Genetic regulation of carnitine metabolism controls lipid damage repair and aging RBC hemolysis in vivo and in vitro.
Document Type
Article
Publication Date
6-13-2024
Original Citation
Nemkov T,
Key A,
Stephenson D,
Earley E,
Keele G,
Hay A,
Amireault P,
Casimir M,
Dussiot M,
Dzieciatkowska M,
Reisz J,
Deng X,
Stone M,
Kleinman S,
Spitalnik S,
Hansen K,
Norris P,
Churchill G,
Busch M,
Roubinian N,
Page G,
Zimring J,
Arduini A,
D'Alessandro A.
Genetic regulation of carnitine metabolism controls lipid damage repair and aging RBC hemolysis in vivo and in vitro. Blood. 2024;143(24):2517-33.
Keywords
JMG, Carnitine, Humans, Animals, Hemolysis, Mice, Erythrocytes, Polymorphism, Single Nucleotide, Erythrocyte Aging, Genome-Wide Association Study, Male, Female, Solute Carrier Family 22 Member 5, Blood Preservation
JAX Source
Blood. 2024;143(24):2517-33.
ISSN
1528-0020
PMID
38513237
DOI
https://doi.org/10.1182/blood.2024023983
Grant
G.R.K. and G.A.C. were sup- ported by grants from the NIH, National Institute of General Medical Sciences (F32GM124599 and R01GM067945, respectively).
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.