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.

我们和其他人已经表明 MPM（线粒体中的微肽）调节肌原性分化和肌肉发育。然而，MPM 在癌症发展中的作用仍然未知。在这里，我们发现 MPM 在人肝细胞癌 (HCC) 组织中显着下调，其降低与转移潜能和 HCC 复发增加有关。功能获得和丧失研究表明，体外迁移/入侵和体内肝癌细胞的肝/肺转移通过恢复 MPM 表达而被抑制，并通过沉默 MPM 而增加。机制调查显示 MPM 与 NDUFA7 相互作用。线粒体复合物 I 活性被过表达 MPM 抑制并被 siMPM 增强，并且 siMPM 的这种作用通过敲低 NDUFA7 减弱。由复合物 I 调节的 NAD ⁺ /NADH 比率被 MPM 降低，但被 siMPM 升高。NAD ^+治疗前体烟酰胺消除了 MPM 对肝癌细胞迁移的抑制作用。进一步的研究表明，miR-17-5p 与 MPM 结合并抑制 MPM 表达。miR-17-5p 上调与 HCC 组织中 MPM 下调有关。这些发现表明 MPM 表达的降低可能通过增加线粒体复合物 I 活性和 NAD ⁺ /NADH 比率来促进肝癌转移。