Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria.
Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria.
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DOI：
10.18632/aging.101089
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发表时间：
2016-10-22
期刊：
影响因子：
--
通讯作者：
Saretzki G
中科院分区：
文献类型：
--
作者：
Miwa S;Czapiewski R;Wan T;Bell A;Hill KN;von Zglinicki T;Saretzki G
端粒酶以其典型功能维持分裂细胞中的端粒。此外，端粒酶蛋白 TERT 具有非端粒功能，例如穿梭至线粒体，从而减少氧化应激、DNA 损伤和细胞凋亡。 TERT 蛋白持续存在于成年神经元中，并且在各种应激条件下可以共定位于线粒体。我们在此表明，随着衰老过程，小鼠大脑中的 TERT 表达下降，而线粒体电子传递链释放的活性氧 (ROS) 增加。饮食限制 (DR) 导致小鼠大脑线粒体中 TERT 蛋白的积累，从而减少 ROS 释放并改善学习和空间短期记忆。 mTOR 信号传导减弱是 DR 的调节因素。因此，给小鼠喂食雷帕霉素会增加大脑线粒体的 TERT 并减少 ROS 的释放。重要的是，当 TERT 穿梭被 Src 激酶抑制剂博舒替尼抑制时，第一代 TERT −/− 小鼠的大脑和成纤维细胞中不存在雷帕霉素对线粒体功能的有益影响。综上所述，我们的数据表明，mTOR 信号通路影响 TERT 蛋白的线粒体定位，这反过来可能有助于 DR 或雷帕霉素保护大脑，防止与年龄相关的线粒体 ROS 增加和认知能力下降。
Telomerase in its canonical function maintains telomeres in dividing cells. In addition, the telomerase protein TERT has non-telomeric functions such as shuttling to mitochondria resulting in a decreased oxidative stress, DNA damage and apoptosis. TERT protein persists in adult neurons and can co-localise to mitochondria under various stress conditions. We show here that TERT expression decreased in mouse brain during aging while release of reactive oxygen species (ROS) from the mitochondrial electron transport chain increased. Dietary restriction (DR) caused accumulation of TERT protein in mouse brain mitochondria correlating to decreased ROS release and improved learning and spatial short-term memory. Decreased mTOR signalling is a mediator of DR. Accordingly, feeding mice with rapamycin increased brain mitochondrial TERT and reduced ROS release. Importantly, the beneficial effects of rapamycin on mitochondrial function were absent in brains and fibroblasts from first generation TERT −/− mice, and when TERT shuttling was inhibited by the Src kinase inhibitor bosutinib. Taken together, our data suggests that the mTOR signalling pathway impinges on the mitochondrial localisation of TERT protein, which might in turn contribute to the protection of the brain by DR or rapamycin against age-associated mitochondrial ROS increase and cognitive decline.
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DOI：
10.1093/geronj/42.1.78
发表时间：
1987-01-01
期刊：
JOURNALS OF GERONTOLOGY
影响因子：
--
作者：
INGRAM, DK;WEINDRUCH, R;WALFORD, RL
通讯作者：
WALFORD, RL
DOI：
10.15252/embj.201592862
发表时间：
2016-04-01
期刊：
The EMBO journal
影响因子：
--
作者：
Correia-Melo C;Marques FD;Anderson R;Hewitt G;Hewitt R;Cole J;Carroll BM;Miwa S;Birch J;Merz A;Rushton MD;Charles M;Jurk D;Tait SW;Czapiewski R;Greaves L;Nelson G;Bohlooly-Y M;Rodriguez-Cuenca S;Vidal-Puig A;Mann D;Saretzki G;Quarato G;Green DR;Adams PD;von Zglinicki T;Korolchuk VI;Passos JF
通讯作者：
Passos JF
影响因子：
4.3
作者：
Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.
DOI：
10.1161/atvbaha.109.185546
发表时间：
2009-06-01
影响因子：
8.7
作者：
Haendeler, Judith;Droese, Stefan;Dimmeler, Stefanie
通讯作者：
Dimmeler, Stefanie
影响因子：
4
作者：
Ahmed, Shaheda;Passos, Joao F.;Saretzki, Gabriele
通讯作者：
Saretzki, Gabriele