AGO2 Protects Against Diabetic Cardiomyopathy by Activating Mitochondrial Gene Translation

BACKGROUND:Diabetes is associated with cardiovascular complications. microRNAs translocate into subcellular organelles to modify genes involved in diabetic cardiomyopathy. However, functional properties of subcellular AGO2 (Argonaute2), a core member of miRNA machinery, remain elusive.METHODS:We elucidated the function and mechanism of subcellular localized AGO2 on mouse models for diabetes and diabetic cardiomyopathy. Recombinant adeno-associated virus type 9 was used to deliver AGO2 to mice through the tail vein. Cardiac structure and functions were assessed by echocardiography and catheter manometer system.RESULTS:AGO2 was decreased in mitochondria of diabetic cardiomyocytes. Overexpression of mitochondrial AGO2 attenuated diabetes-induced cardiac dysfunction. AGO2 recruited TUFM, a mitochondria translation elongation factor, to activate translation of electron transport chain subunits and decrease reactive oxygen species. Malonylation, a posttranslational modification of AGO2, reduced the importing of AGO2 into mitochondria in diabetic cardiomyopathy. AGO2 malonylation was regulated by a cytoplasmic-localized short isoform of SIRT3 through a previously unknown demalonylase function.CONCLUSIONS:Our findings reveal that the SIRT3-AGO2-CYTB axis links glucotoxicity to cardiac electron transport chain imbalance, providing new mechanistic insights and the basis to develop mitochondria targeting therapies for diabetic cardiomyopathy.