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    Oxygen and mitochondria dynamics changes coordinate terminal platelet formation

    Team M. Fontenay, D. Bouscary

    Oxygen and mitochondria dynamics changes coordinate terminal platelet formation from human perivascular megakaryocytes

     

    The group headed by Isabelle Dusanter-Fourt and Evelyne Lauret, in the team “normal and pathological hematopoiesis”, in collaboration with Dominique Baruch’s team (U 1140, UFR Pharmacie, Université de Paris), has identified in a recent article in Blood Advances the essential role played by oxygen variations and mitochondria dynamics changes in initiating blood platelet formation from their immediate precursors, the perivascular megakaryocytes.

     

    Blood platelets are essential for controlling hemostasis. They are released by megakaryocytes (MKs) located in the bone marrow lining the external side of sinusoid vessels, upon extension of cytoplasmic protrusions into the lumen of sinusoids. Their number increases in postpulmonary capillaries, suggesting a role for oxygen gradient in the final step of platelet biogenesis (ie, of thrombopoiesis).

     

    In this study, we show that initiation of thrombopoiesis from human mature MKs was enhanced under hyperoxia or during pro-oxidant treatments, whereas antioxidants dampened it. Quenching mitochondrial reactive oxygen species (mtROS) decreased thrombopoiesis, whereas genetically enhancing mtROS increased it. Initial MK deformation, which assess thrombopoiesis onset, correlated with changes in mitochondrial tubular network and ROS levels, and the mitochondrial recruitment of the fission activator Drp1. Inhibiting Drp1-dependent mitochondrial fission of mature MKs by Mdivi-1 favored a tubular mitochondrial network and lowered both mtROS levels and MKs deformation, whereas enhancing Drp1 activity genetically had opposite effects. Reciprocally, quenching mtROS limited mitochondrial fission in round undeformed MKs.

    Legend: An autoamplification loop links mitochondrial dynamics and ROS production to onset of thrombopoiesis from mature megakaryocytes.

    Onset of thrombopoiesis from mature round MKs occurs when a positive oxygen gradient is present between the extravascular edge of the sinusoids, where the MKs are located, and the blood flow. It is characterized by cell deformation (loss of MK roundness) and cytoskeletal reorganization (loss of MLC phosphorylation) of intermediate MKs, followed by the formation of extended cell protrusions resulting in terminal proplatelet-forming MKs. This loss of roundness is preceded by a strong recruitment of active pDrp1 to mitochondria that triggers fission within nondeformed, round MKs. Initial mitochondrial fission and ROS production are triggered by the positive oxygen gradient, which favors additional mitochondrial pDrp1 recruitment, additional fission, and ROS production in an autoamplifying loop that is necessary for thrombopoiesis to proceed, allowing for the formation of long intravascular proplatelet extensions filled with small, well-delineated mitochondria in terminal MKs.

     

     

     

     These data demonstrate a functional coupling between ROS and mitochondrial fission in MKs, which is crucial for the onset of thrombopoiesis. They provide new molecular cues that control initiation of platelet biogenesis and may help elucidate some unexplained thrombocytopenia.

     

    Reference

    Poirault-Chassac S, Nivet-Antoine V, Houvert A, et al. Mitochondrial dynamics and reactive oxygen species initiate thrombopoiesis from mature megakaryocytes. Blood Adv. 2021;5(6):1706-1718. doi:10.1182/bloodadvances.2020002847

     

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