Linezolid impair proplatelet formation by reducing mitochondrial energy metabolism in MEG-01 cells.

BACKGROUND

Thrombocytopenia is a common adverse side effects of Linezolid (LZD) but the underlying mechanism remains unclear. This study aimed to analyze the mechanism of LZD induced thrombocytopenia for LZD induced thrombocytopenia.

METHODS

Cells proliferation, proplatelet formation assay and platelet production were evaluated in human megakaryoblastic leukemia cell line MEG-01 or C57BL/6 mice following LZD administration. The metabolic profiles and gene expression of MEG-01 cells was subsequently analyzed using molecular and bioinformatics techniques.

RESULTS

LZD induced a dose- and time-dependent decrease in cells proliferation and inhibited proplatelet formation. It alters metabolic pathways including central carbon metabolism as indicated by a decrease in pyruvate, ATP and GTP levels (P < 0.01). Expression of genes related to energy production and conversion and the cytoskeleton were altered, such as SLC25A21, HBB, PRR5, MYL4 and RHoE (P < 0.01). Pyruvate supplementation rescued reduced metabolites induced by LZD, increased proplatelet formation of MEG-01 cells and length of pseudopod (P < 0.05). Furthermore, pyruvate rescued the counts of megakaryocytes in bone marrow and peripheral platelets in LZD treated mice (P < 0.05).

CONCLUSION

LZD inhibits mitochondrial energy metabolism, resulting in proplatelet formation reduction. Pyruvate reverses LZD induced thrombocytopenia, which provide a basis for mechanistic insights of LZD induced thrombocytopenia.