DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?

Abstract

Cellular senescence is the ultimate and irreversible loss of replicative capacity occurring in primary somatic cell culture. It is triggered as a stereotypic response to unrepaired nuclear DNA damage or to uncapped telomeres. In addition to a direct role of nuclear DNA double-strand breaks as inducer of a DNA damage response, two more subtle types of DNA damage induced by physiological levels of reactive oxygen species (ROS) can have a significant impact on cellular senescence: Firstly, it has been established that telomere shortening, which is the major contributor to telomere uncapping, is stress dependent and largely caused by a telomere-specific DNA single-strand break repair inefficiency. Secondly, mitochondrial DNA (mtDNA) damage is closely interrelated with mitochondrial ROS production, and this might also play a causal role for cellular senescence. Improvement of mitochondrial function results in less telomeric damage and slower telomere shortening, while telomere-dependent growth arrest is associated with increased mitochondrial dysfunction. Moreover, telomerase, the enzyme complex that is known to re-elongate shortened telomeres, also appears to have functions independent of telomeres that protect against oxidative stress. Together, these data suggest a self-amplifying cycle between mitochondrial and telomeric DNA damage during cellular senescence.

Figure 1.

Telomeres shorten with cell division due to the ‘end-replication problem’ and single-strand break accumulation due to damage by ROS generated as by-product of mitochondrial respiration. This induces a DNA damage response including formation of telomeric DNA damage foci and activation of p53. Activated p53 triggers senescent growth arrest.

Figure 2.

Possible mechanisms influencing mitochondrial ROS generation: (1) mtDNA damage could lead to dysfunctional respiratory chain activity and increased ROS, (2) mitochondrial elongation by decreased fission has been shown to increase ROS generation, (3) increased mitochondrial biogenesis has been shown to correlate with ROS generation and induce cellular senescence. ROS-generated telomere shortening as well as double-stranded breaks at non-telomeric DNA activate a DNA damage response and cellular senescence.