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Theranostics 2023; 13(10):3165-3187. doi:10.7150/thno.78292 This issue Cite

Research Paper

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

Kun Zhang^1,2#, Linjie Chen^4,5#, Bo Wang^1#, Deyu Chen^1#, Xianglai Ye¹, Xinyu Han¹, Quan Fang⁴, Can Yu¹, Jia Wu¹, Sihan Guo¹, Lifang Chen¹, Yu Shi¹, Lan Wang¹, Huang Cheng¹, Hao Li¹, Lu Shen¹, Qiongya Zhao³, Liqin Jin³, Jianxin Lyu^1,3✉, Hezhi Fang^1,3✉

1. Key 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.
2. Department of Clinical Laboratory, Xi'an Daxing Hospital, Xi'an 710016, China.
3. Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310000, China.
4. School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou 310053, China.
5. Key Laboratory of Biomarkers and In vitro Diagnosis Translation of Zhejiang province, Zhejiang, Hangzhou 310063, China.
# These authors contributed equally to this work.

✉ Corresponding authors: Prof. Jianxin Lyu, Key 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. E-mail: jxlu313com (J.L.). Prof. Hezhi Fang, Key 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. E-mail: FangHedu.cn (H.L.). More

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

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