Role of METTL20 in regulating β-oxidation and heat production in mice under fasting or ketogenic conditions

• Published in: Scientific reports 2018-01, Vol.8 (1), p.1179-12, Article 1179
• Main Authors: Shimazu, Tadahiro, Furuse, Tamio, Balan, Shabeesh, Yamada, Ikuko, Okuno, Shuzo, Iwanari, Hiroko, Suzuki, Takehiro, Hamakubo, Takao, Dohmae, Naoshi, Yoshikawa, Takeo, Wakana, Shigeharu, Shinkai, Yoichi
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 59; 631/337/458/1648; 631/45/320; 64; 64/60; 82; 82/58; 82/80; 82/83; Animals; Body temperature; Catalysis; Coenzyme A; Cold tolerance; Convulsions & seizures; CRISPR-Cas Systems; Dehydrogenase; Dehydrogenases; Electron transfer; Electron-Transferring Flavoproteins - metabolism; Fasting; Fasting - metabolism; Fatty Acids - metabolism; Gene Editing; Glutaryl-CoA dehydrogenase; Heat; High fat diet; Humanities and Social Sciences; Humans; Ketogenesis; Ketone Bodies - metabolism; Loss of Function Mutation; Low carbohydrate diet; Lysine; Lysine - metabolism; Metabolomics - methods; Methylation; Methyltransferase; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Mice, Knockout; Mitochondria; Mitochondria - metabolism; multidisciplinary; Oxidation; Oxidation-Reduction; Oxygen Consumption; Rodents; Science; Science (multidisciplinary); Substrate Specificity; Thermogenesis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-19615-4

METTL20 is a seven-β-strand methyltransferase that is localised to the mitochondria and tri-methylates the electron transfer flavoprotein (ETF) β subunit (ETFB) at lysines 200 and 203. It has been shown that METTL20 decreases the ability of ETF to extract electrons from medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) and glutaryl-CoA dehydrogenase in vitro . METTL20-mediated methylation of ETFB influences the oxygen consumption rate in permeabilised mitochondria, suggesting that METTL20-mediated ETFB methylation may also play a regulatory role in mitochondrial metabolism. In this study, we generated Mettl20 knockout (KO) mice to uncover the in vivo functions of METTL20. The KO mice were viable, and a loss of ETFB methylation was confirmed. In vitro enzymatic assays revealed that mitochondrial ETF activity was higher in the KO mice than in wild-type mice, suggesting that the KO mice had higher β-oxidation capacity. Calorimetric analysis showed that the KO mice fed a ketogenic diet had higher oxygen consumption and heat production. A subsequent cold tolerance test conducted after 24 h of fasting indicated that the KO mice had a better ability to maintain their body temperature in cold environments. Thus, METTL20 regulates ETF activity and heat production through lysine methylation when β-oxidation is highly activated.