Thrombosis research · 2025
Linezolid impair proplatelet formation by reducing mitochondrial energy metabolism in MEG-01 cells.
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Yang Ya, Wang Ning, Xiong Lirong, Fu Peishu, Tian Yanping, Luo Shenglin, Sun Fengjun, Xia Peiyuan
Аннотация
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.
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.