Mitochondrial ribosomal protein L12 potentiates hepatocellular carcinoma by regulating mitochondrial biogenesis and metabolic reprogramming

Abstract Background: Mitochondrial dysfunction and metabolic reprogramming are the key features of hepatocellular carcinoma (HCC); however, the detailed mechanism has not yet been clarified. Mitochondrial ribosomal protein L12 (MRPL12) has been implicated in transcription in human mitochondria. Although the function of MRPL12 has been documented, the role of abnormal MRPL12 expression in HCC remains unknown. Here, we determined the clinical significance, functional implications, and mechanisms underlying the effects of MRPL12 in HCC. Methods: Human HCC obtain from patients was used to evaluate the role of MRPL12 in HCC. For evaluating tumor behavior, we used cell culture for in vitro experiments and for in vivo experiments we used mouse HCC xenograft model. Further we used tissue microarray, immunohistochemistry, flowcytometry, Transwell assay, and CCK-8 assay, mitochondrial DNA copy number quantification methods, and seahorse assay to clarify our hypothesis. Results: Significant upregulation of MRPL12 in patients with HCC correlated with aggressive tumor behavior and poor prognosis. MRPL12 knockdown in HCC cells attenuated cell proliferation and migration in vitro, and tumorigenicity in vivo. We observed that MRPL12 is essential for mitochondrial homeostasis. Gain- and loss-of-function of MRPL12 in HCC altered oxidative phosphorylation (OXPHOS), mitochondrial DNA content, and HCC cell proliferation and invasion. Overall, MRPL12 might play oncogenic role by activating mitochondrial OXPHOS and promoting mitochondrial biosynthesis. Yin Yang 1 (YY1) transcriptionally regulated MRPL12 expression, and YY1 knockdown inhibited MRPL12 activity and suppressed HCC cell proliferation and metastasis. The role of the phosphatidylinositol-3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway in regulating MRPL12 was confirmed. We hypothesize that the PI3K/mTOR-YY1-MRPL12 axis orchestrates HCC cell proliferation and metastasis. Conclusion: Our study provides insights into MRPL12 signaling in HCC and highlights MRPL12 as a potential therapeutic target. Trial registration: N/A.