Pyruvate is an essential fuel for maintaining the tricarboxylic acid(TCA)cycle in the mitochondria.However,the precise mole-cular mechanism of pyruvate uptake by mitochondrial pyruvate carrier(MPC)is largely unknown.H...Pyruvate is an essential fuel for maintaining the tricarboxylic acid(TCA)cycle in the mitochondria.However,the precise mole-cular mechanism of pyruvate uptake by mitochondrial pyruvate carrier(MPC)is largely unknown.Here,we report that the DNA/RNA-binding protein Y-box binding protein 1(YBX1)is localized to the mitochondrial inter-membrane space by its C-terminal domain(CTD)in cancer cells.In mitochondria,YBX1 inhibits pyruvate uptake by associating with MPC1/2,thereby suppressing pyruvate-dependent TCA cycle flux.This association,in turn,promotes MPC-mediated glutaminolysis and histone lactylation.Our findings reveal that the YBX1-MPC axis exhibits a positive correlation with metastatic potential,while does not affect cell proliferation in both cultured cells and tumor xenografts.Therefore,the restricted pyruvate uptake into mitochondria potentially represents a hallmark of metastatic capacity,suggesting that the YBX1-MPC axis is a therapeutic target for combating cancer metastasis.展开更多
基金This study was supported by the National Key Research and Development Program of China(2022YFA0806503)grants from the National Natural Science Foundation of China(No.81972625,No.21907093)+1 种基金Dalian Science and Technology Innovation Funding(2019J12SN52)Liaoning Revitalization Talents Program(XLYC2002035).
文摘Pyruvate is an essential fuel for maintaining the tricarboxylic acid(TCA)cycle in the mitochondria.However,the precise mole-cular mechanism of pyruvate uptake by mitochondrial pyruvate carrier(MPC)is largely unknown.Here,we report that the DNA/RNA-binding protein Y-box binding protein 1(YBX1)is localized to the mitochondrial inter-membrane space by its C-terminal domain(CTD)in cancer cells.In mitochondria,YBX1 inhibits pyruvate uptake by associating with MPC1/2,thereby suppressing pyruvate-dependent TCA cycle flux.This association,in turn,promotes MPC-mediated glutaminolysis and histone lactylation.Our findings reveal that the YBX1-MPC axis exhibits a positive correlation with metastatic potential,while does not affect cell proliferation in both cultured cells and tumor xenografts.Therefore,the restricted pyruvate uptake into mitochondria potentially represents a hallmark of metastatic capacity,suggesting that the YBX1-MPC axis is a therapeutic target for combating cancer metastasis.
