Epitranscriptomic regulation of cortical neurogenesis via Mettl8-dependent mitochondrial tRNA m3C modification

Increasing evidence implicates the critical roles of various epitranscriptomic RNA modifications in different biological processes. Methyltransferase METTL8 installs 3-methylcytosine (m3C) modification of mitochondrial tRNAs in vitro; however, its role in intact biological systems is unknown. Here, we show that Mettl8 is localized in mitochondria and installs m3C specifically on mitochondrial tRNAThr/Ser(UCN) in mouse embryonic cortical neural stem cells. At molecular and cellular levels, Mettl8 deletion in cortical neural stem cells leads to reduced mitochondrial protein translation and attenuated respiration activity. At the functional level, conditional Mettl8 deletion in mice results in impaired embryonic cortical neural stem cell maintenance in vivo, which can be rescued by pharmacologically enhancing mitochondrial functions. Similarly, METTL8 promotes mitochondrial protein expression and neural stem cell maintenance in human forebrain cortical organoids. Together, our study reveals a conserved epitranscriptomic mechanism of Mettl8 and mitochondrial tRNA m3C modification in maintaining embryonic cortical neural stem cells in mice and humans. [Display omitted] •Mettl8 installs m3C modification on mt-tRNAThr/Ser(UCN) in cortical neural stem cells•Mettl8 regulates mitochondrial protein translation and function in neural stem cells•Mettl8-deleted mice exhibit accelerated embryonic cortical neural stem cell depletion•METTL8 plays a conserved role in neurogenesis in human forebrain organoids as in mice Zhang et al. identified an epitranscriptomic mechanism regulating cortical neural stem cells in the embryonic mouse brain and human forebrain organoids. Specifically, Mettl8 installs m3C modification on mitochondrial tRNAThr/Ser(UNC), which regulates mitochondrial protein translation and function, and loss of Mettl8 leads to accelerated embryonic cortical neural stem cell depletion.