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

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Shengnan Sun, Dun Su, Tianyi Dong, Bo Wang, Xingzhao Ji, Lingju Chu, Shicong Lu, Tianyi Zhang, Xiaoming Sun, Yi Liu, Qiang Wan
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引用次数: 0

Abstract

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.

线粒体核糖体蛋白L12通过调节线粒体生物合成介导透明细胞肾细胞癌的代谢重组。
背景:透明细胞肾细胞癌(ccRCC)以线粒体功能障碍和Warburg效应为特征,Warburg效应是指有氧糖酵解增强。线粒体核糖体蛋白12 (MRPL12)通过与POLRMT相互作用促进线粒体转录,在线粒体生物发生中起关键作用。我们之前的研究表明,MRPL12参与糖尿病肾病(DKD)和急性肾损伤(AKI)的进展。然而,它在ccRCC中的具体作用尚不清楚。因此,本研究旨在阐明MRPL12在ccRCC代谢重编程中的功能。方法:利用在线数据库和组织芯片分析,探讨MRPL12在ccRCC中的作用。采用实时荧光定量PCR (Quantitative real-time PCR, qRT-PCR)检测mRNA表达水平,采用Western blotting、免疫荧光(immunofluorescence, IF)和免疫组化(immunohistochemistry, IHC)检测相关基因蛋白表达水平。通过体外功能分析确定MRPL12的生物学效应,并使用Seahorse XF分析仪评估有氧糖酵解作用以测量细胞代谢活性。质谱分析结合基因本体(GO)分析和匠心路径分析(IPA),识别潜在的通路互连。为了研究调控机制,采用染色质免疫沉淀法(ChIP)检测HIF-1α与MRPL12启动子之间的结合相互作用。最后,建立小鼠体内模型,进一步阐明MRPL12在ccRCC进展中的功能作用。结果:MRPL12在ccRCC组织中显著下调,其表达降低与预后不良相关。MRPL12通过调节线粒体代谢抑制ccRCC细胞增殖、迁移和侵袭。MRPL12过表达增强氧化磷酸化(OXPHOS)并抑制有氧糖酵解,而MRPL12敲低则产生相反的作用。MRPL12、ILK、isg酰化和SUMO通路之间的潜在相互联系已被确定。此外,HIF-1α被发现作为MRPL12的转录抑制因子。结论:我们的研究表明,MRPL12通过调节线粒体代谢来抑制ccRCC细胞的增殖、迁移和侵袭,提示靶向MRPL12可能是一种很有前景的ccRCC治疗策略。
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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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