김종헌 (국립암센터, NCC-GCSP)

한빛사논문

조회511

국립암센터, NCC-GCSP

CV File 157 kb

Redox Biol., Available online 6 February 2023 | https://doi.org/10.1016/j.redox.2023.102628 MARS2 drives metabolic switch of non-small-cell lung cancer cells via interaction with MCU

Juhyeon Son ^a,1, Okkeun Jung ^a,1, Jong Heon Kim ^b,c,1, Kyu Sang Park ^d, Hee-Seok Kweon ^e, Nhung Thi Nguyen ^d, Yu Jin Lee^a, Hansol Cha ^a, Yejin Lee ^a, Quangdon Tran ^f, Yoona Seo ^b,c, Jongsun Park ^f, Jungwon Choi ^b, Heesun Cheong ^b, Sang Yeol Lee ^a

^aDepartment of Life Sciences, College of BioNano Technology, Gachon University, Seongnam, Gyeonggi, 13120, South Korea
^bCancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi, 10408, South Korea
^cDepartment of Cancer Biomedical Science, Graduate School of Cancer Sciences and Policy, National Cancer Center, Goyang, Gyeonggi, 10408, South Korea
^dDepartment of Physiology, Yonsei University Wonju College of Medicine, Wonju, Gangwon, 26424, South Korea
^eElectron Microscopy Research Center, Korea Basic Science Institute, Cheongju, Chungbuk, 28119, South Korea
^fDepartment 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

¹These authors contributed equally to this work.
Corresponding author: Sang Yeol Lee

Abstract

Mitochondrial methionyl-tRNA synthetase (MARS2) canonically mediates the formation of fMet-tRNA_i^fMet 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.

논문정보

형식Research article
게재일2023년 02월 (BRIC 등록일 2023-02-20)
연구진국내 연구진
분야 생명과학 > 분자생물학

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