MARS2 drives metabolic switch of non-small-cell lung cancer cells via interaction with MCUopen access
- Authors
- Son, Juhyeon; Jung, Okkeun; Kim, Jong Heon; Park, Kyu Sang; Kweon, Hee-Seok; Nguyen, Nhung Thi; Lee, Yu Jin; Cha, Hansol; Lee, Yejin; Tran, Quangdon; Seo, Yoona; Park, Jongsun; Choi, Jungwon; Cheong, Heesun; Lee, Sang Yeol
- Issue Date
- Apr-2023
- Publisher
- ELSEVIER
- Keywords
- Mitochondrial methionyl-tRNA synthetase; Mitochondrial calcium uniporter; Cancer metabolism; p53; Reactive oxygen species; Epithelial-mesenchymal transition
- Citation
- REDOX BIOLOGY, v.60
- Journal Title
- REDOX BIOLOGY
- Volume
- 60
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/87154
- DOI
- 10.1016/j.redox.2023.102628
- ISSN
- 2213-2317
- 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 inter-action. 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 mecha-nisms of mitochondrial Ca2+ uptake and metabolic control of cancer that are exerted by the key factors of the mitochondrial translational machinery and Ca2+ homeostasis.
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