Santos Janine Hertzog, Meyer Joel N, Skorvaga Milan, Annab Lois A, Van Houten Bennett
Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Natinoal Institutes of Health, 111, Alexander Drive, MD D3-01, Research Triangle Park, NC 27709, USA.
Aging Cell. 2004 Dec;3(6):399-411. doi: 10.1111/j.1474-9728.2004.00124.x.
Telomerase is often re-activated in human cancers and is widely used to immortalize cells in culture. In addition to the maintenance of telomeres, telomerase has been implicated in cell proliferation, genomic instability and apoptosis. Here we show that human telomerase reverse transcriptase (hTERT) is targeted to the mitochondria by an N-terminal leader sequence, and that mitochondrial extracts contain telomerase activity. In seven different human cell lines, mitochondrial telomerase increases hydrogen-peroxide-mediated mitochondrial DNA damage. hTERT expression did not alter the rate of hydrogen peroxide breakdown or endogenous cellular levels. Because the damaging effects of hydrogen peroxide are mediated by divalent metal ions (Fenton chemistry), we examined the levels of bioavailable metals. In all cases, higher levels of chelatable metals were found in hTERT-expressing cells. These results suggest that mitochondrial telomerase sensitizes cells to oxidative stress, which can lead to apoptotic cell death, and imply a novel function of telomerase in mitochondrial DNA transactions.
端粒酶在人类癌症中常被重新激活，并广泛用于使培养中的细胞永生化。除了维持端粒外，端粒酶还与细胞增殖、基因组不稳定和细胞凋亡有关。在此我们表明，人类端粒酶逆转录酶（hTERT）通过N端前导序列定位于线粒体，并且线粒体提取物含有端粒酶活性。在七种不同的人类细胞系中，线粒体端粒酶会增加过氧化氢介导的线粒体DNA损伤。hTERT的表达并未改变过氧化氢的分解速率或细胞内源性水平。由于过氧化氢的损伤作用是由二价金属离子介导的（芬顿化学反应），我们检测了生物可利用金属的水平。在所有情况下，在表达hTERT的细胞中发现了更高水平的可螯合金属。这些结果表明，线粒体端粒酶使细胞对氧化应激敏感，这可能导致细胞凋亡死亡，并暗示了端粒酶在线粒体DNA事务中的新功能。
