MARS2 drives metabolic switch of non-small-cell lung cancer cells via interaction with MCU
Juhyeon Son,
Okkeun Jung,
Jong Heon Kim,
Kyu Sang Park,
Hee-Seok Kweon,
Nhung Thi Nguyen,
Yu Jin Lee,
Hansol Cha,
Yejin Lee,
Quangdon Tran,
Yoona Seo,
Jongsun Park,
Jungwon Choi,
Heesun Cheong,
Sang Yeol Lee
Affiliations
Juhyeon Son
Department of Life Sciences, College of BioNano Technology, Gachon University, Seongnam, Gyeonggi, 13120, South Korea
Okkeun Jung
Department of Life Sciences, College of BioNano Technology, Gachon University, Seongnam, Gyeonggi, 13120, South Korea
Jong Heon Kim
Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi, 10408, South Korea; Department of Cancer Biomedical Science, Graduate School of Cancer Sciences and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, South Korea
Kyu Sang Park
Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Gangwon, 26424, South Korea
Hee-Seok Kweon
Electron Microscopy Research Center, Korea Basic Science Institute, Cheongju, Chungbuk, 28119, South Korea
Nhung Thi Nguyen
Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Gangwon, 26424, South Korea
Yu Jin Lee
Department of Life Sciences, College of BioNano Technology, Gachon University, Seongnam, Gyeonggi, 13120, South Korea
Hansol Cha
Department of Life Sciences, College of BioNano Technology, Gachon University, Seongnam, Gyeonggi, 13120, South Korea
Yejin Lee
Department of Life Sciences, College of BioNano Technology, Gachon University, Seongnam, Gyeonggi, 13120, South Korea
Quangdon Tran
Department of Pharmacology and Medical Sciences, Metabolic Syndrom and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea
Yoona Seo
Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi, 10408, South Korea; Department of Cancer Biomedical Science, Graduate School of Cancer Sciences and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, South Korea
Jongsun Park
Department of Pharmacology and Medical Sciences, Metabolic Syndrom and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea
Jungwon Choi
Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi, 10408, South Korea
Heesun Cheong
Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi, 10408, South Korea
Sang Yeol Lee
Department of Life Sciences, College of BioNano Technology, Gachon University, Seongnam, Gyeonggi, 13120, South Korea; Corresponding author.
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.
