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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:929.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Mitochondrial Telomerase Reverse Transcriptase Binds to and Protects Mitochondrial DNA and Function From Damage

Judith Haendeler; Stefan Dröse; Nicole Büchner; Sascha Jakob; Joachim Altschmied; Christine Goy; Ioakim Spyridopoulos; Andreas M. Zeiher; Ulrich Brandt; Stefanie Dimmeler

From Molecular Cardiology, Department of Internal Medicine III (J.H., C.G., I.S., A.M.Z., S.D.), and the Molecular Bioenergetics Group (S.D., U.B.), Centre of Biological Chemistry, University of Frankfurt; and IUF (J.H., N.B., S.J., J.A.), University of Düsseldorf gGmbH, Germany.

Correspondence to Judith Haendeler, PhD, IUF at the University of Düsseldorf gGmbH, Auf’m Hennekamp 50, 40225 Düsseldorf, Germany. E-mail juhae001{at}uni-duesseldorf.de

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.

Methods and 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 H₂O₂-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.

Conclusion— Mitochondrial TERT exerts a novel protective function by binding to mitochondrial DNA, increasing respiratory chain activity and protecting against oxidative stress–induced damage.

TERT is localized in the mitochondrial matrix and binds to mitochondrial DNA. TERT increases respiratory chain activity and protects mitochondria from damage. Lung fibroblasts from TERT^–/– mice show increased sensitivity toward UVB radiation, and mitochondria isolated from hearts of TERT^–/– mice demonstrates reduced respiratory chain activity. Mitochondrially targeted TERT is most effective in protecting from apoptosis induction. Thus, mitochondrial TERT exerts a novel protective function by protecting mitochondria from damage in vitro and in vivo.

Key Words: aging • apoptosis • mitochondrial functions • mitochondrial DNA • reactive oxygen species • telomerase reverse transcriptase