Aging-dependent changes in rat heart mitochondrial glutaredoxins--Implications for redox regulation.
Aging-dependent changes in rat heart mitochondrial glutaredoxins--Implications for redox regulation.
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DOI：
10.1016/j.redox.2013.10.010
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发表时间：
2013
期刊：
影响因子：
11.4
通讯作者：
Mieyal JJ
中科院分区：
文献类型：
--
作者：
Gao XH;Qanungo S;Pai HV;Starke DW;Steller KM;Fujioka H;Lesnefsky EJ;Kerner J;Rosca MG;Hoppel CL;Mieyal JJ
临床和动物研究证明，与年轻人相比，老年人的心脏更容易受到缺血/再灌注损伤。最近我们发现，衰老依赖性心肌细胞凋亡敏感性增加可归因于胞质谷氧还蛋白 1 (Grx1) 的减少以及随之而来的 NF-κB 介导的抗凋亡蛋白表达的减少。除了主要定位于细胞质外，Grx1 还存在于线粒体膜间隙 (IMS) 中。相比之下，Grx2 仅限于线粒体基质。在这里，我们报道了 IMS 中的 Grx1 减少了 50-60%，但老年大鼠心脏线粒体基质中的 Grx2 增加了 1.4-2.6 倍。对来自肌膜下 (SSM) 和纤维间 (IFM) 线粒体的 Grx 同工酶的原位活性测定表明，Grx1 在 IMS 中完全活跃。然而，Grx2 在基质中大多处于非活性形式，这与与铁硫簇复合的两个 Grx2 分子的活性位点半胱氨酸的可逆隔离一致。我们对 Grx2 活性/非活性比率的定量评估表明，老年大鼠心脏中 SSM 和 IFM 中铁硫簇二聚体 Grx2 复合物的水平增加。我们发现失活的 Grx2 可以通过连二亚硫酸钠或黄嘌呤氧化酶介导的外源超氧化物产生完全重新激活。然而，鱼藤酮通过抑制线粒体呼吸链复合物 I 产生线粒体内超氧化物，但治疗并不会导致 Grx2 激活。这些发现表明，二聚体 Grx2 附近积累的 ROS 不足，无法原位激活它。 。谷氧还蛋白在细胞氧化还原调节中发挥关键作用，细胞氧化还原调节对衰老依赖性失调很敏感。衰老心脏线粒体膜间隙中的 Grx1 减少；矩阵 Grx2 有所增加，但大部分处于非活动状态。失活的 Grx2 被超氧化物选择性激活。线粒体谷氧还蛋白的变化可能导致衰老过程中氧化还原稳态的失调。心脏线粒体 Grx1 和 Grx2 的原位活性随衰老的变化为未来的研究提供了机制见解。
Clinical and animal studies have documented that hearts of the elderly are more susceptible to ischemia/reperfusion damage compared to young adults. Recently we found that aging-dependent increase in susceptibility of cardiomyocytes to apoptosis was attributable to decrease in cytosolic glutaredoxin 1 (Grx1) and concomitant decrease in NF-κB-mediated expression of anti-apoptotic proteins. Besides primary localization in the cytosol, Grx1 also exists in the mitochondrial intermembrane space (IMS). In contrast, Grx2 is confined to the mitochondrial matrix. Here we report that Grx1 is decreased by 50–60% in the IMS, but Grx2 is increased by 1.4–2.6 fold in the matrix of heart mitochondria from elderly rats. Determination of in situ activities of the Grx isozymes from both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria revealed that Grx1 was fully active in the IMS. However, Grx2 was mostly in an inactive form in the matrix, consistent with reversible sequestration of the active-site cysteines of two Grx2 molecules in complex with an iron–sulfur cluster. Our quantitative evaluations of the active/inactive ratio for Grx2 suggest that levels of dimeric Grx2 complex with iron–sulfur clusters are increased in SSM and IFM in the hearts of elderly rats. We found that the inactive Grx2 can be fully reactivated by sodium dithionite or exogenous superoxide production mediated by xanthine oxidase. However, treatment with rotenone, which generates intramitochondrial superoxide through inhibition of mitochondrial respiratory chain Complex I, did not lead to Grx2 activation. These findings suggest that insufficient ROS accumulates in the vicinity of dimeric Grx2 to activate it in situ. . Glutaredoxins play key roles in cellular redox regulation, which is sensitive to aging-dependent dysregulation. Grx1 is diminished in the intermembrane space of mitochondria from aged heart; matrix Grx2 is increased but mostly in an inactive form. The inactive Grx2 is selectively activated by superoxide. Mitochondrial glutaredoxin changes may contribute to dysregulation of redox homeostasis during aging. Changes in in situ activities of heart mitochondrial Grx1 and Grx2 with aging provide mechanistic insights for future studies.
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影响因子：
4.8
作者：
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