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ResearchIn-Press PreviewCell biologyHematology Open Access | 10.1172/JCI183099

Proteostasis and metabolic dysfunction characterize a subset of storage-induced senescent erythrocytes targeted for post-transfusion clearance

Sandy Peltier,1 Mickaël Marin,1 Monika Dzieciatkowska,2 Michaël Dussiot,3 Micaela Kalani Roy,2 Johanna Bruce,4 Louise Leblanc,1 Youcef Hadjou,1 Sonia Georgeault,5 Aurélie Fricot,1 Camille Roussel,1 Daniel Stephenson,2 Madeleine Casimir,3 Abdoulaye Sissoko,1 François Paye,6 Safi Dokmak,7 Papa Alioune Ndour,1 Philippe Roingeard,5 Emilie-Fleur Gautier,4 Steven L. Spitalnik,8 Olivier Hermine,3 Pierre A. Buffet,1 Angelo D’Alessandro,2 and Pascal Amireault1

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Peltier, S. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Marin, M. in: JCI | PubMed | Google Scholar |

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Dzieciatkowska, M. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Dussiot, M. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Roy, M. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Bruce, J. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Leblanc, L. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Hadjou, Y. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Georgeault, S. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Fricot, A. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Roussel, C. in: JCI | PubMed | Google Scholar |

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Stephenson, D. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Casimir, M. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Sissoko, A. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Paye, F. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Dokmak, S. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Ndour, P. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Roingeard, P. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Gautier, E. in: JCI | PubMed | Google Scholar |

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Spitalnik, S. in: JCI | PubMed | Google Scholar |

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Hermine, O. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Buffet, P. in: JCI | PubMed | Google Scholar

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by D’Alessandro, A. in: JCI | PubMed | Google Scholar |

1INSERM, BIGR, Université Paris Cité, Paris, France

2Department of Molecular Genetics and Biochemistry, University of Colorado Denver – Anschutz Medical Campus, Aurora, United States of America

3Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders , Imagine Institute, Université Paris Cité, Paris, France

4Proteom’IC facility, Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

5Plateforme des Microscopies, Infrastructures de Recherche en Biologie Santé et Agronomie, Tours, France

6Department of Digestive Surgery, Hôpital Saint Antoine, Paris, France

7Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Clichy, France

8Department of Pathology and Cell Biology, Columbia University, New York, United States of America

Find articles by Amireault, P. in: JCI | PubMed | Google Scholar |

Published March 11, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI183099.
Copyright © 2025, Peltier et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 11, 2025 - Version history
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Abstract

Although refrigerated storage slows the metabolism of volunteer donor RBCs, which is essential in transfusion medicine, cellular aging still occurs throughout this in vitro process. Storage-induced microerythrocytes (SMEs) are morphologically-altered senescent RBCs that accumulate during storage and are cleared from circulation following transfusion. However, the molecular and cellular alterations that trigger clearance of this RBC subset remain to be identified. Using a staining protocol that sorts long-stored SMEs (i.e., CFSEhigh) and morphologically-normal RBCs (CFSElow), these in vitro aged cells were characterized. Metabolomics analysis identified depletion of energy, lipid-repair, and antioxidant metabolites in CFSEhigh RBCs. By redox proteomics, irreversible protein oxidation primarily affected CFSEhigh RBCs. By proteomics, 96 proteins, mostly in the proteostasis family, had relocated to CFSEhigh RBC membranes. CFSEhigh RBCs exhibited decreased proteasome activity and deformability; increased phosphatidylserine exposure, osmotic fragility, and endothelial cell adherence; and were cleared from the circulation during human spleen perfusion ex vivo. Conversely, molecular, cellular, and circulatory properties of long-stored CFSElow RBCs resembled those of short-stored RBCs. CFSEhigh RBCs are morphologically and metabolically altered, have irreversibly oxidized and membrane-relocated proteins, and exhibit decreased proteasome activity. In vitro aging during storage selectively alters metabolism and proteostasis in these storage-induced senescent RBCs targeted for clearance.

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