Telomerase Reverse Transcriptase Improves Mitochondrial Function

Telomerase gene therapies usual deliver telomerase reverse transcriptase (TERT), which might be thought of as the most important part of the full telomerase complex. Most research has focused on the ability of telomerase to lengthen telomeres, and where overexpression of telomerase is seen to extend life span in animal models, lengthening of telomeres is the mechanism most explored by the research community. However, TERT also acts on mitochondria. Here, researchers advance the understanding of how mitochondrially localized TERT can improve mitochondrial function. Given the importance of mitochondria in aging, it is an interesting question as to the degree to which telomere lengthening versus improved mitochondrial function produce the improved health, lower cancer incidence, and extension of life span observed in mice as a result of telomerase gene therapies.

The catalytic subunit of telomerase, telomerase reverse transcriptase (TERT) has protective functions in the cardiovascular system. TERT is not only present in the nucleus, but also in mitochondria. However, it is unclear whether nuclear or mitochondrial TERT is responsible for the observed protection and appropriate tools are missing to dissect this. We generated new mouse models containing TERT exclusively in the mitochondria (mitoTERT mice) or the nucleus (nucTERT mice) to finally distinguish between the functions of nuclear and mitochondrial TERT. Outcome after ischemia/reperfusion, mitochondrial respiration in the heart as well as cellular functions of cardiomyocytes, fibroblasts, and endothelial cells were determined.

All mice were phenotypically normal. While respiration was reduced in cardiac mitochondria from TERT-deficient and nucTERT mice, it was increased in mitoTERT animals. The latter also had smaller infarcts than wildtype mice, whereas nucTERT animals had larger infarcts. The decrease in ejection fraction after one, two and four weeks of reperfusion was attenuated in mitoTERT mice. Scar size was also reduced and vascularization increased. Mitochondrial TERT protected a cardiomyocyte cell line from apoptosis. Myofibroblast differentiation, which depends on complex I activity, was abrogated in TERT-deficient and nucTERT cardiac fibroblasts and completely restored in mitoTERT cells. Mechanistically, mitochondrial TERT improved the ratio between complex I matrix arm and membrane subunits explaining the enhanced complex I activity. In human right atrial appendages, TERT was localized in mitochondria and there increased by remote ischemic preconditioning.

In conclusion, mitochondrial, but not nuclear TERT, is critical for mitochondrial respiration and during ischemia/reperfusion injury. Mitochondrial TERT improves complex I subunit composition. TERT is present in human heart mitochondria, and remote ischemic preconditioning increases its level in those organelles. We conclude that mitochondrial TERT is responsible for cardioprotection and its increase could serve as a therapeutic strategy.


Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.