β2-glycoprotein I promotes the clearance of circulating mitochondria

• Published in: PloS one 2024-01, Vol.19 (1), p.e0293304
• Main Authors: Dasgupta, Swapan Kumar, Gollamudi, Jahnavi, Rivera, Stefanie, Poche, Ross A, Rumbaut, Rolando E, Thiagarajan, Perumal
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Antiphospholipid; Antiphospholipid antibodies; Antiphospholipid Syndrome; Autoimmune diseases; beta 2-Glycoprotein I; Biology and Life Sciences; Blood; Blood circulation; Cardiolipin; Cardiolipins - metabolism; Cytochrome; Glycoprotein I; Glycoproteins; Humans; Life sciences; Macrophages; Macrophages - metabolism; Medicine and Health Sciences; Mice; Mitochondria; Mitochondrial DNA; Monoclonal antibodies; Phagocytosis; Physiology; Polymerase chain reaction; Proteins; Research and Analysis Methods
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0293304

β2-glycoprotein I (β2-Gp1) is a cardiolipin-binding plasma glycoprotein. It is evolutionarily conserved from invertebrates, and cardiolipin-bound β2-Gp1 is a major target of antiphospholipid antibodies seen in autoimmune disorders. Cardiolipin is almost exclusively present in mitochondria, and mitochondria are present in circulating blood. We show that β2-Gp1 binds to cell-free mitochondria (CFM) in the circulation and promotes its phagocytosis by macrophages at physiological plasma concentrations. Exogenous CFM had a short circulation time of less than 10 minutes in mice. Following infusion of CFM, β2-Gp1-deficient mice had significantly higher levels of transfused mitochondria at 5 minutes (9.9 ± 6.4 pg/ml versus 4.0 ± 2.3 pg/ml in wildtype, p = 0.01) and at 10 minutes (3.0 ± 3.6 pg/ml versus 1.0 ± 0.06 pg/ml in wild-type, p = 0.033, n = 10). In addition, the splenic macrophages had less phagocytosed CFM in β2-Gp1-deficient mice (24.4 ± 2.72% versus 35.6 ± 3.5 in wild-type, p = 0.001, n = 5). A patient with abnormal β2-Gp1, unable to bind cardiolipin, has increased CFM in blood (5.09 pg/ml versus 1.26 ± 1.35 in normal) and his plasma induced less phagocytosis of CFM by macrophages (47.3 ± 1.6% versus 54.3 ± 1.3, p = 0.01) compared to normal plasma. These results show the evolutionarily conserved β2-Gp1 is one of the mediators of the clearance of CFM in circulation.