Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase
Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase
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DOI：
10.1152/ajpregu.00249.2012
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发表时间：
2013-04-01
影响因子：
2.8
通讯作者：
Hollander, John M.
中科院分区：
文献类型：
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作者：
Baseler, Walter A.;Dabkowski, Erinne R.;Hollander, John M.
Baseler WA，Dabkowski ER，Jagannathan R，Thapa D，Nichols CE，Shepherd DL，Croston TL，Powell M，Razunguzwa TT，刘易斯SE，Schnell DM，霍兰德JM.磷脂氢过氧化物谷胱甘肽过氧化物酶过度表达对1型糖尿病心脏线粒体蛋白质组丢失的恢复Am J Physiol Regul Integr Comp Physiol 304：R553-R565，2013年。首次发表于2013年2月13日; doi：10.1152/ajpregu.00249.2012.-线粒体功能障碍是糖尿病性心肌病的一个促成因素。以前，我们观察到线粒体内膜（IMM）和糖尿病心肌原纤维间线粒体（IFM）的基质内的蛋白质组减少与功能失调的线粒体蛋白输入。本研究的目的是确定线粒体磷脂氢过氧化物谷胱甘肽过氧化物酶4（mPHGPx），一种能够清除IMM中膜相关脂质过氧化物的抗氧化酶的过度表达是否可以逆转蛋白质组学改变，功能失调的蛋白质输入，并最终逆转与糖尿病心脏相关的线粒体功能障碍。通过多次低剂量链脲佐菌素注射使MPHGPx转基因小鼠和对照小鼠患糖尿病，并在高血糖5周后进行检查。高血糖发作5周后，心脏收缩功能的体内分析显示，糖尿病心脏的射血分数和缩短分数降低，mPHGPx过表达可逆转。在糖尿病mPHGPx IFM中，MPHGPx过表达增加电子传递链功能，同时减弱过氧化氢的产生和脂质过氧化。MPHGPx过表达减少糖尿病IFM中观察到的蛋白质组丢失。翻译后修饰，包括氧化和脱酰胺，减弱糖尿病IFM与mPHGPx过表达。糖尿病IFM中线粒体蛋白质输入功能障碍被逆转与蛋白质输入成分保存相关的mPHGPx过表达。免疫途径分析表明，氧化磷酸化，三羧酸循环，脂肪酸氧化过程中最受影响的糖尿病IFM保存mPHGPx过表达。特定的线粒体网络保存包括复合物I和II，线粒体超微结构，和线粒体蛋白质进口。这些结果表明mPHGPx过表达可以保护线粒体蛋白质组，并为糖尿病心脏提供心脏保护益处。
Baseler WA, Dabkowski ER, Jagannathan R, Thapa D, Nichols CE, Shepherd DL, Croston TL, Powell M, Razunguzwa TT, Lewis SE, Schnell DM, Hollander JM. Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase. Am J Physiol Regul Integr Comp Physiol 304: R553-R565, 2013. First published February 13, 2013; doi:10.1152/ajpregu.00249.2012.-Mitochondrial dysfunction is a contributor to diabetic cardiomyopathy. Previously, we observed proteomic decrements within the inner mitochondrial membrane (IMM) and matrix of diabetic cardiac interfibrillar mitochondria (IFM) correlating with dysfunctional mitochondrial protein import. The goal of this study was to determine whether overexpression of mitochondria phospholipid hydroperoxide glutathione peroxidase 4 (mPHGPx), an antioxidant enzyme capable of scavenging membrane-associated lipid peroxides in the IMM, could reverse proteomic alterations, dysfunctional protein import, and ultimately, mitochondrial dysfunction associated with the diabetic heart. MPHGPx transgenic mice and controls were made diabetic by multiple low-dose streptozotocin injections and examined after 5 wk of hyperglycemia. Five weeks after hyperglycemia onset, in vivo analysis of cardiac contractile function revealed decreased ejection fraction and fractional shortening in diabetic hearts that was reversed with mPHGPx overexpression. MPHGPx overexpression increased electron transport chain function while attenuating hydrogen peroxide production and lipid peroxidation in diabetic mPHGPx IFM. MPHGPx overexpression lessened proteomic loss observed in diabetic IFM. Posttranslational modifications, including oxidations and deamidations, were attenuated in diabetic IFM with mPHGPx overexpression. Mitochondrial protein import dysfunction in diabetic IFM was reversed with mPHGPx overexpression correlating with protein import constituent preservation. Ingenuity Pathway Analyses indicated that oxidative phosphorylation, tricarboxylic acid cycle, and fatty acid oxidation processes most influenced in diabetic IFM were preserved by mPHGPx overexpression. Specific mitochondrial networks preserved included complex I and II, mitochondrial ultrastructure, and mitochondrial protein import. These results indicate that mPHGPx overexpression can preserve the mitochondrial proteome and provide cardioprotective benefits to the diabetic heart.