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.

中文翻译：

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AGO2 通过激活线粒体基因翻译来预防糖尿病心肌病

背景：糖尿病与心血管并发症有关。 microRNA 易位到亚细胞细胞器中，以修饰与糖尿病心肌病相关的基因。然而，miRNA机制的核心成员亚细胞AGO2（Argonaute2）的功能特性仍然难以捉摸。方法：我们在糖尿病和糖尿病心肌病小鼠模型上阐明了亚细胞局部AGO2的功能和机制。使用重组腺相关病毒 9 型通过尾静脉将 AGO2 递送至小鼠体内。通过超声心动图和导管测压系统评估心脏结构和功能。结果：糖尿病心肌细胞线粒体中AGO2减少。线粒体 AGO2 的过度表达可减轻糖尿病引起的心功能障碍。 AGO2 招募了TUFM（一种线粒体翻译延伸因子）来激活电子传递链亚基的翻译并减少活性氧。丙二酰化是 AGO2 的翻译后修饰，可减少糖尿病心肌病中 AGO2 进入线粒体的情况。 AGO2 丙二酰化是由SIRT3的细胞质短亚型通过以前未知的去丙二酰化酶功能来调节的。 结论：我们的研究结果表明，SIRT3 – AGO2 – CYTB轴将糖毒性与心脏电子传递链失衡联系起来，提供了新的机制见解和基础开发针对糖尿病心肌病的线粒体靶向疗法。