Downregulation of a Mitochondrial Micropeptide, MPM, Promotes Hepatoma Metastasis by Enhancing Mitochondrial Complex I Activity

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2021 Sep 3

PMID 34478872

Citations 13

Authors

Man-Huan Xiao

Yi-Fang Lin

Peng-Peng Xie

Hua-Xing Chen

Jun-Wen Deng

Wei Zhang

Na Zhao

Chen Xie

Yu Meng

Xingguo Liu

Shi-Mei Zhuang

Ying Zhu

Jian-Hong Fang

Affiliations

Soon will be listed here.

Abstract

We and others have shown that MPM (micropeptide in mitochondria) regulates myogenic differentiation and muscle development. However, the roles of MPM in cancer development remain unknown. Here we revealed that MPM was downregulated significantly in human hepatocellular carcinoma (HCC) tissues and its decrease was associated with increased metastasis potential and HCC recurrence. Gain- and loss-of-function investigations disclosed that in vitro migration/invasion and in vivo liver/lung metastasis of hepatoma cells were repressed by restoring MPM expression and increased by silencing MPM. Mechanism investigations revealed that MPM interacted with NDUFA7. Mitochondrial complex I activity was inhibited by overexpressing MPM and enhanced by siMPM, and this effect of siMPM was attenuated by knocking down NDUFA7. The NAD/NADH ratio, which was regulated by complex I, was reduced by MPM but increased by siMPM. Treatment with the NAD precursor nicotinamide abrogated the inhibitory effect of MPM on hepatoma cell migration. Further investigations showed that miR-17-5p bound to MPM and inhibited MPM expression. miR-17-5p upregulation was associated with MPM downregulation in HCC tissues. These findings indicate that a decrease in MPM expression may promote hepatoma metastasis by increasing mitochondrial complex I activity and the NAD/NADH ratio.

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