Mitochondrial gene expression is required for platelet function and blood clotting
Tara R. Richman,
Judith A. Ermer,
Jessica Baker,
Stefan J. Siira,
Benjamin T. Kile,
Matthew D. Linden,
Oliver Rackham,
Aleksandra Filipovska
Affiliations
Tara R. Richman
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia; ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Nedlands, WA 6009, Australia; Centre for Medical Research, The University of Western Australia, QEII Medical Centre, Nedlands, WA 6009, Australia; Telethon Kids Institute, Northern Entrance, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands, WA, Australia
Judith A. Ermer
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia; ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Nedlands, WA 6009, Australia; Centre for Medical Research, The University of Western Australia, QEII Medical Centre, Nedlands, WA 6009, Australia
Jessica Baker
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia; ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Nedlands, WA 6009, Australia; Centre for Medical Research, The University of Western Australia, QEII Medical Centre, Nedlands, WA 6009, Australia; Telethon Kids Institute, Northern Entrance, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands, WA, Australia
Stefan J. Siira
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia; ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Nedlands, WA 6009, Australia; Centre for Medical Research, The University of Western Australia, QEII Medical Centre, Nedlands, WA 6009, Australia; Telethon Kids Institute, Northern Entrance, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands, WA, Australia
Benjamin T. Kile
Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
Matthew D. Linden
Pathology and Laboratory Science, The University of Western Australia, Perth, WA, Australia
Oliver Rackham
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia; ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Nedlands, WA 6009, Australia; Telethon Kids Institute, Northern Entrance, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands, WA, Australia; Curtin Medical School, Curtin University, Bentley, WA 6102, Australia; Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
Aleksandra Filipovska
ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Nedlands, WA 6009, Australia; Telethon Kids Institute, Northern Entrance, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands, WA, Australia; Corresponding author
Summary: Platelets are anucleate blood cells that contain mitochondria and regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery that relies on nuclear-encoded factors for the biogenesis of the oxidative phosphorylation system to produce energy required for thrombosis. The autonomy of the mitochondrial gene expression machinery from the nucleus is unclear, and platelets provide a valuable model to understand its importance in anucleate cells. Here, we conditionally delete Elac2, Ptcd1, or Mtif3 in platelets, which are essential for mitochondrial gene expression at the level of RNA processing, stability, or translation, respectively. Loss of ELAC2, PTCD1, or MTIF3 leads to increased megakaryocyte ploidy, elevated circulating levels of reticulated platelets, thrombocytopenia, and consequent extended bleeding time. Impaired mitochondrial gene expression reduces agonist-induced platelet activation. Transcriptomic and proteomic analyses show that mitochondrial gene expression is required for fibrinolysis, hemostasis, and blood coagulation in response to injury.
