Role of mitochondrial Telomerase Reverse Transcriptase and mitochondrial p27 in myocardial infarction

Typical hallmarks after acute myocardial infarction are the damage of mitochondria, reduced ATP production in cardiomyocytes and migratory capacity of endothelial cells as well as an impaired ability of cardiac fibroblasts to differentiate into myofibroblasts. We assigned crucial functions to Telomerase Reverse Transcriptase (TERT) and the cell cycle inhibitor CDKN1B (p27), both originally described as nuclear proteins, inside the mitochondria. We have shown that exclusive mitochondrial localization of TERT in mice and in cells ex vivo improves the outcomes after ischemia/reperfusion (I/R) and reverts dysfunction of cardiomyocytes, endothelial cells and fibroblasts when compared to TERT-deficiency or presence of TERT in the nucleus and the mitochondria. Furthermore, caffeine improved the outcome after I/R with concomitant translocation of p27 into the mitochondria. Having demonstrated that mitochondrial TERT and mitochondrial p27 have a protective impact after I/R, translational approaches will be tested, e.g. delivery of recombinant mitochondrial p27 or activation of TERT by the Telomerase activator TA-65, which has already been tested for safety in humans. On the molecular level, both mitochondrial TERT and mitochondrial p27 improve mitochondrial functions, thus, common upstream regulators could exist. The protein kinase Akt1, which itself is negatively regulated by the phosphatase PTP1B, phosphorylates both proteins, therefore, Akt1 and PTP1B could be potential common regulators. As functions of TERT and p27 within the mitochondria are still elusive, the characterization of transcriptome changes evoked by retrograde signaling to the nucleus and the identification of mitochondrial interaction partners in the heart could give deeper insights into potential targets for therapeutic intervention.

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This project is funded within the framework of the collaborative research center CRC1116 (A04) by the DFG.
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Prof. Dr. Judith Haendeler -
Prof. Dr. Joachim Altschmied -
Dr. Nilo Ale-Agha
Dr. Philipp Jakobs -
B.Sc. Fiona Cox -
Dr. rer. nat. Nadine Dyballa-Rukes -
Dipl. Biol. Olaf Eckermann -
Florian von Ameln -

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