Contributors: Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM); Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB Université de Savoie Université de Chambéry ); Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex); Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); ERYTECH Pharma; LEHNA - Laboratoire d'Ecologie des Hydrosystèmes Naturels et Anthropisés équipe E2C (LEHNA E2C); Laboratoire d'Ecologie des Hydrosystèmes Naturels et Anthropisés (LEHNA); Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE)-Centre National de la Recherche Scientifique (CNRS); Institut Pluridisciplinaire Hubert Curien (IPHC); Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS); Hémostase & thrombose; Université de Lyon-Université de Lyon; Laboratoire de Biochimie et de Biologie Moléculaire; Centre Hospitalier Universitaire Strasbourg (CHU Strasbourg); Les Hôpitaux Universitaires de Strasbourg (HUS)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Hôpital de Hautepierre Strasbourg; Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory; University of Amsterdam Amsterdam = Universiteit van Amsterdam (UvA); Institut d’Hématologique et d’Oncologique Pédiatrique; Hospices Civils de Lyon, Lyon, France; Service de Médecine Interne Hôpital Edouard Herriot - HCL; Hôpital Edouard Herriot CHU - HCL; Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL); Université de Paris, UMR_S1134, BIGR, Inserm, F-75015 Paris, France; Institut National de la transfusion sanguine, F-75015 Paris, France.; ANR-11-LABX-0051,GR-Ex,Biogenèse et pathologies du globule rouge(2011)
Abstract: International audience ; Abnormal retention of mitochondria in mature red blood cells (RBC) has been recently reported in sickle cell anemia (SCA) but their functionality and their role in the pathophysiology of SCA remain unknown. The presence of mitochondria within RBC was determined by flow cytometry in 61 SCA patients and ten healthy donors. Patients were classified according to the percentage of mature RBC with mitochondria contained in the whole RBC population: low (0-4%), moderate (>4% and <8%), or high level (>8%). RBC rheological, hematological, senescence and oxidative stress markers were compared between the three groups. RBC senescence and oxidative stress markers were also compared between mature RBC containing mitochondria and those without. The functionality of residual mitochondria in sickle RBC was measured by high-resolution respirometry assay and showed detectable mitochondrial oxygen consumption in sickle mature RBC but not in healthy RBC. Increased levels of mitochondrial reactive oxygen species were observed in mature sickle RBC when incubated with Antimycin A versus without. In addition, mature RBC retaining mitochondria exhibited greater levels of reactive oxygen species compared to RBC without mitochondria, as well as greater Ca2+, lower CD47 and greater phosphatidylserine exposure. Hematocrit and RBC deformability were lower, and the propensity of RBC to sickle under deoxygenation was higher, in the SCA group with a high percentage of mitochondria retention in mature RBC. This study showed the presence of functional mitochondria in mature sickle RBC, which could favor RBC sickling and accelerate RBC senescence, leading to increased cellular fragility and hemolysis.
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