The role of telomerase reverse transcriptase in preserving mitochondrial function following doxorubicin treatment

Doxorubicin (Dox) is a frequently used and potent chemotherapeutic, but its use is severely limited by well-established cardiovascular toxicity. Only recently has the effect of Dox on the circulatory system been recognized as an potential contributor to this problem via the development of Dox-induced endothelial dysfunction. Unpublished data by the Beyer lab demonstrates that in a rodent model of Dox-induced cardiovascular toxicity, Dox-induced endothelial dysfunction can be prevented via the treatment with cycloastragenol (CAG), a transcriptional activator of telomerase reverse transcriptase (TERT). TERT is primarily located in the nucleus and is canonically known to elongate telomeres, but TERT also translocates to the mitochondria, where TERT presents cardiovascular protective effects. TERT has been shown to reduce reactive oxygen species production, modulate mitochondrial respiration, and protect against mitochondrial DNA damage. Therefore, we hypothesize that TERT transcriptional activation prevents Dox-induced endothelial dysfunction by preserving normal mitochondrial respiration and DNA integrity. To test our hypothesis, the seahorse assay was performed to evaluate mitochondrial respiration in human microvascular endothelial cells (HMECs). Mitochondrial DNA damage using rodent microvessels was tested via qPCR. In HMECs, Dox treatment (500 & 1000nM) resulted in reduced mitochondrial respiratory readouts, which appeared to be prevented via TERT transcriptional activation via CAG following 500nM Dox only. The level of mitochondrial DNA damage appeared to be increased following Dox treatment, which was prevented via TERT in two out of the four tested mitochondrial DNA regions. In summary, our results suggest that the transcriptional activation of TERT via CAG may preserve mitochondrial respiration and DNA integrity following Doxorubicin treatment. Thank you to the NIH grant R25HL168782 and R01HL173549 for funding. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.