Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage.
OBJECTIVE
The enzyme telomerase and its catalytic subunit the telomerase reverse transcriptase (TERT) are important for maintenance of telomere length in the nucleus. Recent studies provided evidence for a mitochondrial localization of TERT. Therefore, we investigated the exact localization of TERT within the mitochondria and its function.


RESULTS
Here, we demonstrate that TERT is localized in the matrix of the mitochondria. TERT binds to mitochondrial DNA at the coding regions for ND1 and ND2. Binding of TERT to mitochondrial DNA protects against ethidium bromide-induced damage. TERT increases overall respiratory chain activity, which is most pronounced at complex I and dependent on the reverse transcriptase activity of the enzyme. Moreover, mitochondrial reactive oxygen species are increased after genetic ablation of TERT by shRNA. Mitochondrially targeted TERT and not wild-type TERT revealed the most prominent protective effect on H(2)O(2)-induced apoptosis. Lung fibroblasts from 6-month-old TERT(-/-) mice (F2 generation) showed increased sensitivity toward UVB radiation and heart mitochondria exhibited significantly reduced respiratory chain activity already under basal conditions, demonstrating the protective function of TERT in vivo.


CONCLUSIONS
Mitochondrial TERT exerts a novel protective function by binding to mitochondrial DNA, increasing respiratory chain activity and protecting against oxidative stress-induced damage.
Haendeler
Judith
J
Molecular Cardiology, Department of Internal Medicine III, Centre of Biological Chemistry, University of Frankfurt, Germany. juhae001@uni-duesseldorf.de
Dröse
Stefan
S
Büchner
Nicole
N
Jakob
Sascha
S
Altschmied
Joachim
J
Goy
Christine
C
Spyridopoulos
Ioakim
I
Zeiher
Andreas M
AM
Brandt
Ulrich
U
Dimmeler
Stefanie
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004579:Electron Transport; D042783:Endothelial Cells / Q000201:enzymology; D004996:Ethidium / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008168:Lung / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000528:radiation effects; D008929:Mitochondria, Heart / Q000201:enzymology; D018384:Oxidative Stress; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014466:Ultraviolet Rays
D004272:DNA, Mitochondrial; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse; D004996:Ethidium