Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers The State University of New Jersey, 185 South Orange Avenue, Medical Sciences Building, Newark, NJ 07103, USA.
Department of Molecular Biology and Genetics, Dr. D.Y. Patil Vidyapeeth's, Dr. D.Y. Patil Biotechnology and Bioinformatics Institute, Mumbai- Bangalore Highway, Tathawade, Pune 411033, India.
Int J Mol Sci. 2019 Mar 26;20(6):1509. doi: 10.3390/ijms20061509.
Telomerase has cellular functions beyond telomere stabilization, including a role in mitochondria. The function of the catalytic component-TERT-in mitochondria is still unknown, but it seems to play a role in the response to oxidative stress. Here, we interrogated the role of the subcellular localization of TERT to the response to hydrogen peroxide (H₂O₂) treatment. Using normal human fibroblasts (NHF) expressing non-tagged wild type (WT) human TERT (hTERT) or nuclear localization and function (hTERT), a mutant that we previously described as being competent in telomere elongation, while not being able to localize to mitochondria, we found the differential activation of autophagy as a function of hTERT's subcellular localization. Specifically, we found that only cells expressing the mutant had significant increases in autophagy markers as a response to H₂O₂ challenge. Either the reintroduction of the mitochondrial pool of hTERT or the expression of mitochondrially-targeted catalase in mutant cells blunted the autophagic response under oxidative stress. Interestingly, autophagy activation was also associated with decreased levels of mitochondrial DNA damage. Taken together, these results suggest that the loss of hTERT in mitochondria initiates a signaling cascade that allows for cells to adapt to and cope with the lack of mitochondrial telomerase. Such effects also influence the cellular response to oxidative damage.
端粒酶除了稳定端粒外，还具有细胞功能，包括在线粒体中的作用。催化成分 TERT 在线粒体中的功能尚不清楚，但它似乎在应对氧化应激中发挥作用。在这里，我们探讨了 TERT 亚细胞定位对过氧化氢（H₂O₂）处理反应的作用。使用表达非标记野生型（WT）人端粒酶（hTERT）或核定位和功能（hTERT）的正常人类成纤维细胞（NHF），我们之前描述过的一种突变体在端粒延长方面具有能力，但不能定位于线粒体，我们发现 hTERT 的亚细胞定位是作为自噬作用的函数的差异激活。具体来说，我们发现只有表达突变体的细胞在受到 H₂O₂ 挑战时，自噬标志物才会显著增加。要么重新引入 hTERT 的线粒体池，要么在突变细胞中表达靶向线粒体的过氧化氢酶，都可以减轻氧化应激下的自噬反应。有趣的是，自噬的激活也与线粒体 DNA 损伤水平的降低有关。总之，这些结果表明，线粒体中 hTERT 的缺失会引发信号级联反应，使细胞能够适应和应对缺乏线粒体端粒酶的情况。这种效应也会影响细胞对氧化损伤的反应。
