Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation

Yong Yi (), Guoqiang Wang, Wenhua Zhang, Shuhan Yu, Junjie Fei, Tingting An, Jianqiao Yi, Fengtian Li, Ting Huang, Jian Yang, Mengmeng Niu, Yang Wang (), Chuan Xu () and Zhi-Xiong Jim Xiao ()
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Yong Yi: Sichuan University
Guoqiang Wang: Sichuan University
Wenhua Zhang: Sichuan University
Shuhan Yu: Sichuan University
Junjie Fei: Sichuan University
Tingting An: Sichuan University
Jianqiao Yi: Sichuan University
Fengtian Li: Chengdu Medical College
Ting Huang: University of Electronic Science and Technology of China
Jian Yang: Sichuan University
Mengmeng Niu: Sichuan University
Yang Wang: Sichuan University
Chuan Xu: University of Electronic Science and Technology of China
Zhi-Xiong Jim Xiao: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Glucose deprivation, a hallmark of the tumor microenvironment, compels tumor cells to seek alternative energy sources for survival and growth. Here, we show that glucose deprivation upregulates the expression of mitochondrial-cytochrome c oxidase II (MT-CO2), a subunit essential for the respiratory chain complex IV, in facilitating glutaminolysis and sustaining tumor cell survival. Mechanistically, glucose deprivation activates Ras signaling to enhance MT-CO2 transcription and inhibits IGF2BP3, an RNA-binding protein, to stabilize MT-CO2 mRNA. Elevated MT-CO2 increases flavin adenosine dinucleotide (FAD) levels in activating lysine-specific demethylase 1 (LSD1) to epigenetically upregulate JUN transcription, consequently promoting glutaminase-1 (GLS1) and glutaminolysis for tumor cell survival. Furthermore, MT-CO2 is indispensable for oncogenic Ras-induced glutaminolysis and tumor growth, and elevated expression of MT-CO2 is associated with poor prognosis in lung cancer patients. Together, these findings reveal a role for MT-CO2 in adapting to metabolic stress and highlight MT-CO2 as a putative therapeutic target for Ras-driven cancers.

Date: 2025
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DOI: 10.1038/s41467-024-55768-9

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