Editorial The Secret Life of Telomerase Donald G. Welsh
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is inversely related to mitochondrial H2O2 production. They additionally reveal in cell systems that telomerase activation elevates nitric oxide production and that interfering with the mitochondrial TERT targeting leads to a deleterious rise in superoxide production. From these findings, it is provocatively argued that nonnuclear telomerase activity is biologically important to the maintenance of endothelial function, the production of reactive oxygen species, and the setting of arterial tone (Figure). In its widest context, the findings of Beyer et al7 are notable in 2 key aspects. First, the authors forwarded a nuanced understanding of the literature to launch a novel hypothesis that ties distinct fields together. Next, instead of relying on animal models, the authors shrewdly exploited variances in human tissue function to garner new insight into TERT’s alternative role in cell function. This was an intriguing twist and one worth recognition given its clear translational significance. Juxtaposed to these strengths are the limitations that come with human work, the most significant being a limited ability to develop strong mechanistic linkages. The authors, for example, could not determine the precise means by which (1) telomerase modulates mitochondrial reactive oxygen species or how (2) TERT translocates from the nucleus. Irrespective of these issues, the observations of Beyer et al7 are enticing as they raise awareness to the nonnuclear function of telomerase in endothelial cells as a regulator of arterial tone. Is this an end to telomerase’s secret life in the mitochondria or is there another story to be told?
o prevent DNA loss during mitosis, nature has cleverly placed telomeres on the ends of chromosomes to function as disposable nucleotide sequences. Telomeres do, however, shorten with progressive cell division and without a mechanism to compensate; cells are eventually forced into senescence.1 Telomerase is an essential ribonucleoprotein complex responsible for adding TTAGGG to 3′ ends, and the catalytic subunit at its core is telomerase reverse transcriptase (TERT).2,3 Although it is clear that telomerase’s primary function is to prevent the gene truncation, reports of TERT and other complex subunits in mitochondria have fueled speculation of a secret life.4–6 That life may entail TERT affecting on sensitivity to, or the production of, reactive oxygen species.4,5 Reactive oxygen species, such as H2O2, may in turn serve as signaling molecules connecting telomerase activity to a broader spectrum of biological processes.
Article, see p 856 In the current issue of Circulation Research, Beyer et al7 build on this conceptual thread pursuing a unique line of inquiry in the resistance vasculature. Could telomerase, or more specifically TERT, regulate arterial tone by localizing to mitochondria and influencing the production of reactive oxygen species? The authors make a strategic choice to focus on flow-mediated dilation, a process enabled by nitric oxide production, except during coronary artery disease when vessels switch to H2O2.8 To assess whether this switch is coupled to TERT and mitochondrial H2O2 production, the authors generated 2 central observations. First, arteries from patients without coronary artery disease experienced a transformation in flow-mediated dilation (nitric oxide to mitochondrial H2O2) if incubated with the telomerase inhibitor, BIBR-1532. Next, the reverse transformation is cleverly demonstrated in arteries harvested from patients with coronary artery disease, exposed to the telomerase activator AGS-499. With the table set, the authors bring TERT closer with the switch in vascular function. They specifically show in intact tissues that (1) TERT is present in vascular cells, (2) TERT expression decreases in patients with coronary artery disease, and (3) telomerase activity
Sources of Funding This work was supported by an operating grant to Dr Welsh from the Natural Science and Engineering Council of Canada. Dr Welsh is also the Rorabeck Chair in Neuroscience and Vascular Biology at the University of Western Ontario.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Physiology and Pharmacology, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada. Correspondence to Donald G. Welsh, PhD, Department of Physiology and Pharmacology, Robarts Research Institute, University of Western Ontario, Rm 4245C, 1151 Richmond St N, London, Ontario, Canada N6A-5B7. E-mail [email protected]
(Circ Res. 2016;118:781-782. DOI: 10.1161/CIRCRESAHA.116.308290.) © 2016 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.116.308290
1 Olovnikow AM. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol. 1973; 41:181–190. 2. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985;43:405–413. 3. Weinrich SL, Pruzan R, Ma L, et al. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet. 1997;17:498–502. doi: 10.1038/ng1297-498. 4. Santos JH, Meyer JN, Skorvaga M, Annab LA, Van Houten B. Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage. Aging Cell. 2004;3:399–411. doi: 10.1111/j.1474-9728.2004.00124.x. 5. Ahmed S, Passos JF, Birket MJ, Beckmann T, Brings S, Peters H, BirchMachin MA, von Zglinicki T, Saretzki G. Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci. 2008;121:1046–1053. doi: 10.1242/jcs.019372. 6. Chen LY, Zhang Y, Zhang Q, Li H, Luo Z, Fang H, Kim SH, Qin L, Yotnda P, Xu J, Tu BP, Bai Y, Songyang Z. Mitochondrial localization of
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Figure. Illustrative diagram highlighting the role of telomerase in flow-induced dilation in human arteries. MLCK indicates myosin light chain kinase; MLCP, myosin light chain phosphatase; mtROS, mitochondrial reactive oxygen species; and TERT, telomerase reverse transcriptase. Downloaded from http://circres.ahajournals.org/ by guest on January 22, 2018
telomeric protein TIN2 links telomere regulation to metabolic control. Mol Cell. 2012;47:839–850. doi: 10.1016/j.molcel.2012.07.002. 7. Beyer AM, Freed JK, Durand MJ, et al. Cirtical role for telomerase in the mechanism of flow-mediated dilation in the human microcirculation. Circ Res. 2016;118:856–866. doi: 10.1161/ CIRCRESAHA.115.307918.
8. Liu Y, Zhao H, Li H, Kalyanaraman B, Nicolosi AC, Gutterman DD. Mitochondrial sources of H2O2 generation play a key role in flowmediated dilation in human coronary resistance arteries. Circ Res. 2003;93:573–580. doi: 10.1161/01.RES.0000091261.19387.AE. Key Words: Editorials ■ hydrogen peroxide ■ mitochondria ■ telomerase
The Secret Life of Telomerase Donald G. Welsh Downloaded from http://circres.ahajournals.org/ by guest on January 22, 2018
Circ Res. 2016;118:781-782 doi: 10.1161/CIRCRESAHA.116.308290 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2016 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
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