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Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage
Janine Hertzog Santos1, Joel N Meyer, Milan Skorvaga
1Laboratory 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
|December 1, 2004
Summary
Human telomerase reverse transcriptase (hTERT) localizes to mitochondria, increasing mitochondrial DNA damage and sensitizing cells to oxidative stress. This suggests a new role for telomerase in mitochondrial function and potential induction of apoptotic cell death.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Telomerase is reactivated in human cancers, maintaining telomeres and influencing cell proliferation, genomic instability, and apoptosis.
- The precise functions of telomerase beyond telomere maintenance are still being investigated.
Purpose of the Study:
- To investigate the subcellular localization and novel functions of human telomerase reverse transcriptase (hTERT).
- To determine the impact of mitochondrial telomerase on cellular oxidative stress and DNA damage.
Main Methods:
- Utilized cell lines to track hTERT localization using an N-terminal leader sequence.
- Assessed telomerase activity in mitochondrial extracts.
- Measured hydrogen peroxide-mediated mitochondrial DNA damage in hTERT-expressing cells.
- Quantified levels of bioavailable divalent metal ions.
Main Results:
- Human telomerase reverse transcriptase (hTERT) is targeted to mitochondria via an N-terminal sequence, exhibiting activity there.
- Mitochondrial telomerase enhances hydrogen peroxide-induced mitochondrial DNA damage.
- hTERT expression correlates with increased levels of chelatable metals, suggesting a role in Fenton chemistry.
- No significant changes were observed in hydrogen peroxide breakdown rates or cellular levels.
Conclusions:
- Mitochondrial telomerase sensitizes cells to oxidative stress, potentially leading to apoptotic cell death.
- Telomerase may have a novel function in mitochondrial DNA transactions.
- These findings offer new insights into telomerase's role in cancer biology and cellular stress responses.