Research published in Circulation has shown that mitochondrial, but not nuclear, telomerase reverse transcriptase (TERT) protects against damage caused by heart attacks in a murine model.
A non-canonical role
While TERT’s name comes from its main function, the protection of telomere length in the cellular nucleus, the researchers make it clear that TERT has other functions as well, even when it is not expressed in the nucleus. For example, prior research has shown that mitochondrial telomerase protects against DNA damage in cancer cells by decreasing the amounts of reactive oxygen species (ROS) [1].
The mouse experiment
In order to determine the contributions of mitochondrial and nuclear TERT to cellular protection, the researchers tested four lines of mice. Wild-type mice were used as the controls, another strain had a complete knockout of TERT, another strain had no TERT in the nucleus but additional TERT in the mitochondria (mitoTERT), and the final strain had no TERT in the mitochondria but additional TERT in the nucleus (nucTERT).
They then subjected these mice to ischemic heart attacks and observed their recovery. One of the first things they found was that nucTERT mice performed slightly worse than TERT-knockout mice. Because their immediate death rate was so high (50%) and the size of the resulting infarctions did not differ from TERT-knockout mice, the researchers chose not to continue experiments with nucTERT mice.
Instead, they focused on the mitoTERT mice, which had substantially lower death rates than even the wild-type mice. Vascularization, a measurement of the blood vessels entering tissue, was substantially reduced in TERT-knockout mice, but less so in wild-type and mitoTERT mice. While the hearts of wild-type and TERT-knockout mice were substantially enlarged 28 days after heart attack, mitoTERT mice had much less enlarged hearts. Wild-type mice had smaller scars than TERT-deficient mice, and mitoTERT mice had even smaller scars than wild-type mice.
In sum, the researchers had found that mitoTERT mice had only slightly reduced heart function after their injuries, while wild-type and TERT-knockout mice were much more injured. These results clearly show that the researchers’ hypothesis is correct: mitochondrial TERT is protective against heart attack.
A closer examination
The researchers performed an in-depth examination of the functions of mitochondrial TERT in the cell. They found that cardiomyocytes (heart muscle cells) that had additional mitochondrial TERT were protected from apoptosis (cellular death), both at baseline and when exposed to hydrogen peroxide. Mitochondrial TERT was also found to increase migration in a wound test.
The researchers pin their results on the actions of Complex I, a critical component of mitochondrial respiration. After performing a proteomic analysis, the researchers found that one of the key differences between wild-type, TERT-knockout, and mitoTERT cells was a protein called Prohibitin. This protein was found to be increased in TERT-knockout mice but decreased in mitoTERT mice, and prior research has found that it is increased with aging [2].
How can this discovery be used?
Armed with this new knowledge, the researchers then investigated two methods of potentially defending against ischemic disease. They considered remote ischemic preconditioning (RIPC), a procedure in which patients are artificially given ischemic attacks in one organ in order to protect them from additional ischemia in other organs. The researchers sampled the mitochondrial TERT levels of patients that had undergone this procedure, finding that their levels were greater than those of a placebo group.
The researchers then examined TA-65, a telomerase activator that has been shown to be generally safe in humans. Their investigation found that TA-65 improved mitochondrial TERT in human endothelial cells and made them more like those of mitoTERT mice.
Conclusion
This research is in its infancy, and the exact biochemical relationships between mitochondrial TERT, respiratory complex I, and Prohibitin have not been elucidated. However, it seems clear that further research into this area might lead to effective interventions for ischemic heart attack, including both preventative measures and post-operative treatments.
Literature
[1] Singhapol, C., Pal, D., Czapiewski, R., Porika, M., Nelson, G., & Saretzki, G. C. (2013). Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. PloS one, 8(1), e52989.
[2] Miwa, S., Jow, H., Baty, K., Johnson, A., Czapiewski, R., Saretzki, G., … & Von Zglinicki, T. (2014). Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice. Nature communications, 5(1), 1-12.
