METTL15, a methyltransferase, is crucial for mitochondrial ribosome biogenesis. It specifically methylates position C839 (human numbering) in mitochondrial 12S rRNA, introducing N4-methylcytidine (m4C) [4]. This modification is essential for the assembly and proper function of mitoribosomes, which are key for the synthesis of bioenergetic proteins in mitochondria [4,5,7]. METTL15 also seems to be involved in maintaining mitochondrial homeostasis [5].

In homozygous Mettl15-/- knockout mice, despite being viable, there are several phenotypic changes. They exhibit a lower blood glucose level after physical exercise, suboptimal muscle performance, and decreased levels of Cox3 protein in oxidative soleus muscles. Additionally, these mice show decreased learning capabilities in both positive and negative reinforcement tests, making them a suitable model for mild mitochondriopathies [3]. In cell-based studies, knockdown of METTL15 reduces mitochondrial de novo protein synthesis, decreases the steady-state levels of components of the oxidative phosphorylation system, and impairs the assembly of the mitochondrial ribosome, especially the incorporation of late-assembly components into the small subunit [4]. In cancer research, circular RNA Circ-METTL15 is highly expressed in colorectal, lung, and papillary thyroid cancer tissues and cells. Knocking down Circ-METTL15 inhibits the proliferation, migration, invasion, and EMT of cancer cells and induces apoptosis, while overexpression has the opposite effects [1,2,6].

In summary, METTL15 is essential for mitochondrial rRNA methylation, mitoribosome biogenesis, and mitochondrial function. Its knockout mouse models have been valuable in understanding its role in metabolic and learning-related functions, as well as providing insights into its potential as a target in cancer research.

References:

1. Guo, Feng, Luo, Yang, Ye, GuangYao, Tang, WeiJun. . Circular RNA METTL15/miR-374a-5p/ESCO2 axis induces colorectal cancer development. In Acta biochimica Polonica, 70, 541-549. doi:10.18388/abp.2020_6470. https://pubmed.ncbi.nlm.nih.gov/37715994/

2. Zhang, Rui, Shang, Liang, Nan, Jinniang, Jin, Xintian, Zhang, Xianghua. 2021. Circ-METTL15 contributes to the proliferation, metastasis, immune escape and restrains apoptosis in lung cancer by regulating miR-1299/PDL1 axis. In Autoimmunity, 55, 8-20. doi:10.1080/08916934.2021.2001801. https://pubmed.ncbi.nlm.nih.gov/34796777/

3. Averina, Olga A, Laptev, Ivan G, Emelianova, Mariia A, Dontsova, Olga A, Sergiev, Petr V. 2022. Mitochondrial rRNA Methylation by Mettl15 Contributes to the Exercise and Learning Capability in Mice. In International journal of molecular sciences, 23, . doi:10.3390/ijms23116056. https://pubmed.ncbi.nlm.nih.gov/35682734/

4. Van Haute, Lindsey, Hendrick, Alan G, D'Souza, Aaron R, Andrews, Byron, Minczuk, Michal. . METTL15 introduces N4-methylcytidine into human mitochondrial 12S rRNA and is required for mitoribosome biogenesis. In Nucleic acids research, 47, 10267-10281. doi:10.1093/nar/gkz735. https://pubmed.ncbi.nlm.nih.gov/31665743/

5. Lv, Mengqi, Zhou, Wanwan, Hao, Yijie, Shi, Yunyu, Zhang, Liang. 2024. Structural insights into the specific recognition of mitochondrial ribosome-binding factor hsRBFA and 12 S rRNA by methyltransferase METTL15. In Cell discovery, 10, 11. doi:10.1038/s41421-023-00634-z. https://pubmed.ncbi.nlm.nih.gov/38291322/

6. Huang, YuHao, Zeng, XinYu, Cai, YanLing, Ma, YiQi, Li, SuPing. 2023. Circ-METTL15 stimulates the aggressive behaviors of papillary thyroid cancer cells by coordinating the miR-200c-3p/XIAP axis. In Turkish journal of biology = Turk biyoloji dergisi, 48, 142-152. doi:10.55730/1300-0152.2689. https://pubmed.ncbi.nlm.nih.gov/39051062/

7. Itoh, Yuzuru, Khawaja, Anas, Laptev, Ivan, Rorbach, Joanna, Amunts, Alexey. 2022. Mechanism of mitoribosomal small subunit biogenesis and preinitiation. In Nature, 606, 603-608. doi:10.1038/s41586-022-04795-x. https://pubmed.ncbi.nlm.nih.gov/35676484/