Abstract
Telomerase has cellular functions beyond telomere stabilization, including a role in mitochondria. The function of the catalytic component—TERT—in mitochondria is still unknown, but it seems to play a role in the response to oxidative stress. Here, we interrogated the role of the subcellular localization of TERT to the response to hydrogen peroxide (H2O2) treatment. Using normal human fibroblasts (NHF) expressing non-tagged wild type (WT) human TERT (hTERT) or nuclear localization and function (nuchTERT), a mutant that we previously described as being competent in telomere elongation, while not being able to localize to mitochondria, we found the differential activation of autophagy as a function of hTERT’s subcellular localization. Specifically, we found that only cells expressing the mutant had significant increases in autophagy markers as a response to H2O2 challenge. Either the reintroduction of the mitochondrial pool of hTERT or the expression of mitochondrially-targeted catalase in mutant cells blunted the autophagic response under oxidative stress. Interestingly, autophagy activation was also associated with decreased levels of mitochondrial DNA damage. Taken together, these results suggest that the loss of hTERT in mitochondria initiates a signaling cascade that allows for cells to adapt to and cope with the lack of mitochondrial telomerase. Such effects also influence the cellular response to oxidative damage.
Highlights
Telomerase is a ribonucleoprotein that is primarily responsible for telomere maintenance that is a common target in cancer therapy
Consistent with this view, we previously showed in a cell culture model that the expression of mutant human TERT that is unable to enter mitochondria, while maintaining its nuclear localization and function, led to decreased mitochondrial DNA integrity, increased mitochondrial reactive oxygen species, and altered mitochondrial ultrastructure [3]
As autophagy can enable cells to maintain homeostatic functions in response to cellular stresses, including mitochondrial dysfunction [12], we started by evaluating the autophagy markers beclin and LC3-II by Western blots in normal human fibroblasts (NHF) expressing wild type (WT) or nuchTERT
Summary
Telomerase is a ribonucleoprotein that is primarily responsible for telomere maintenance that is a common target in cancer therapy. Since the catalytic component of telomerase (TERT) is mitochondrial [1,2,3,4,5], it is anticipated that the inhibition of telomerase will affect telomere biology, and mitochondrial function. In a TERT (mTERT) knockout (KO) mouse model, systemic mitochondrial dysfunction prior to telomere defects was observed [6]. Later, it was shown, in a cancer-prone mouse model, that mTERT extinction resulted in mitochondrial dysfunction and short telomeres. While the reinstatement of telomere maintenance by recombination (ALT) allowed for the re-emergence of resistant tumors, it did not completely alleviate mitochondria dysfunction [7], indicating that TERT has an impact on mitochondria that cannot be compensated by telomere stabilization
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