Mitochondrial TERT enhances mitochondria functions in vivo by protecting mitochondrial DNA integrity from oxidative damage : meeting abstract

Mitochondria are essential for respiration and oxidative phosphorylation. Mitochondrial dysfunction due to aging processes is involved in pathologies and pathogenesis of a series of cardiovascular disorders. New results accumulate showing that the enzyme telomerase with its catalytic subunit telomerase reverse transcriptase (TERT) has a beneficial effect on heart functions. The benefit of short-term running of mice for heart function is dependent on TERT expression. TERT can translocate into the mitochondria and mitochondrial TERT (mtTERT) is protective against stress induced stimuli and binds to mitochondrial DNA (mtDNA). Because mtDNA is highly susceptible to damage produced by reactive oxygen species (ROS) which are generated in close proximity to the respiratory chain, the aim of this study was to determine the functions of mtTERT in vivo and in vitro. Therefore, mitochondria from hearts of adult, 2nd generation TERT-deficient mice (TERT -/-) and wt littermates were isolated and state 3 respiration was measured. Strikingly mitochondria from TERT -/- revealed a significantly lower state 3 respiration (TERTwt: 987 +/- 72 pmol/s*mg vs. TERT-/-: 774 +/- 38 pmol/s*mg, p < 0.05, n = 5). These results demonstrated that TERT -/- mice have a so far undiscovered heart phenotype. In contrast mitochondria isolated from liver tissues did not show any differences. To get further insights in the molecular mechanisms, we reduced endogenous TERT levels by shRNA and measured mitochondrial reactive oxygen species (mtROS). mtROS were increased after ablation of TERT (scrambled: 4.98 +/- 1.1% gated vs. shTERT: 2.03 +/- 0.7% gated, p < 0.05, n = 4). We next determined mtDNA deletions, which are caused by mtROS. Semiquantitative realtime PCR of mtDNA deletions revealed that mtTERT protects mtDNA from oxidative damage. To analyze whether mitochondrial integrity is required to protect from apoptosis, vectors with mitochondrially targeted TERT (mitoTERT) and wildtype TERT (wtTERT) were transfected and apoptosis was measured. mitoTERT showed the most prominent protective effect on H2O2 induced apoptosis. In conclusion, mtTERT has a protective role in mitochondria by importantly contributing to mtDNA integrity and thereby enhancing respiration capacity of the heart

Atlas al-‘Aīn: The Performativity of “return” and Common Memory Production

Theorizing landscape as a site where Palestinian “return” is enacted and performed allows us to better understand the intersections of memory construction, “return” and spatial practices. The atlas al-‘aīn is a collective, open-ended, and performative counter-archive of common memories. Ontologically and geographically the atlas revolves around the water springs of Al-Walaja and foregrounds the villagers’ oral histories. This essay reflects on three assemblies from the atlas al-‘aīn in the light of their pedagogical, historical, material and theoretical implications. Grounded in the atlas, the essay puts forth “common memory” as a category that is inherently performative, shared and spatialized, mobilizing “to return” as a performative practice against the Nakba as an ongoing process of genocide and erasure

Telomerase as a Therapeutic Target in Cardiovascular Disease.

Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials. Graphic Abstract: A graphic abstract is available for this article.Work in the VA laboratory is supported by the Spanish Ministerio de Ciencia e Innovación (MCIN) (PID2019-108489RB-I00) and the Instituto de Salud Carlos III (ISCIII) (AC17/00067) with co-funding from the European Regional Development Fund (ERDF, “Una manera de hacer Europa”), and the Progeria Research Foundation (Award PRF 2019–77). The CNIC is supported by the ISCIII, the MCIN, and the Pro CNIC Foundation. I. Spyridopoulos is funded by the British Heart Foundation (PG/18/25/33587) and National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The work of J. Haendeler and J. Altschmied is in part supported by the Deutsche Forschungsgemeinschaft (DFG) SFB1116, A04 (J. Haendeler and J. Altschmied), HA2868/14-1 (J. Haendeler) and AL288/5-1 (J. Altschmied). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health’. I. Spyridopoulos also receives a grant from TA-Science for the TACTIC trial (Telomerase Activator to Reverse Immunosenescence in Acute Coronary Syndrome).S

