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

Redox Biol. 2023 Apr:60:102628. doi: 10.1016/j.redox.2023.102628. Epub 2023 Feb 6.

Abstract

Mitochondrial methionyl-tRNA synthetase (MARS2) canonically mediates the formation of fMet-tRNAifMet for mitochondrial translation initiation. Mitochondrial calcium uniporter (MCU) is a major gate of Ca2+ flux from cytosol into the mitochondrial matrix. We found that MARS2 interacts with MCU and stimulates mitochondrial Ca2+ influx. Methionine binding to MARS2 would act as a molecular switch that regulates MARS2-MCU interaction. Endogenous knockdown of MARS2 attenuates mitochondrial Ca2+ influx and induces p53 upregulation through the Ca2+-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 Ca2+ uptake and metabolic control of cancer that are exerted by the key factors of the mitochondrial translational machinery and Ca2+ homeostasis.

Keywords: Cancer metabolism; Epithelial-mesenchymal transition; Mitochondrial calcium uniporter; Mitochondrial methionyl-tRNA synthetase; Reactive oxygen species; p53.

MeSH terms

  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Methionine-tRNA Ligase / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism

Substances

  • Calcium
  • Calcium Channels
  • mitochondrial calcium uniporter
  • Methionine-tRNA Ligase