Vazquez Edwin J, Berthiaume Jessica M, Kamath Vasudeva, Achike Olisaemeka, Buchanan Elizabeth, Montano Monica M, Chandler Margaret P, Miyagi Masaru, Rosca Mariana G
Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA.
Department of Physiology, Case Western Reserve University, Cleveland, OH, USA.
Cardiovasc Res. 2015 Sep 1;107(4):453-65. doi: 10.1093/cvr/cvv183. Epub 2015 Jun 22.
Cardiomyopathy is a major complication of diabetes. Our study was aimed to identify the sites of mitochondrial dysfunction and delineate its consequences on mitochondrial metabolism in a model of type 1 diabetes.
Diabetes was induced by streptozotocin injection to male Lewis rats. We found a decrease in mitochondrial biogenesis pathway and electron transport chain complex assembly that targets Complex I. Oxidation of Complex II and long-chain fatty acid substrates support the electron leak and superoxide production. Mitochondrial defects do not limit fatty acid oxidation as the heart's preferred energy source indicating that the diabetic heart has a significant reserve in Complex I- and II-supported ATP production. Both mitochondrial fatty acid oxidation and Complex I defect are responsible for increased protein lysine acetylation despite an unchanged amount of the NAD(+)-dependent mitochondrial deacetylase sirt3. We quantitatively analysed mitochondrial lysine acetylation post-translational modifications and identified that the extent of lysine acetylation on 54 sites in 22 mitochondrial proteins is higher in diabetes compared with the same sites in the control. The increased lysine acetylation of the mitochondrial trifunctional protein subunit α may be responsible for the increased fatty acid oxidation in the diabetic heart.
We identified the specific defective sites in the electron transport chain responsible for the decreased mitochondrial oxidative phosphorylation in the diabetic heart. Mitochondrial protein lysine acetylation is the common consequence of both increased fatty acid oxidation and mitochondrial Complex I defect, and may be responsible for the metabolic inflexibility of the diabetic heart.
心肌病是糖尿病的主要并发症。我们的研究旨在确定线粒体功能障碍的部位，并在1型糖尿病模型中描绘其对线粒体代谢的影响。
通过向雄性Lewis大鼠注射链脲佐菌素诱导糖尿病。我们发现线粒体生物发生途径和靶向复合体I的电子传递链复合体组装减少。复合体II和长链脂肪酸底物的氧化支持电子泄漏和超氧化物产生。线粒体缺陷并不限制脂肪酸氧化作为心脏的首选能量来源，这表明糖尿病心脏在复合体I和II支持的ATP产生方面有显著储备。尽管依赖NAD(+)的线粒体脱乙酰酶sirt3的量没有变化，但线粒体脂肪酸氧化和复合体I缺陷均导致蛋白质赖氨酸乙酰化增加。我们定量分析了线粒体赖氨酸乙酰化的翻译后修饰，发现与对照组相同位点相比，糖尿病中22种线粒体蛋白上54个位点的赖氨酸乙酰化程度更高。线粒体三功能蛋白亚基α的赖氨酸乙酰化增加可能是糖尿病心脏脂肪酸氧化增加的原因。
我们确定了电子传递链中导致糖尿病心脏线粒体氧化磷酸化降低的特定缺陷位点。线粒体蛋白赖氨酸乙酰化是脂肪酸氧化增加和线粒体复合体I缺陷的共同结果，可能是糖尿病心脏代谢不灵活性的原因。
