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Although treatment of SCD can include RBC transfusion, patients with SCD have high rates of alloimmunization. We hypothesized that RBCs from patients with SCD have functionally active mitochondria and can elicit a type 1 interferon response. We evaluated blood samples from more than 100 patients with SCD and found elevated frequencies of mitochondria in reticulocytes and mature RBCs, as compared to healthy blood donors. The presence of mitochondria in mature RBCs was confirmed by flow cytometry, electron microscopy, and proteomic analysis. The mitochondria in mature RBCs were metabolically competent, as determined by enzymatic activities and elevated levels of mitochondria\u2010derived metabolites. Metabolically\u2010active mitochondria in RBCs may increase oxidative stress, which could facilitate and\/or exacerbate SCD complications. Coculture of mitochondria\u2010positive RBCs with neutrophils induced production of type 1 interferons, which are known to increase RBC alloimmunization rates. These data demonstrate that mitochondria retained in mature RBCs are functional and can elicit immune responses, suggesting that inappropriate retention of mitochondria in RBCs may play an underappreciated role in SCD complications and be an RBC alloimmunization risk factor.<\/jats:p>","DOI":"10.1111\/bjh.18287","type":"journal-article","created":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T13:15:16Z","timestamp":1654607716000},"page":"574-586","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Retention of functional mitochondria in mature red blood cells from patients with sickle cell disease"],"prefix":"10.1111","volume":"198","author":[{"given":"Chiara","family":"Moriconi","sequence":"first","affiliation":[{"name":"Laboratory of Transfusion Biology, Department of Pathology and Cell Biology Columbia University Irving Medical Center  New York City New York 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