MARS2 drives metabolic switch of non-small-cell lung cancer cells via interaction with MCU.

Mitochondrial methionyl-tRNA synthetase (MARS2) canonically mediates the formation of fMet-tRNA for mitochondrial translation initiation. Mitochondrial calcium uniporter (MCU) is a major gate of Ca flux from cytosol into the mitochondrial matrix. We found that MARS2 interacts with MCU and stimulates mitochondrial Ca influx. Methionine binding to MARS2 would act as a molecular switch that regulates MARS2-MCU interaction. Endogenous knockdown of MARS2 attenuates mitochondrial Ca influx and induces p53 upregulation through the Ca-dependent CaMKII/CREB signaling. Subsequently, metabolic rewiring from glycolysis into pentose phosphate pathway is triggered and cellular reactive oxygen species level decreases. This metabolic switch induces inhibition of epithelial-mesenchymal transition (EMT) via cellular redox regulation. Expression of MARS2 is regulated by ZEB1 transcription factor in response to Wnt signaling. Our results suggest the mechanisms of mitochondrial Ca uptake and metabolic control of cancer that are exerted by the key factors of the mitochondrial translational machinery and Ca homeostasis.