Megakaryocyte (MK) maturation and platelet generation need a translation. However, it was uncertain how the translational pathways are controlled in this process. In the study, researchers discovered that MK/platelet–specific lactate dehydrogenase A (LdhA) had more platelets, and MK maturation and proplatelet production were significantly accelerated.
The impact of LDHA on MK maturation and platelet production was not dependent on lactate concentration, which is LDHA’s primary product. LDHA interacts with eukaryotic elongation factor 2 (eEF2) in the cytoplasm, influencing eEF2’s role in ribosome translation, according to mechanism studies.
Furthermore, nicotinamide adenine dinucleotide (NADH), a cofactor of LDHA, was required for the interaction between LDHA with eEF2. In vitro, NADH-competitive LDHA inhibitors might liberate eEF2 from the LDHA pool, increase translation, and improve MK maturation. Stiripentol, an LDHA inhibitor, dramatically increased platelet production in vivo in a healthy condition and in an immune thrombocytopenia paradigm. Stiripentol may also have a synergistic impact with romiplostim, promoting platelet formation from MKs generated from human cord blood mononuclear cells. In summary, the research revealed a unique nonclassical role of LDHA in translation that might be used to treat thrombocytopenia.
