Mitochondrial Telomerase Reverse Transcriptase Binds to and Protects Mitochondrial DNA and Function From Damage
Mitochondrial Telomerase Reverse Transcriptase Binds to and Protects Mitochondrial DNA and Function From Damage
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DOI：
10.1161/atvbaha.109.185546
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发表时间：
2009-06-01
影响因子：
8.7
通讯作者：
Dimmeler, Stefanie
中科院分区：
文献类型：
--
作者：
Haendeler, Judith;Droese, Stefan;Dimmeler, Stefanie
目的-端粒酶及其催化亚基端粒酶逆转录酶（TERT）对于维持细胞核内端粒长度非常重要。最近的研究为 TERT 的线粒体定位提供了证据。因此，我们研究了TERT在线粒体内的精确定位及其功能。方法和结果-在这里，我们证明TERT定位于线粒体基质中。 TERT 在 ND1 和 ND2 的编码区与线粒体 DNA 结合。 TERT 与线粒体 DNA 的结合可防止溴化乙锭引起的损伤。 TERT 增加整体呼吸链活性，这在复合物 I 中最为明显，并且依赖于该酶的逆转录酶活性。此外，通过 shRNA 基因消除 TERT 后，线粒体活性氧会增加。线粒体靶向 TERT（而非野生型 TERT）对 H2O2 诱导的细胞凋亡具有最显着的保护作用。 6 月龄 TERT-/- 小鼠（F2 代）的肺成纤维细胞对 UVB 辐射的敏感性增加，心脏线粒体在基础条件下表现出呼吸链活性显着降低，证明了 TERT 在体内的保护功能。 结论 - 线粒体 TERT 通过与线粒体 DNA 结合、增加呼吸链活性并防止线粒体损伤，发挥了一种新的保护功能。 氧化应激引起的损伤。 （动脉硬化血栓 Vasc Biol. 2009；29:929-935。）
Objective-The enzyme telomerase and its catalytic subunit the telomerase reverse transcriptase (TERT) are important for maintenance of telomere length in the nucleus. Recent studies provided evidence for a mitochondrial localization of TERT. Therefore, we investigated the exact localization of TERT within the mitochondria and its function.Methods and Results-Here, we demonstrate that TERT is localized in the matrix of the mitochondria. TERT binds to mitochondrial DNA at the coding regions for ND1 and ND2. Binding of TERT to mitochondrial DNA protects against ethidium bromide-induced damage. TERT increases overall respiratory chain activity, which is most pronounced at complex I and dependent on the reverse transcriptase activity of the enzyme. Moreover, mitochondrial reactive oxygen species are increased after genetic ablation of TERT by shRNA. Mitochondrially targeted TERT and not wild-type TERT revealed the most prominent protective effect on H2O2-induced apoptosis. Lung fibroblasts from 6-month-old TERT-/- mice (F2 generation) showed increased sensitivity toward UVB radiation and heart mitochondria exhibited significantly reduced respiratory chain activity already under basal conditions, demonstrating the protective function of TERT in vivo.Conclusion-Mitochondrial TERT exerts a novel protective function by binding to mitochondrial DNA, increasing respiratory chain activity and protecting against oxidative stress-induced damage. (Arterioscler Thromb Vasc Biol. 2009;29:929-935.)