Mettl8-flox Mouse

Mettl8, also known as Methyltransferase-like 8, is an RNA methyltransferase. It is crucial for installing 3-methylcytosine (m3C) modification on mitochondrial tRNAs, especially mt-tRNAThr/Ser(UCN), which is involved in mitochondrial translation and respiration processes, and thus holds significance in various biological systems [1,2,3,4,5,6].

In mouse embryonic cortical neural stem cells, conditional Mettl8 deletion leads to reduced mitochondrial protein translation, attenuated respiration activity, and impaired embryonic cortical neural stem cell maintenance in vivo. These defects can be rescued by enhancing mitochondrial functions. Similarly, in human forebrain cortical organoids, METTL8 promotes mitochondrial protein expression and neural stem cell maintenance [1]. In pancreatic cancer, high METTL8 levels correlate with lower patient survival and enhanced respiratory chain activity. METTL8 knockout cells show reduced respiratory chain activity, and mitochondrial ribosome profiling reveals mitoribosome stalling on mt-tRNASer(UCN)-and mt-tRNAThr-dependent codons, along with reduced incorporation of ND6 and ND1 into complex I [2]. In glioblastoma (GBM), METTL8 depletion in glioma stem cells (GSCs) impairs self-renewal and differentiation, retarding tumor growth in an intracranial GBM xenograft model. It also decreases HIF1α protein levels, inactivating the RTK/Akt axis and increasing sensitivity to Akt inhibitor treatment [3].

In conclusion, Mettl8-mediated m3C modification of mitochondrial tRNAs is essential for optimal mitochondrial translation and respiration. The use of Mettl8 KO/CKO mouse models has revealed its role in embryonic cortical neurogenesis, and its dysregulation in diseases like pancreatic cancer and GBM, providing potential therapeutic targets for these diseases.