Mechanisms of resistance to Hsp90 inhibitor drugs: a complex mosaic emerges

The molecular chaperone Hsp90 holds great promise as a cancer drug target, despite some of the initial clinical trials of Hsp90 inhibitor drugs having not lived up to expectation. Effective use of these drugs will benefit greatly from a much more detailed understanding of the factors that contribute to resistance, whether intrinsic or acquired. We review how cell culture studies have revealed a number of different mechanisms whereby cells can be rendered less susceptible to the effects of Hsp90 inhibitor treatment. A major influence is Hsp90 inhibition causing strong induction of the heat shock response, a stress response that increases cellular levels of prosurvival chaperones such as Hsp27 and Hsp70. Another problem seems to be that these inhibitors do not always access the Hsp90 proteins of the mitochondrion, forms of Hsp90 that-in cancer cells-are operating to suppress apoptosis. It should be possible to overcome these drawbacks through the appropriate drug redesign or with the combinatorial use of an Hsp90 inhibitor with a drug that targets either heat shock factor or the chaperone Hsp70. Still though, cells will often differ in the key antiapoptotic versus proapoptotic activities that are dependent on Hsp90, in the key steps in their apoptotic pathways responsive to Hsp90 inhibition or Hsp70 level, as well as the extents to which their survival is dependent on oncogenic tyrosine kinases that are clients of Hsp90. A systems approach will therefore often be required in order to establish the most prominent effects of Hsp90 inhibition in each type of cancer cell. © 2011 by the authors; licensee MDPI, Basel, Switzerland

A Lexicon of Migration: OSUN Connected Learning Contest Winner

Course: A Lexicon of Migration is course examines the history of migration from local, national, and global perspectives. It also traces the emergence of new modes of border regulation and migration governance as well as novel forms of migrant cultural production and representation. Above all, it aims to provide students with the tools to engage critically with many of the concepts and buzzwords—among them “asylum,” “border,” “belonging,” “citizenship,” and “illegality”—that define contemporary public debates. NOTE: A Lexicon of Migration is a Bard network course, and my course was coordinated with similar courses at the American University of Central Asia, Al-Quds Bard, and Bard College Berlin. My collaborators were Shirin Tumenbaeva (AUCA), Jens Haendeler (AQB), and Agata Lisiak (BCB)

Telomere shortening may be associated with human keloids

<p>Abstract</p> <p>Background</p> <p>Keloids are benign skin tumors that are the effect of a dysregulated wound-healing process in genetically predisposed patients. They are inherited with an autosomal dominant mode with incomplete clinical penetrance and variable expression. Keloids are characterized by formation of excess scar tissue beyond the boundaries of the wound. The exact etiology is still unknown and there is currently no appropriate treatment for keloid disease.</p> <p>Methods</p> <p>We analyzed sample tissues were obtained from 20 patients with keloid skin lesions and normal skin was obtained from 20 healthy donors. The telomeres were measured by Terminal Restriction Fragment (TRF) analysis and Real-Time PCR assay. Quantitative Real-Time RT-PCR analysis of hTERT gene expression was performed and intracellular ROS generation was measured.</p> <p>Results</p> <p>In this study, we determined whether telomeric shortening and the expression of human telomerase reverse transcriptase (hTERT) occurs in keloid patients. Using Terminal Restriction Fragment (TRF) analysis and Real-Time PCR assay, we detected a significant telomere shortening of 30% in keloid specimens compared to normal skin. Using quantitative Real-Time RT-PCR, telomerase activity was found absent in the keloid tissues. Moreover, an increase in ROS generation was detected in fibroblasts cell cultures from keloid specimens as more time elapsed compared to fibroblasts from normal skin.</p> <p>Conclusion</p> <p>Telomere shortening has been reported in several metabolic and cardiovascular diseases. We found that telomere shortening can also be associated with human keloids. Chronic oxidative stress plays a major role in the pathophysiology of several chronic inflammatory diseases. Here we found increased ROS generation in fibroblasts from keloid fibroblasts cell cultures when compared to normal skin fibroblasts. Hence we conclude that oxidative stress might be an important modulator of telomere loss in keloid because of the absence of active telomerase that counteracts telomere shortening.</p