Accumulation of TERT in Mitochondria Shows Two Opposing Effects on Apoptosis
Accumulation of TERT in Mitochondria Shows Two Opposing Effects on Apoptosis
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线粒体中 TERT 的积累对细胞凋亡显示出两种相反的作用
DOI：
10.1101/2021.12.21.473585
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Uemura Sotaro
中科院分区：
文献类型：
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作者：
Ebata Hiroshi;Shima Tomohiro;Iizuka Ryo;Uemura Sotaro
端粒酶逆转录酶（Telomerase reverse transcriptase，TERT）是一种催化端粒延长的逆转录蛋白。除了端粒延长外，TERT还被认为发挥着非经典的作用，因为它不仅定位于细胞核，而且定位于线粒体，而线粒体中不存在端粒。一些研究已经报道线粒体TERT调节氧化应激诱导的细胞凋亡。然而，关于线粒体TERT是否促进或抑制细胞凋亡仍然存在争议，主要是由于缺乏关于个体细胞中TERT分布随时间变化的信息。在这里，我们同时检测细胞凋亡和端粒酶逆转录酶定位后，在个别HeLa细胞的氧化应激活细胞跟踪。这种跟踪显示，压力诱导的线粒体中的TERT积累导致细胞凋亡，但积累与细胞死亡前的时间呈正相关。结果表明，一种新的模型，其中线粒体TERT在细胞凋亡的不同阶段具有两种相反的作用：它在细胞命运决定的第一阶段预先决定细胞凋亡，但也在第二阶段延迟细胞凋亡。由于这些不同的影响分别支持关于线粒体TERT在细胞凋亡中的作用的争论的双方，我们的模型整合了两个相反的假设。此外，详细的统计分析的TERT突变，这已被预测为抑制TERT转运到线粒体，揭示了这些突变抑制细胞凋亡独立的线粒体定位的TERT。总之，这些结果表明，非典型功能的TERT影响广泛的凋亡途径。
Telomerase reverse transcriptase (TERT) is a protein that catalyzes the reverse transcription of telomere elongation. TERT is also expected to play a noncanonical role beyond telomere lengthening since it localizes not only in the nucleus but also in mitochondria, where telomeres do not exist. Several studies have reported that mitochondrial TERT regulates apoptosis induced by oxidative stress. However, there remains controversy about whether mitochondrial TERT promotes or inhibits apoptosis, mainly due to the lack of information on changes in the TERT distribution in individual cells over time. Here we simultaneously detected apoptosis and TERT localization after oxidative stress in individual HeLa cells by live-cell tracking. This tracking revealed that the stress-induced accumulation of TERT in mitochondria resulted in apoptosis but that the accumulation positively correlated with the time until cell death. The results suggest a new model in which mitochondrial TERT has two opposing effects at different stages of apoptosis: it predetermines apoptosis at the first stage of cell-fate determination but also delays apoptosis at the second stage. Because these distinct effects respectively support both sides of the controversy regarding the role of mitochondrial TERT in apoptosis, our model integrates two opposing hypotheses. Furthermore, detailed statistical analysis of TERT mutations, which have been predicted to inhibit TERT transport to mitochondria, revealed that these mutations suppress apoptosis independent of the mitochondrial localization of TERT. Together, these results indicate that the non-canonical functions of TERT affect a wide range of apoptotic pathways.
影响因子：
4.7
作者：
Kowarz, Eric;Loescher, Denise;Marschalek, Rolf
通讯作者：
Marschalek, Rolf
H.增本：细胞。
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