Inhibition of LDHA to induce eEF2 release enhances thrombocytopoiesis

Translation is essential for megakaryocyte (MK) maturation and platelet production. However, how the translational pathways are regulated in this process remains unknown. In this study, we found that megakaryocyte/platelet-specific lactate dehydrogenase A (LdhA)-knockout mice showed an increased number of platelets with remarkably accelerated MK maturation and proplatelet formation. Interestingly, the role of LDHA in MK maturation and platelet formation did not depend on lactate content, which was the major product of LDHA. Mechanism studies revealed that LDHA interacted with eukaryotic elongation factor 2 (eEF2) in the cytoplasm, controlling the participation of eEF2 in translation at the ribosome. Furthermore, the interaction of LDHA and eEF2 was dependent on NADH, a coenzyme of LDHA. NADH-competitive inhibitors of LDHA could release eEF2 from the LDHA pool, up-regulate translation and enhance MK maturation in vitro. Among LDHA inhibitors, stiripentol significantly promoted the production of platelets in vivo under physiological state and in the immune thrombocytopenia model. Moreover, stiripentol could promote platelet production from human cord blood mononuclear cells (CBMCs)-derived megakaryocytes, and also have a superposed effect with romiplostim. In short, this study reveals a novel non-classical function of LDHA in translation and may serve as a potential target for thrombocytopenia therapy.