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

doi:10.1016/j.redox.2023.102628

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

Physiology

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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.

Original language	English
Article number	102628
Journal	Redox Biology
Volume	60
DOIs	https://doi.org/10.1016/j.redox.2023.102628
Publication status	Published - 2023 Apr

Bibliographical note

Publisher Copyright:
© 2023 The Authors

All Science Journal Classification (ASJC) codes

Organic Chemistry

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.redox.2023.102628

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

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",

author = "Juhyeon Son and Okkeun Jung and Kim, {Jong Heon} and Park, {Kyu Sang} and Kweon, {Hee Seok} and Nguyen, {Nhung Thi} and Lee, {Yu Jin} and Hansol Cha and Yejin Lee and Quangdon Tran and Yoona Seo and Jongsun Park and Jungwon Choi and Heesun Cheong and Lee, {Sang Yeol}",

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year = "2023",

month = apr,

doi = "10.1016/j.redox.2023.102628",

language = "English",

volume = "60",

journal = "Redox Biology",

issn = "2213-2317",

publisher = "Elsevier B.V.",

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TY - JOUR

T1 - MARS2 drives metabolic switch of non-small-cell lung cancer cells via interaction with MCU

AU - Son, Juhyeon

AU - Jung, Okkeun

AU - Kim, Jong Heon

AU - Park, Kyu Sang

AU - Kweon, Hee Seok

AU - Nguyen, Nhung Thi

AU - Lee, Yu Jin

AU - Cha, Hansol

AU - Lee, Yejin

AU - Tran, Quangdon

AU - Seo, Yoona

AU - Park, Jongsun

AU - Choi, Jungwon

AU - Cheong, Heesun

AU - Lee, Sang Yeol

PY - 2023/4

Y1 - 2023/4

N2 - 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.

AB - 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.

KW - Cancer metabolism

KW - Epithelial-mesenchymal transition

KW - Mitochondrial calcium uniporter

KW - Mitochondrial methionyl-tRNA synthetase

KW - Reactive oxygen species

KW - p53

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SN - 2213-2317

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M1 - 102628

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

Abstract

Bibliographical note

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UN SDGs

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