Mitochondrial gene expression is required for platelet function and blood clotting

Platelets are anucleate blood cells that contain mitochondria, that regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery which relies on nuclear encoded factors for the biogenesis of the oxidative phosphorylation (OXPHOS) system to produce energy, ions and metabolites required for thrombosis. The autonomy of the mitochondrial gene expression machinery from the nucleus is not known and platelets provide a valuable model to understand the importance of mitochondrial gene expression in anucleate cells. We generated three different platelet-specific conditional knockout mouse models, each lacking a gene that is essential for mitochondrial gene expression at the level of RNA processing, stability and translation (Elac2Pf4?/Pf4?, Ptcd1Pf4?/Pf4 and Mtif3Pf4?/Pf4?). Loss of ELAC2, PTCD1 or MTIF3, leads to increased megakaryocyte ploidy, elevated circulating levels of reticulated platelets, thrombocytopenia and consequent extended bleeding time. Loss of ELAC2, PTCD1 and MTIF3 reduced agonist induced platelet activation. Transcriptomic and proteomic analyses showed that mitochondrial gene expression and protein synthesis facilitate fibrinolysis, haemostasis and blood coagulation in response to injury. Overall design: RNA sequencing and differential gene expression performed on megakaryocytes, resting platelets and activated platelets in PTCD1, MTIF3 and ELAC2 knockout and wild type mice.