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MRPL12 K163 acetylation inhibits ccRCC via driving mitochondrial metabolic reprogramming
Xingzhao Ji1,2,3, Fuyuan Xue1, Ying Wang2
1Shandong Provincial Key Medical and Health Laboratory of cell metabolism, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
Abstract:
Renal cell carcinoma (RCC) is a common urological tumor, with clear cell renal cell carcinoma (ccRCC) being the most prevalent subtype. Metabolic reprogramming plays a critical role in ccRCC progression, making it a promising target for therapeutic intervention, though effective treatments remain unavailable. Our previous studies have shown that mitochondrial ribosomal protein L12 (MRPL12) contributes to various metabolic diseases, including diabetic kidney disease and HCC, by regulating mitochondrial biosynthesis. In this study, we demonstrated that MRPL12 is acetylated at lysine 163 (K163) in ccRCC cells, a key modification that influences its regulatory effect on mitochondrial metabolism. Mechanistically, we clarified that acetylation at the K163 site enhances mitochondrial biosynthesis by promoting MRPL12's binding to POLRMT, which subsequently increases mitochondrial metabolism and suppresses cellular glycolysis. Additionally, we found that MRPL12 K163 acetylation levels were significantly downregulated in ccRCC and that restoring this acetylation inhibited ccRCC progression in both in vitro and in vivo models. Furthermore, we demonstrated that the acetyltransferase TIP60 and the deacetylase SIRT5 bind to MRPL12 and regulate its acetylation. These findings highlight K163 acetylation as a critical site for MRPL12-mediated regulation of mitochondrial metabolism and reveal that this modification inhibits renal cancer development by promoting mitochondrial biosynthesis, reducing glycolysis, and driving metabolic reprogramming. This study suggests a potential therapeutic strategy for targeting MRPL12 acetylation in ccRCC.
Insights
MRPL12 acetylation at K163 suppresses clear cell renal cell carcinoma (ccRCC) progression. Restoring this modification enhances mitochondrial biosynthesis and inhibits tumor growth, suggesting a novel therapeutic target for ccRCC.
Area of Science:
- Molecular oncology
- Cancer metabolism
- Mitochondrial biology
Background:
- Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer subtype, characterized by metabolic reprogramming.
- Mitochondrial ribosomal protein L12 (MRPL12) regulates mitochondrial biosynthesis and is implicated in metabolic diseases.
- Effective therapeutic strategies for ccRCC remain limited, highlighting the need for novel treatment targets.
Purpose of the Study:
- To investigate the role of MRPL12 acetylation in ccRCC pathogenesis.
- To elucidate the mechanism by which MRPL12 acetylation affects ccRCC cell metabolism.
- To evaluate the therapeutic potential of targeting MRPL12 acetylation in ccRCC.
Main Methods:
- Analysis of MRPL12 acetylation status in ccRCC cells and tissues.
- Investigation of MRPL12 binding to POLRMT and its effect on mitochondrial biosynthesis and glycolysis.
- In vitro and in vivo experiments to assess the impact of restoring MRPL12 K163 acetylation on ccRCC progression.
- Identification of TIP60 and SIRT5 as regulators of MRPL12 acetylation.
Main Results:
- MRPL12 is acetylated at lysine 163 (K163) in ccRCC cells, enhancing its binding to POLRMT and promoting mitochondrial biosynthesis.
- MRPL12 K163 acetylation suppresses cellular glycolysis and is significantly downregulated in ccRCC.
- Restoring MRPL12 K163 acetylation inhibits ccRCC progression in vitro and in vivo.
- TIP60 and SIRT5 were identified as key enzymes regulating MRPL12 acetylation.
Conclusions:
- K163 acetylation is a critical modification site for MRPL12, regulating mitochondrial metabolism in ccRCC.
- MRPL12 K163 acetylation inhibits renal cancer development by promoting mitochondrial biosynthesis and reducing glycolysis.
- Targeting MRPL12 acetylation represents a promising therapeutic strategy for ccRCC.
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