Cité, Institut Imagine, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM, Paris, France., Dussiot M; Université Paris Cité et Université des Antilles, INSERM, Biologie Intégrée du Globule Rouge, Paris, France.; Université Paris Cité, Institut Imagine, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM, Paris, France., Dzieciatkowska M; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO., Reisz JA; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO., Deng X; Vitalant Research Institute, San Francisco, CA., Stone M; Vitalant Research Institute, San Francisco, CA.; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA., Kleinman S; The University of British Columbia, Victoria, BC, Canada., Spitalnik SL; Department of Pathology and Cell Biology, Columbia University, New York, NY., Hansen KC; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO., Norris PJ; Vitalant Research Institute, San Francisco, CA.; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA., Churchill GA; The Jackson Laboratory, Bar Harbor, ME., Busch MP; Vitalant Research Institute, San Francisco, CA.; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA., Roubinian N; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA.; Kaiser Permanente Northern California Division of Research, Oakland, CA., Page GP; Genomics and Translational Research Center, RTI International, Research Triangle Park, NC., Zimring JC; Department of Pathology, University of Virginia, Charlottesville, VA., Arduini A; Department of Research and Development, CoreQuest Sagl, Lugano, Switzerland., D'Alessandro A; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO.; Omix Technologies Inc, Aurora, CO.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Jun 13; Vol. 143 (24), pp. 2517-2533.
DOI:	10.1182/blood.2024023983
Abstrakt:	Abstract: Recent large-scale multiomics studies suggest that genetic factors influence the chemical individuality of donated blood. To examine this concept, we performed metabolomics analyses of 643 blood units from volunteers who donated units of packed red blood cells (RBCs) on 2 separate occasions. These analyses identified carnitine metabolism as the most reproducible pathway across multiple donations from the same donor. We also measured l-carnitine and acyl-carnitines in 13 091 packed RBC units from donors in the Recipient Epidemiology and Donor Evaluation study. Genome-wide association studies against 879 000 polymorphisms identified critical genetic factors contributing to interdonor heterogeneity in end-of-storage carnitine levels, including common nonsynonymous polymorphisms in genes encoding carnitine transporters (SLC22A16, SLC22A5, and SLC16A9); carnitine synthesis (FLVCR1 and MTDH) and metabolism (CPT1A, CPT2, CRAT, and ACSS2), and carnitine-dependent repair of lipids oxidized by ALOX5. Significant associations between genetic polymorphisms on SLC22 transporters and carnitine pools in stored RBCs were validated in 525 Diversity Outbred mice. Donors carrying 2 alleles of the rs12210538 SLC22A16 single-nucleotide polymorphism exhibited the lowest l-carnitine levels, significant elevations of in vitro hemolysis, and the highest degree of vesiculation, accompanied by increases in lipid peroxidation markers. Separation of RBCs by age, via in vivo biotinylation in mice, and Percoll density gradients of human RBCs, showed age-dependent depletions of l-carnitine and acyl-carnitine pools, accompanied by progressive failure of the reacylation process after chemically induced membrane lipid damage. Supplementation of stored murine RBCs with l-carnitine boosted posttransfusion recovery, suggesting this could represent a viable strategy to improve RBC storage quality. (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
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