2. Academic Validation
  3. Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation

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

  • Nat Commun. 2025 Jan 2;16(1):212. doi: 10.1038/s41467-024-55768-9.
Yong Yi 1,  Guoqiang Wang 2,  Wenhua Zhang 2,  Shuhan Yu 2 3,  Junjie Fei 2,  Tingting An 2,  Jianqiao Yi 2,  Fengtian Li 4,  Ting Huang 3,  Jian Yang 2,  Mengmeng Niu 2,  Yang Wang 5,  Chuan Xu 6,  Zhi-Xiong Jim Xiao 7 8 9
Affiliations

Affiliations

  • 1 Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China. yy-yiyong@scu.edu.cn.
  • 2 Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.
  • 3 Department of Oncology & Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • 4 School of Biosciences and Technology, Chengdu Medical College, Chengdu, China.
  • 5 Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China. wangy90@scu.edu.cn.
  • 6 Department of Oncology & Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. xuchuan100@163.com.
  • 7 Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China. jimzx@scu.edu.cn.
  • 8 Department of Oncology & Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. jimzx@scu.edu.cn.
  • 9 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. jimzx@scu.edu.cn.
PMID: 39747079 DOI: 10.1038/s41467-024-55768-9
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.

Figures
Products