Resveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3
Resveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3
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DOI：
10.1016/j.freeradbiomed.2016.04.027
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发表时间：
2016-07-01
影响因子：
7.4
通讯作者：
Djouadi, Fatima
中科院分区：
文献类型：
--
作者：
Mathieu, Lise;Costa, Alexandra Lopes;Djouadi, Fatima
复合物I （CI）缺陷的病理生理机制仅被部分理解，这严重限制了这种常见的、毁灭性的线粒体疾病的治疗。最近，我们发现白藜芦醇（resveratrol， RSV）是一种天然多酚，对核源性CI缺乏有有益作用。在这里，我们证明了RSV能够纠正13个ci缺乏患者细胞系中5个的耗氧生化缺陷。RSV的其他有益作用包括减少细胞内ROS总量和上调线粒体超氧化物歧化酶（SOD2）蛋白的表达，SOD2是一种关键的抗氧化防御酶。RSV上调SOD2蛋白表达的分子机制需要雌激素受体（ER）和雌激素相关受体（ERR α）的参与。虽然RSV增加了患者成纤维细胞中SOD2蛋白的水平，但与正常成纤维细胞相比，酶活性并未增加。这使我们假设SOD2酶活性在翻译后受到调节。这种调节涉及SIRT3，一种线粒体NAD（+）依赖的去乙酰化酶，并且严重依赖于NAD（+）水平。综上所述，我们的数据表明RSV的代谢作用及其抗氧化能力使RSV作为治疗CI缺陷的候选分子特别有趣。(C) 2016 Elsevier Inc.版权所有。
The pathophysiological mechanisms underlying Complex I (CI) deficiencies are understood only partially which severely limits the treatment of this common, devastating, mitochondrial disorder. Recently, we have shown that resveratrol (RSV), a natural polyphenol, has beneficial effects on CI deficiency of nuclear origin. Here, we demonstrate that RSV is able to correct the biochemical defect in oxygen consumption in five of thirteen CI-deficient patient cell lines. Other beneficial effects of RSV include a decrease of total intracellular ROS and the up-regulation of the expression of mitochondrial superoxide dismutase (SOD2) protein, a key antioxidant defense enzyme. The molecular mechanisms leading to the up-regulation of SOD2 protein expression by RSV require the estrogen receptor (ER) and the estrogen-related receptor alpha (ERR alpha). Although RSV increases the level of SOD2 protein in patients' fibroblasts, the enzyme activity is not increased, in contrast to normal fibroblasts. This led us to hypothesize that SOD2 enzyme activity is regulated post-translationally. This regulation involves SIRT3, a mitochondrial NAD(+)-dependent deacetylase and is critically dependent on NAD(+) levels. Taken together, our data show that the metabolic effects of RSV combined with its antioxidant capacities makes RSV particularly interesting as a candidate molecule for the therapy of CI deficiencies. (C) 2016 Elsevier Inc. All rights reserved.