Authors: 
S.S. Ahmed, J. Passos, T. von Zglinicki, G.C. Saretzki
Category: 
Oral
Conference: 
Abstract: 

Oxidative damage is thought to be a major cause for replicative senescence and human ageing. We and others have shown that external modulation of oxidative stress levels can modify telomere shortening rates and the replicative life span of a given cell culture. Hyperoxia (40% oxygen partial pressure) accelerates production of reactive oxygen species mitochondrial respiration and increases telomere shortening dramaticly.

Transfection of normal fibroblasts with the catalytic subunit of telomerase (hTERT) counteracts telomere shortening and cellular senescence. It has also been shown that these cells are more resistant against different types of damage and apoptosis.

The aim of the study was to investigate how telomerase over-expression affects cellular ROS production, telomere maintenance and growth arrest under chronic oxidative stress.

hTERT over-expression resulted in reduced mitochondrial ROS production and cellular peroxide levels, lower frequencies of telomeric single strand breaks, a delayed induction of gamma-H2A.X foci formation and an incomplete growth arrest. Surprisingly, MRC/hTERT cells undergo accelerated telomere shortening under oxidative stress comparable to that of parental MRC-5 cells despite high telomerase activity in whole cell lysates. However, in contrast to parental MRC-5 cells, the growth arrest and telomere shortening of MRC/hTERT fibroblasts under hyperoxia were reversible when these cells were set back to normal culture conditions. The data suggest that hTERT overexpression confers resistance of fibroblasts to oxidative stress by improving mitochondrial function, but cannot ensure telomere maintenance under chronic oxidative stress. Preliminary data suggest that hyperoxia excludes hTERT, at least partially, from the nucleus and we are recently testing the hypothesis that it might directly interact with mitochondria.

Keywords (Optional): 
senescence
oxidative stress
telomerase
hTERT
mitochondria