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

Abstract

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). http://www.fasebj.org

The human mitochondrial 12S rRNA m4C methyltransferase METTL15 is required for proper mitochondrial function

“…Furthermore, the enzymatically inactive METTL15 can partially restore the m 5 C841 methylation decreased in METTL15-null cells, raising the question of whether the crosstalk is mediated by physical interactions between METTL15 and the m 5 C methyltransferase, NSUN4. Undoubtedly, the investigation of how modifications of mt-rRNA are coordinately deposited in an orderly manner will significantly increase our understanding of mitoribosome maturation (31) .…”

Methylation of Ribosomal RNA: A Mitochondrial Perspective

“…METTL17 localizes to mitochondria and associates with the mt-SSU. Loss of METTL17 leads to around 70% reduction of m 4 C840 and 50% reduction of m 5 C842 of 12S mt-rRNA, severely compromising integrity of the mt-SSU and mitochondrial protein translation (Shi et al, 2019). Collectively, these data suggest an important role for METTL17 in mitochondrial function, although further work is needed to assess potential interdependence of METTL15 and METTL17 in m 4 C839 methylation.…”

“…Interestingly, Shi et al have recently identified another member of the METTL family, METTL17, to modulate m 4 C839 modification (Shi et al, 2019). METTL17 localizes to mitochondria and associates with the mt-SSU.…”

Epitranscriptomics of Mammalian Mitochondrial Ribosomal RNA

“…It is also likely that NSUN4 methylates 12S rRNA after the formation of m 4 C839 by METTL15, since inactivation of the latter inhibits NSUN4 ability to modify 12S rRNA [ 10 , 12 , 13 ]. Inactivation of a mitochondrial methyltransferase METTL17, whose target is yet unknown, also leads to a decrease in the efficiency of C841 methylation [ 103 ]. At the same time, methylation of C841 by NSUN4 does not influence an efficiency of m 2 6 A936 and m 2 6 A937 methylation by TFB1M [ 98 ].…”

“…Another mitochondrial rRNA methyltransferase, NSUN4, was found to act inefficiently upon inactivation of METTL15 gene [ 10 , 12 , 13 ], which is discussed in a previous section. In turn, activity of METTL15 was found to be reduced upon inactivation of the mitochondrial methyltransferase METTL17 [ 103 ].…”