IDH2 deficiency promotes mitochondrial dysfunction and cardiac hypertrophy in mice
IDH2 deficiency promotes mitochondrial dysfunction and cardiac hypertrophy in mice
复制标题
DOI：
10.1016/j.freeradbiomed.2014.12.018
复制
发表时间：
2015-03-01
影响因子：
7.4
通讯作者：
Park, Jeen-Woo
中科院分区：
文献类型：
--
作者：
Ku, Hyeong Jun;Ahn, Youngkeun;Park, Jeen-Woo
心肌肥厚是心力衰竭的危险因素，与线粒体氧化应激增强有关，线粒体氧化应激是由高水平的活性氧物种(ROS)引起的。ROS生成和ROS解毒之间的平衡决定了ROS水平。因此，这些过程的中断会导致ROS水平的上升或下降。在以前的文献中，我们已经证明了线粒体NADP(+)依赖的异柠檬酸脱氢酶(IDH2)的主要功能之一是控制线粒体的氧化还原平衡，从而通过产生NADPH来介导细胞对氧化损伤的防御。为了探讨IDH2表达与心功能的关系，我们测量了IDH2基因敲除(IDH2(-/-))和野生型(IDH2(+/+))小鼠的心肌肥大、细胞凋亡和收缩功能障碍。正如预期的那样，基因敲除小鼠心脏的线粒体缺乏IDH2活性，IDH2缺陷小鼠的心脏出现加速心力衰竭，细胞凋亡和肥大水平增加，并表现出线粒体功能障碍，这与氧化还原动态平衡的丧失有关。我们的结果表明，IDH2通过防止氧化应激，在维持压力超负荷性肥厚后的基础线粒体功能和心肌收缩功能方面发挥着重要作用。(C)2014 Elsevier Inc.保留所有权利。
Cardiac hypertrophy, a risk factor for heart failure, is associated with enhanced oxidative stress in the mitochondria, resulting from high levels of reactive oxygen species (ROS). The balance between ROS generation and ROS detoxification dictates ROS levels. As such, disruption of these processes results in either increased or decreased levels of ROS. In previous publications, we have demonstrated that one of the primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) is to control the mitochondrial redox balance, and-thereby mediate the cellular defense against oxidative damage, via the production of NADPH. To explore the association between IDH2 expression and cardiac function, we measured myocardial hypertrophy, apoptosis, and contractile dysfunction in IDH2 knockout (idh2(-/-)) and wild-type (idh2(+/+)) mice. As expected, mitochondria from the hearts of knockout mice lacked IDH2 activity and the hearts of IDH2-deficient mice developed accelerated heart failure, increased levels of apoptosis and hypertrophy, and exhibited mitochondrial dysfunction, which was associated with a loss of redox homeostasis. Our results suggest that IDH2 plays an important role in maintaining both baseline mitochondrial function and cardiac contractile function following pressure-overload hypertrophy, by preventing oxidative stress. (C) 2014 Elsevier Inc. All rights reserved.