Down-regulation of a Mitochondrial Micropeptide MPM Promotes Hepatoma Metastasis by Enhancing Mitochondrial Complex I Activity.

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 significantly down-regulated in human hepatocellular carcinoma (HCC) tissues, and its decrease was associated with increased metastasis potential and HCC recurrence. Both in vitro and in vivo orthotopic xenograft models disclosed that the 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. The mitochondrial complex I activity was inhibited by overexpressing MPM and enhanced by siMPM, and this effect of siMPM was attenuated by knocking down NDUFA7. Consistently, the NAD+/NADH ratio, which was regulated by complex I, was reduced by MPM but increased by siMPM. And treatment with 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 up-regulation was associated with MPM down-regulation in HCC tissues. These findings indicate that decrease of MPM expression may promote hepatoma metastasis by increasing mitochondrial complex I activity and NAD+/NADH ratio.