Pharmacology & Physiology

Research Interests

The mitochondrion represents a target of reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) appears to be an early and sensitive marker of this stress. Many human diseases are associated with ROS, including cancer, heart disease and neurodegenerative disorders. The mtDNA encodes 13 polypeptides, 11 involved in electron transport and two serving as subunits of ATP synthase. Damage to mtDNA is repaired, but prolonged oxidant treatment results in persistent mtDNA damage, loss of mitochondrial function, and apoptosis. These observations suggest that mtDNA damage is important in the toxicity induced by ROS. Recently, I have identified that the protein component of telomerase (hTERT) is also targeted to the mitochondria. More importantly, presence of hTERT in mitochondria increases the susceptibility of human cells to hydrogen peroxide-induced apoptosis, while nuclear-only hTERT is protective.

Telomerase is a reverse transcriptase well recognized for its role in telomere biology. It is normally expressed during early stages of development. As development progresses, expression of hTERT is down-regulated in most somatic tissues. Thus, the majority of normal cells in the adult do not show much telomerase activity, but non-differentiated somatic cells (such as hematopoetic, germ cells and the cryptic cells of the intestine) are telomerase-positive. Yet even in these cells, telomerase activity is insufficient to prevent telomere attrition with age. Telomerase, therefore, may have functions other than telomere elongation in highly proliferative normal adult somatic cells.

The major focus of my laboratory is, therefore, to explore hypothesis that will help understand the biological role(s) of hTERT in the cell, with particular emphasis in its activity in the mitochondria. To this end, we are using different approaches, including biochemistry, molecular and cell biology techniques.