Akt-mediated mitochondrial metabolism regulates proplatelet formation and platelet shedding post vasopressin exposure

Background: Platelet shedding from mature megakaryocytes (MKs) in thrombopoiesis is the critical step for elevating circulating platelets fast and efficiently, however, the under-lying mechanism is still not well-illustrated, and the therapeutic targets and candidates are even less.Objectives: In order to investigate the mechanisms for platelet shedding after vaso-pressin treatment and find new therapeutic targets for thrombocytopenia.Methods: Platelet production was evaluated both in vivo and in vitro after arginine vaso-pressin (AVP) administration. The underlying biological mechanism of AVP-triggered thrombopoiesis were then investigated by a series of molecular and bioinformatics techniques. Results: it is observed that proplatelet formation and platelet shedding in the final stages of thrombopoiesis promoted by AVP, an endogenous hormone, can quickly in-creases peripheral platelets. This rapid elevation is thus able to speed up platelet re-covery after radiation as expected. The mechanism analysis reveal that proplatelet formation and platelet release from mature MKs facilitated by AVP is mainly mediated by Akt-regulated mitochondrial metabolism. In particular, phosphorylated Akt regu-lates mitochondrial metabolism through driving the association of hexokinase-2 with mitochondrial voltage dependent anion channel-1 in AVP-mediated thrombopoiesis. Further studies suggest that this interaction is stabilized by I & kappa;B & alpha;, the expression of which is controlled by insulin-regulated membrane aminopeptidase. Conclusion: these data demonstrate that phosphorylated Akt-mediated mitochondrial metabolism regulates platelet shedding from MKs in response to AVP, which will provide new therapeutic targets and further drug discovery clues for thrombocytopenia treatment.

Automated summary

Platelet shedding from mature megakaryocytes is crucial for increasing circulating platelets rapidly, and this study investigates the mechanisms behind it and identifies new therapeutic targets for thrombocytopenia.