Mettl17, a regulator of mitochondrial ribosomal RNA modifications, is required for the translation of mitochondrial coding genes

Embryonic stem cells (ESCs) are pluripotent stem cells with the ability to self‐renew and to differentiate into any cell types of the 3 germ layers. Recent studies have demonstrated that there is a strong connection between mitochondrial function and pluripotency. Here, we report that methyltransferase like (Mettl) 17, identified from the clustered regularly interspaced short palindromic repeats knockout screen, is required for proper differentiation of mouse embryonic stem cells (mESCs). Mettl17 is located in mitochondria through its N‐terminal targeting sequence and specifically interacts with 12S mitochondrial ribosomal RNA (mt‐rRNA) as well as small subunits of mitochondrial ribosome (MSSUs). Loss of Mettl17 affects the stability of both 12S mt‐rRNA and its associated proteins of MSSUs. We further showed that Mettl17 is an S ‐adenosyl methionine (SAM)‐binding protein and regulates mitochondrial ribosome function in a SAM‐binding–dependent manner. Loss of Mettl17 leads to around 70% reduction of m4C840 and 50% reduction of m5C842 of 12S mt‐rRNA, revealing the first regulator of the m4C840 and indicating a crosstalk between the 2 nearby modifications. The defects of mitochondrial ribosome caused by deletion of Mettl17 lead to the impaired translation of mitochondrial protein‐coding genes, resulting in significant changes in mitochondrial oxidative phosphorylation and cellular metabolome, which are important for mESC pluripotency.—Shi, Z., Xu, S., Xing, S., Yao, K., Zhang, L., Xue, L., Zhou, P., Wang, M., Yan, G., Yang, P., Liu, J., Hu, Z., Lan, F. Mettl17 a regulator of mitochondrial ribosomal RNA modifications is required for the translation of mitochondrial coding genes. FASEB J. 33, 13040–13050 (2019). www.fasebj.org