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The Impact of Progressive Telomere Shortening on Mitochondria Function and Energy Metabolism

Luis Batista, Ph.D.

Project Overview:

Telomeres, the physical ends of eukaryotic chromosomes, are progressively shortened upon each cellular division. Telomere shortening can be prevented by telomerase, a ribonucleoprotein complex that synthesizes telomeres from an RNA template, TERC. As tissue-resident stem cells and their downstream progenitors are required to generate functional cell types throughout life, efficient telomere maintenance and therefore telomerase activity in these cells is essential for tissue homeostasis. However, telomerase activity in stem cell niches is not sufficient to prevent telomere erosion over time, and a large body of evidence supports that human telomeres shorten with aging. In fact, telomere erosion is seen as a hallmark of aging and several age-associated diseases, such as cancer, reduced immune function, diabetes and cardiovascu+lar disease, are associated and/or predicted by telomere shortening. Recent data established that more than a simple bystander in aging, telomere shortening is a driving force behind this response, acting as a disease potentiator and mortality predictor. However, the precise molecular mechanisms responsible for impact of telomere shortening on the onset and contribution to diseases that affect the broad elderly population remain unclear.

Surprisingly, experiments with model organisms have recently shown that telomere shortening has a direct and deleterious effect on mitochondrial biogenesis and function, another well-known hallmark of cellular aging. Clinical data suggests that several phenotypes observed in settings of short telomeres are shared with patients with mitochondrial dysfunction, including cardiovascular diseases and diabetes. However, the processes linking telomere shortening to mitochondria dysfunction in human tissue-renewing cells is still unknown, due in large part to difficulties in isolating and maintaining these cells in culture.

The goal of this proposal is to understand if telomere erosion can affect mitochondria function, and if this interplay between different hallmarks of the aging process can impair stem-cell homeostasis. Moreover, we want to understand if the deleterious consequences of telomere shortening can be rescued by direct, nongenetic interventions that could potentially be translated in a future clinical approach against tissue dysfunction caused by telomere shortening and mitochondrial decline. A broad multidisciplinary approach will be used for us to achieve these goals. We have recently engineered human isogenic pluripotent stem cells harboring different mutations in telomerase that are found in patients suffering from premature aging syndromes. These pluripotent stem cells express endogenous levels of telomerase and resemble in many ways the adult stem cells that are responsible for tissue homeostasis. Surprisingly, our preliminary results indicate that telomerase mutant cells display altered oxygen consumption and respiratory spare capacity, as well as a reduction in mitochondrial DNA copy number and increased mitochondrial DNA deletions, all of these phenotypes that are associated to aging. These results give us confidence that we have developed an absolutely novel and extremely robust model to study the role od telomere shortening on mitochondrial decline.

In this proposal we will use our human stem cells with defective telomere maintenance to directly understand the consequences of telomere dysfunction to cellular metabolism and mitochondria function, as well as elucidate its consequences to stem cell fitness. Moreover, we will also directly interrogate if mitochondrial dysfunction due to telomere shortening in human stem cells can be rescued, a first step in the process of uncovering a direct intervention capable of rescuing fitness in elderly patients with dysfunctional telomeres. We believe this proposal directly addresses the LLF’s mission and our lab has the expertise necessary to perform all of these experiments, which, combined with our unique reagents, puts us in an optimal position to address these questions.