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Background <p>Clear cell renal cell carcinoma (ccRCC) is characterized by mitochondrial dysfunction and the Warburg effect, which refers to enhanced aerobic glycolysis. Mitochondrial ribosomal protein 12 (MRPL12) plays a pivotal role in mitochondrial biogenesis by promoting mitochondrial transcription through its interaction with POLRMT. Our previous studies have demonstrated that MRPL12 is involved in the progression of diabetic kidney disease (DKD) and acute kidney injury (AKI). However, its specific role in ccRCC remains unclear. Therefore, this study aims to elucidate the function of MRPL12 in the metabolic reprogramming of ccRCC.</p> Methods <p>Online databases and tissue microarray analysis were utilized to explore the role of MRPL12 in ccRCC. Quantitative real-time PCR (qRT-PCR) was performed to quantify mRNA expression levels, while Western blotting, immunofluorescence (IF), and immunohistochemistry (IHC) were employed to evaluate protein expression of the relevant genes. In vitro functional assays were conducted to determine the biological effects of MRPL12, and aerobic glycolysis was assessed using Seahorse XF Analyzers to measure cellular metabolic activity. Mass spectrometry analysis, combined with Gene Ontology (GO) analysis and integrated with Ingenuity Pathway Analysis (IPA), was carried out to identify potential pathway interconnections. To investigate the regulatory mechanism, chromatin immunoprecipitation (ChIP) assays were performed to examine the binding interaction between HIF-1α and the MRPL12 promoter. Finally, an in vivo mouse model was established to further elucidate the functional role of MRPL12 in ccRCC progression.</p> Results <p>MRPL12 is significantly downregulated in ccRCC tissues, and its reduced expression is associated with poor prognosis. MRPL12 inhibits ccRCC cell proliferation, migration, and invasion by modulating mitochondrial metabolism. Overexpression of MRPL12 enhances oxidative phosphorylation (OXPHOS) and suppresses aerobic glycolysis, while MRPL12 knockdown produces the opposite effects. Potential interconnections between the MRPL12, ILK, ISGylation, and SUMO pathways have been identified. Additionally, HIF-1α was found to act as a transcriptional repressor of MRPL12.</p> Conclusion <p>Our study reveals that MRPL12 regulates mitochondrial metabolism to inhibit ccRCC cell proliferation, migration, and invasion, suggesting that targeting MRPL12 may represent a promising therapeutic strategy for ccRCC.</p>

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Mitochondrial ribosomal protein L12 mediates metabolic reorganization in clear cell renal cell carcinoma by regulating mitochondrial biosynthesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月14日

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  • Shengnan Sun,
  • Dun Su,
  • Tianyi Dong,
  • Bo Wang,
  • Xingzhao Ji,
  • Lingju Chu,
  • Shicong Lu,
  • Tianyi Zhang,
  • Xiaoming Sun,
  • Yi Liu,
  • Qiang Wan

摘要

Background

Clear cell renal cell carcinoma (ccRCC) is characterized by mitochondrial dysfunction and the Warburg effect, which refers to enhanced aerobic glycolysis. Mitochondrial ribosomal protein 12 (MRPL12) plays a pivotal role in mitochondrial biogenesis by promoting mitochondrial transcription through its interaction with POLRMT. Our previous studies have demonstrated that MRPL12 is involved in the progression of diabetic kidney disease (DKD) and acute kidney injury (AKI). However, its specific role in ccRCC remains unclear. Therefore, this study aims to elucidate the function of MRPL12 in the metabolic reprogramming of ccRCC.

Methods

Online databases and tissue microarray analysis were utilized to explore the role of MRPL12 in ccRCC. Quantitative real-time PCR (qRT-PCR) was performed to quantify mRNA expression levels, while Western blotting, immunofluorescence (IF), and immunohistochemistry (IHC) were employed to evaluate protein expression of the relevant genes. In vitro functional assays were conducted to determine the biological effects of MRPL12, and aerobic glycolysis was assessed using Seahorse XF Analyzers to measure cellular metabolic activity. Mass spectrometry analysis, combined with Gene Ontology (GO) analysis and integrated with Ingenuity Pathway Analysis (IPA), was carried out to identify potential pathway interconnections. To investigate the regulatory mechanism, chromatin immunoprecipitation (ChIP) assays were performed to examine the binding interaction between HIF-1α and the MRPL12 promoter. Finally, an in vivo mouse model was established to further elucidate the functional role of MRPL12 in ccRCC progression.

Results

MRPL12 is significantly downregulated in ccRCC tissues, and its reduced expression is associated with poor prognosis. MRPL12 inhibits ccRCC cell proliferation, migration, and invasion by modulating mitochondrial metabolism. Overexpression of MRPL12 enhances oxidative phosphorylation (OXPHOS) and suppresses aerobic glycolysis, while MRPL12 knockdown produces the opposite effects. Potential interconnections between the MRPL12, ILK, ISGylation, and SUMO pathways have been identified. Additionally, HIF-1α was found to act as a transcriptional repressor of MRPL12.

Conclusion

Our study reveals that MRPL12 regulates mitochondrial metabolism to inhibit ccRCC cell proliferation, migration, and invasion, suggesting that targeting MRPL12 may represent a promising therapeutic strategy for ccRCC.