GSH or palmitate preserves mitochondrial energetic/redox balance, preventing mechanical dysfunction in metabolically challenged myocytes/hearts from type 2 diabetic mice.
GSH or palmitate preserves mitochondrial energetic/redox balance, preventing mechanical dysfunction in metabolically challenged myocytes/hearts from type 2 diabetic mice.
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GSH 或棕榈酸酯可保持线粒体能量/氧化还原平衡，防止 2 型糖尿病小鼠代谢受损的肌细胞/心脏发生机械功能障碍
作者：
Tocchetti CG;Caceres V;Stanley BA;Xie C;Shi S;Watson WH;O'Rourke B;Spadari-Bratfisch RC;Cortassa S;Akar FG;Paolocci N;Aon MA
在2型糖尿病中，高血糖和交感神经驱动的增加可能改变线粒体的能量/氧化还原特性，降低细胞器的功能。这些扰动可能促使或维持基础低心率和有限的运动能力。然而，线粒体衰竭的具体步骤仍然难以捉摸。本研究发现，在高糖（HG）和β-激动剂异丙肾上腺素（ISO）刺激下，2型糖尿病db/db小鼠心脏线粒体显示的状态4→3能量转换受损的主要过程是复合物I、II和IV底物和硫氧还蛋白-2/谷胱甘肽（GSH）池的降低。通过模拟2型糖尿病患者的临床相关情况，该方案触发线粒体活性氧（ROS）的大量溢出，直接扰乱心脏电收缩耦合，最终导致心脏功能障碍。外源性谷胱甘肽，或者更重要的是，棕榈酸脂肪酸可以恢复暴露于HG/ISO的db/db肌细胞/心脏制剂的基础和β刺激功能。这是因为两种干预措施都提供了对抗线粒体ROS爆发和能量衰竭所需的减少等量。因此，在血糖控制不佳的情况下，糖尿病患者无法应对增加的心脏工作需求主要源于线粒体氧化还原/能量紊乱，这些紊乱相互影响，导致心肌细胞或整个心脏的机械功能障碍。
In type 2 diabetes, hyperglycemia and increased sympathetic drive may alter mitochondria energetic/redox properties, decreasing the organelle’s functionality. These perturbations may prompt or sustain basal low-cardiac performance and limited exercise capacity. Yet the precise steps involved in this mitochondrial failure remain elusive. Here, we have identified dysfunctional mitochondrial respiration with substrates of complex I, II, and IV and lowered thioredoxin-2/glutathione (GSH) pools as the main processes accounting for impaired state 4→3 energetic transition shown by mitochondria from hearts of type 2 diabetic db/db mice upon challenge with high glucose (HG) and the β-agonist isoproterenol (ISO). By mimicking clinically relevant conditions in type 2 diabetic patients, this regimen triggers a major overflow of reactive oxygen species (ROS) from mitochondria that directly perturbs cardiac electro-contraction coupling, ultimately leading to heart dysfunction. Exogenous GSH or, even more so, the fatty acid palmitate rescues basal and β-stimulated function in db/db myocyte/heart preparations exposed to HG/ISO. This occurs because both interventions provide the reducing equivalents necessary to counter mitochondrial ROS outburst and energetic failure. Thus, in the presence of poor glycemic control, the diabetic patient’s inability to cope with increased cardiac work demand largely stems from mitochondrial redox/energetic disarrangements that mutually influence each other, leading to myocyte or whole-heart mechanical dysfunction.
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DOI：
10.1016/j.biocel.2009.02.016
发表时间：
2009-10
影响因子：
4
作者：
Aon, M. A.;Cortassa, S.;Akar, F. G.;Brown, D. A.;Zhou, L.;O'Rourke, B.
通讯作者：
O'Rourke, B.
影响因子：
15.9
作者：
Anderson, Ethan J.;Lustig, Mary E.;Neufer, P. Darrell
通讯作者：
Neufer, P. Darrell
DOI：
10.1152/ajpheart.01264.2008
发表时间：
2009-05-01
影响因子：
4.8
作者：
Boardman, Neoma;Hafstad, Anne D.;Aasum, Ellen
通讯作者：
Aasum, Ellen
影响因子：
4.8
作者：
Aon, Miguel A.;Cortassa, Sonia;O'Rourke, Brian
通讯作者：
O'Rourke, Brian
影响因子：
3.4
作者：
Cortassa, S;Aon, MA;O'Rourke, B
通讯作者：
O'Rourke, B