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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts
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O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts

机译：O-GlcNAcylation的8-氧鸟嘌呤DNA糖基化酶（Ogg1）损害糖尿病性心脏的氧化线粒体DNA损伤修复。

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mtDNA damage in cardiac myocytes resulting from increased oxidative stress is emerging as an important factor in the pathogenesis of diabetic cardiomyopathy. A prevalent lesion that occurs in mtDNA damage is the formation of 8-hydroxy-2′-deoxyguanosine (8-OHdG), which can cause mutations when not repaired properly by 8-oxoguanine DNA glycosylase (Ogg1). Although the mtDNA repair machinery has been described in cardiac myocytes, the regulation of this repair has been incompletely investigated. Here we report that the hearts of type 1 diabetic mice, despite having increased Ogg1 protein levels, had significantly lower Ogg1 activity than the hearts of control, non-type 1 diabetic mice. In diabetic hearts, we further observed increased levels of 8-OHdG and an increased amount of mtDNA damage. Interestingly, Ogg1 was found to be highly O-GlcNAcylated in diabetic mice compared with controls. In vitro experiments demonstrated that O-GlcNAcylation inhibits Ogg1 activity, which could explain the mtDNA lesion accumulation observed in vivo. Reducing Ogg1 O-GlcNAcylation in vivo by introducing a dominant negative O-GlcNAc transferase mutant (F460A) restored Ogg1 enzymatic activity and, consequently, reduced 8-OHdG and mtDNA damage despite the adverse hyperglycemic milieu. Taken together, our results implicate hyperglycemia-induced O-GlcNAcylation of Ogg1 in increased mtDNA damage and, therefore, provide a new plausible biochemical mechanism for diabetic cardiomyopathy.
机译：氧化应激增加导致心肌细胞中的mtDNA损伤正在成为糖尿病性心肌病发病机理中的重要因素。 mtDNA损伤中最普遍的病变是形成8-羟基-2'-脱氧鸟苷（8-OHdG），如果未通过8-氧代鸟嘌呤DNA糖基化酶（Ogg1）正确修复，会引起突变。尽管已经在心肌细胞中描述了mtDNA修复机制，但尚未完全研究这种修复的调控。在这里我们报告说，尽管1型糖尿病小鼠的心脏具有增加的Ogg1蛋白水平，但其Ogg1活性却明显低于非1型糖尿病对照小鼠的心脏。在糖尿病心脏中，我们进一步观察到8-OHdG水平升高和mtDNA损伤程度增加。有趣的是，与对照组相比，在糖尿病小鼠中发现Ogg1被高度O-GlcNAcy酰化。体外实验表明O-GlcNAcylation抑制Ogg1活性，这可以解释体内观察到的mtDNA损伤积累。通过引入显性负性O-GlcNAc转移酶突变体（F460A）减少体内Ogg1 O-GlcNAcy的还原，可恢复Ogg1的酶活性，因此尽管存在不利的高血糖环境，也可降低8-OHdG和mtDNA的损伤。综上所述，我们的研究结果暗示高血糖诱导的Ogg1的O-GlcNAcylation会增加mtDNA损伤，因此，为糖尿病性心肌病提供了一种新的可能的生化机制。

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