The Relationships Between Telomeres, Telomerase, and Mitochondrial Function
Telomerase is best known for its role in lengthening telomeres. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes; a little is lost with each cell division, and telomere length is a vital part of the mechanisms of the Hayflick limit on the number of times a somatic cell can replicate. Stem cells and cancer cells use telomerase to maintain long telomeres, allowing for indefinite replication. This is not the only function of telomerase, however. It has been shown to act on mitochondria, but the nature of this relationship is nowhere near as well explored.
The present consensus on beneficial effects on health and life span in mice that result from telomerase gene therapy is that increased telomere length is the central and vital mechanism. Many lines of evidence show declining mitochondrial function to be very important in the aging process, however. To the degree that telomerase improves mitochondrial function directly, independently of effects resulting from telomere length, we might expect this to contribute to health and life span effects. As is usually the case in the matter of aging, picking apart the mechanisms in order to compare effect sizes is a challenging prospect, however.
Mitochondrial functions and telomere functions have mostly been studied independently. In recent years, it, however, has become clear that there are intimate links between mitochondria, telomeres, and telomerase subunits. Mitochondrial dysfunctions cause telomere attrition, while telomere damage leads to reprogramming of mitochondrial biosynthesis and mitochondrial dysfunctions, which has important implications in aging and diseases. In addition, evidence has accumulated that telomere-independent functions of telomerase also exist and that the protein component of telomerase TERT shuttles between the nucleus and mitochondria under oxidative stress.
Our previously published data show that the RNA component of telomerase TERC is also imported into mitochondria, processed, and exported back to the cytosol. Mitochondrial localization of TERT is a cell type-specific event that protects the cells from oxidative stress. What is the exact function of mitochondrion-localized TERT within the mitochondrial matrix, however, remains to be elucidated. This data shows a complex regulation network where telomeres, nuclear genome, and mitochondria are co-regulated by multi-localization and multi-function proteins and RNAs.