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

ABSTRACT: METTL20 is a seven-?-strand methyltransferase that is localised to the mitochondria and tri-methylates the electron transfer flavoprotein (ETF) ? 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 ?-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 ?-oxidation is highly activated.

SUBMITTER: Shimazu T 

PROVIDER: S-EPMC5775328 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature