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other·preclinical research, biomedical research, oncology, research methods·PMC10283060

Mitochondrial supercomplex assembly regulates metabolic features and glutamine dependency in mammalian cells

Theranostics · 20 authors, 5 centres

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TL;DR

This preclinical study used CRISPR knockout of the COX7A2L gene in human and mouse cell lines to show that mitochondrial supercomplex assembly controls electron flux and metabolic preference. The central finding was that loss of COX7A2L increased Complex II-dependent respiration and promoted glutamine utilization for proliferation.

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This disruption increased electron flux through Complex II, as evidenced by upregulated Complex II-dependent respiration without affecting its intrinsic activity. Metabolically, this shift led to a decreased succinate/fumarate ratio and promoted a dependency on glutamine to fuel the TCA cycle, which was linked to cell proliferation.

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other

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preclinical research

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ORIGINAL PAPER

PMC10283060

Mitochondrial supercomplex assembly regulates metabolic features and glutamine dependency in mammalian cells

Theranostics

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ABSTRACT

Abstract Rationale: Mitochondria generate ATP via the oxidative phosphorylation system, which mainly comprises five respiratory complexes found in the inner mitochondrial membrane. A high-order assembly of respiratory complexes is called a supercomplex. COX7A2L is a supercomplex assembly factor that has been well-investigated for studying supercomplex function and assembly. To date, the effects of mitochondrial supercomplexes on cell metabolism have not been elucidated. Methods: We depleted COX7A2L or Cox7a2l in human and mouse cells to generate cell models lacking mitochondrial supercomplexes as well as in DBA/2J mice as animal models. We tested the effect of impaired supercomplex assembly on cell proliferation with different nutrient supply. We profiled the metabolic features in COX7A2L -/- cells and Cox7a2l -/- mice via the combined use of targeted and untargeted metabolic profiling and metabolic flux analysis. We further tested the role of mitochondrial supercomplexes in pancreatic ductal adenocarcinoma (PDAC) through PDAC cell lines and a nude mouse model. Results: Impairing mitochondrial supercomplex assembly by depleting COX7A2L in human cells reprogrammed metabolic pathways toward anabolism and increased glutamine metabolism, cell proliferation and antioxidative defense. Similarly, knockout of Cox7a2l in DBA/2J mice promoted the use of proteins/amino acids as oxidative carbon sources. Mechanistically, impaired supercomplex assembly increased electron flux from CII to CIII/CIV and promoted CII-dependent respiration in COX7A2L -/- cells which further upregulated glutaminolysis and glutamine oxidation to accelerate the reactions of the tricarboxylic acid cycle. Moreover, the proliferation of PDAC cells lacking COX7A2L was inhibited by glutamine deprivation. Conclusion: Our results reveal the regulatory role of mitochondrial supercomplexes in glutaminolysis which may fine-tune the fate of cells with different nutrient availability. Keywords: SCAF1, COX7A2L, mitochondrial supercomplex, metabolism, PDAC

CITATION EXPORT

Kun Zhang, Linjie Chen, Bo Wang et al.. Mitochondrial supercomplex assembly regulates metabolic features and glutamine dependency in mammalian cells. Theranostics. (2023). https://doi.org/10.7150/thno.78292

AUTHORS

20 · 5 CENTRES

Kun Zhang, Linjie Chen, Bo Wang, Deyu Chen, Xianglai Ye, Xinyu Han, Quan Fang, Can Yu, Jia Wu, Sihan Guo, Lifang Chen, Yu Shi, Lan Wang, Huang Cheng, Hao Li, Lu Shen, Qiongya Zhao, Liqin Jin, Jianxin Lyu, Hezhi Fang

1Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Cell Biology and Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325035, China.
2Department of Clinical Laboratory, Xi'an Daxing Hospital, Xi'an 710016, China.
3Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310000, China.
4School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou 310053, China.
5Key Laboratory of Biomarkers and In vitro Diagnosis Translation of Zhejiang province, Zhejiang, Hangzhou 310063, China.