Mitochondrial ribosomal protein family in cancers: Mechanistic insights and therapeutic implications

This review is collaboratively prepared by Prof. Yingli Zhang (Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences), Prof. Jin-Jian Lu, Dr. Ting Li, and Ms. Qian Chen (Institute of Chinese Medical Sciences, University of Macau). Mitochondria, as the main site for aerobic respiration in cells, are indispensable participants in the reprogrammed metabolic activities of tumor cells. Mitochondrial ribosomal proteins (MRPs), essential components of the mitochondrial ribosome (mitoribosome), are pivotal for mitochondrial integrity and function. Dysfunction in MRPs impairs mitochondrial structure and energy production. Beyond mitochondria, MRPs also regulate multiple cellular processes and signaling, such as cell cycle, immune response within tumors. In recent years, MRPs have garnered significant attention in cancer research due to their multiple functions in mitochondria and the nucleus. The authors reviewed the detailed mechanisms of some MRPs members in cancers, including MRPS5，MRPS29，MRPL9，MRPL12，MRPL13，MRPL33, MRPL58, and MRPL59. They also analyze the potential of MRPs as prospective clinical biomarkers and discuss their relationship with clinical prognosis and treatment response based on data from The Human Protein Atlas and BEST.

MRPs are dysregulated in various cancers. The authors comprehensively summarized the roles of eight MRP members in tumor initiation and progression to clarify how MRPs function in this process. The classic function of MRPs is to ensure the proper conduct of mitochondrial translation. MRPs regulate the expression of oncogenic or tumor suppressor genes by affecting the activity of RNA editing-related enzymes, such as the adenosine deaminase acting on RNA family. Except for the effects on tumor cells themselves, MRPs play an important role in the metabolic reprogramming of immune cells within the tumor microenvironment. These actions are tightly linked to tumor growth, migration, invasion, and chemoresistance, which highlights the pivotal role of MRPs in tumor initiation and progression. In addition, MRP family members are critical downstream targets of signaling pathways essential for cancer cell survival, such as sirtuin-1 (SIRT1), UBASH3B, PI3K/Akt/mTOR, and ILF3.

Furthermore, many MRPs are known to be closely associated with the survival and recurrence rates of patients with cancer. And a holistic analysis of the relationship between MRPs and different cancers are lacking. So, they explore the clinical value of MRPs with The Human Protein Atlas and BEST website and found that MRPs have great potential in predicting the prognosis, disease progression, and treatment response of cancer patients, especially in the context of liver cancer.

Importantly, they proposed some feasible methods and challenges for targeting MRPs. The expression and function of MRPs are regulated by transcription factors (such as YY1, NRF2, ILF3, and HIF-1), miRNA and post-translational modifications. These mechanisms collectively offer multiple druggable nodes for developing MRP-directed therapeutic strategies. However, the roles of MRPs in cancer are complex and even contradictory. Certain MRPs may exhibit opposite effects in different cancer types, such as MRPS29, MRPL13, MRPL33, and MRPL59. This poses a huge challenge to therapeutic applications of MRPs. Then the authors further discussed the reason for functional complexity of MRPs, such as the subcellular localization differences, splice variants generated by alternative splicing, and loss-of-function mutation. Developing isoform-selective inhibitors or agents targeting distinct subcellular MRP populations may enable precise therapeutic intervention. Furthermore, nanoparticles, proteolysis targeting chimeric molecules and mitochondria through mitochondrial protease targeting chimera are practical strategies for targeting MRPs.

Based on a thorough understanding and summary of the roles of MRPs in cancer, their potential as clinical biomarkers, and their therapeutic implications, the authors also provided novel insights regarding future directions of research in the field of MRPs and cancer. This comprehensive review is beneficial to enhance the understanding of MRPs in cancer and promote the development of novel strategies targeting MRPs.

See the article:

Mitochondrial Ribosomal Protein Family in Cancers: Mechanistic Insights and Therapeutic Implications

https://doi.org/10.1002/mog2.70024