Proteostasis and metabolic dysfunction characterize a subset of storage-induced senescent erythrocytes targeted for posttransfusion clearance
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., CFSEhi) and morphologically normal RBCs (CFSElo), these in vitro aged cells were characterized. Metabolomics analysis identified depletion of energy, lipid-repair, and antioxidant metabolites in CFSEhi RBCs. By redox proteomics, irreversible protein oxidation primarily affected CFSEhi RBCs. By proteomics, 96 proteins, mostly in the proteostasis family, had relocated to CFSEhi RBC membranes. CFSEhi 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 CFSElo RBCs resembled those of short-stored RBCs. CFSEhi 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.
Authors
- Emilie‐Fleur Gautier (ORCID: https://orcid.org/0000-0002-0394-6606)
- Papa Alioune Ndour (ORCID: https://orcid.org/0000-0001-7203-9754)
- Johanna Bruce (ORCID: https://orcid.org/0000-0002-1522-9604)
- Abdoulaye Sissoko (ORCID: https://orcid.org/0000-0002-9986-0494)
- Madeleine Casimir
- Youcef Hadjou
- Micaela Kalani Roy (ORCID: https://orcid.org/0000-0002-1045-6752)
- Pierre Buffet (ORCID: https://orcid.org/0000-0003-4010-929X)
- Aurélie Fricot (ORCID: https://orcid.org/0000-0002-8648-2770)
- S. Peltier (ORCID: https://orcid.org/0000-0002-5520-7346)
- Pascal Amireault (ORCID: https://orcid.org/0000-0002-5562-7586)
- Mickaël Marin (ORCID: https://orcid.org/0000-0002-4094-022X)
- Angelo D’Alessandro (ORCID: https://orcid.org/0000-0002-2258-6490)
- François Paye (ORCID: https://orcid.org/0000-0002-7193-2628)
- Steven L. Spitalnik (ORCID: https://orcid.org/0000-0002-8528-4561)
- Olivier Hermine (ORCID: https://orcid.org/0000-0003-2574-3874)
- Daniel Stephenson (ORCID: https://orcid.org/0000-0002-5698-3400)
- Michaël Dussiot (ORCID: https://orcid.org/0000-0002-6804-1621)
- Sonia Georgeault (ORCID: https://orcid.org/0000-0002-2567-8593)
- Philippe Roingeard (ORCID: https://orcid.org/0000-0001-9131-3341)
- Camille Roussel (ORCID: https://orcid.org/0000-0003-0194-7696)
- Monika Dzieciątkowska (ORCID: https://orcid.org/0000-0002-9947-2520)
- Safi Dokmak (ORCID: https://orcid.org/0000-0002-3335-4388)
- Louise Leblanc
Institutions
- Université de Tours (FR)
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Université Libre de Bruxelles (BE)
- Inserm (FR)
- Université Paris Cité (FR)
- Hôpital Beaujon (FR)
- Sorbonne Université (FR)
- Sorbonne Paris Cité (FR)
- Centre Hospitalier Universitaire de Tours (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hôpital Saint-Antoine (FR)
- Institut Cochin (FR)
- Institut des Maladies Génétiques Imagine (FR)
- University of Colorado Anschutz Medical Campus (US)
- Columbia University (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1172/jci183099
- Citations
- 19
- Primary Topic
- Erythrocyte Function and Pathophysiology
- Type
- article
- Field-Weighted Citation Impact
- 22.12