mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs

Zhenzhen Chen (), Qiankun He, Tiankun Lu, Jiayi Wu, Gaoli Shi, Luyun He, Hong Zong, Benyu Liu () and Pingping Zhu ()
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Zhenzhen Chen: Zhengzhou University
Qiankun He: Zhengzhou University
Tiankun Lu: Zhengzhou University
Jiayi Wu: Nankai University
Gaoli Shi: Zhengzhou University
Luyun He: Zhengzhou University
Hong Zong: The First Affiliated Hospital of Zhengzhou University
Benyu Liu: Zhengzhou University
Pingping Zhu: Zhengzhou University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Liver tumour-initiating cells (TICs) contribute to tumour initiation, metastasis, progression and drug resistance. Metabolic reprogramming is a cancer hallmark and plays vital roles in liver tumorigenesis. However, the role of metabolic reprogramming in TICs remains poorly explored. Here, we identify a mitochondria-encoded circular RNA, termed mcPGK1 (mitochondrial circRNA for translocating phosphoglycerate kinase 1), which is highly expressed in liver TICs. mcPGK1 knockdown impairs liver TIC self-renewal, whereas its overexpression drives liver TIC self-renewal. Mechanistically, mcPGK1 regulates metabolic reprogramming by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and promoting glycolysis. This alters the intracellular levels of α-ketoglutarate and lactate, which are modulators in Wnt/β-catenin activation and liver TIC self-renewal. In addition, mcPGK1 promotes PGK1 mitochondrial import via TOM40 interactions, reprogramming metabolism from oxidative phosphorylation to glycolysis through PGK1-PDK1-PDH axis. Our work suggests that mitochondria-encoded circRNAs represent an additional regulatory layer controlling mitochondrial function, metabolic reprogramming and liver TIC self-renewal.

Date: 2023
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DOI: 10.1038/s41467-023-36651-5

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