Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases

Abstract

Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, etc. Cellular senescence is causally related to the occurrence and development of age-related disease. The elderly is liable to suffer from disorders such as neurodegenerative diseases, cancer, and diabetes. Therefore, it is increasingly imperative to explore specific countermeasures for the treatment of age-related diseases. Numerous studies on humans and mice emphasize the significance of metabolic imbalance caused by short telomeres and mitochondrial damages in the onset of age-related diseases. Although the experimental data are relatively independent, more and more evidences have shown that there is mutual crosstalk between telomeres and mitochondrial metabolism in the process of cellular senescence. This review systematically discusses the relationship between telomere length, mitochondrial metabolic disorder, as well as their underlying mechanisms for cellular senescence and age-related diseases. Future studies on telomere and mitochondrial metabolism may shed light on potential therapeutic strategies for age-related diseases. Graphical Abstract The characteristics of cellular senescence mainly include mitochondrial dysfunction and telomere attrition. Mitochondrial dysfunction will cause mitochondrial metabolic disorders, including decreased ATP production, increased ROS production, as well as enhanced cellular apoptosis. While oxidative stress reaction to produce ROS, leads to DNA damage, and eventually influences telomere length. Under the stimulation of oxidative stress, telomerase catalytic subunit TERT mainly plays an inhibitory role on oxidative stress, reduces the production of ROS and protects telomere function. Concurrently, mitochondrial dysfunction and telomere attrition eventually induce a range of age-related diseases, such as T2DM, osteoporosis, AD, etc. :increase; :reduce;⟝:inhibition.

Keywords: Aging; Cellular senescence; Mitochondrial metabolism; Telomeres.

Graphical Abstract

The characteristics of cellular senescence mainly include mitochondrial dysfunction and telomere attrition. Mitochondrial dysfunction will cause mitochondrial metabolic disorders, including decreased ATP production, increased ROS production, as well as enhanced cellular apoptosis. While oxidative stress reaction to produce ROS, leads to DNA damage, and eventually influences telomere length. Under the stimulation of oxidative stress, telomerase catalytic subunit TERT mainly plays an inhibitory role on oxidative stress, reduces the production of ROS and protects telomere function. Concurrently, mitochondrial dysfunction and telomere attrition eventually induce a range of age-related diseases, such as T2DM, osteoporosis, AD, etc. :increase; :reduce;⟝:inhibition.

Fig. 1

Telomeres are repeating ends of linear chromosomes. The composition of the shelterin complex, CST complex and telomerase and its binding site to telomere DNA are described in the figure. Shelterin complex are primarily involved in inhibiting DDR. CST is mainly located in single-stranded telomere DNA, inhibiting telomerase activity and thus preventing telomere overstretching. Telomerase adds DNA repeat sequences at the end of telomere 3’ through its RNA template. Continuous cell division leads to telomere shortening, causing cellular senescence

Fig. 2

ROS produced by mitochondria enters the cell nucleus and causes the telomere DDR, activates p53, inhibits PGC-1α signaling pathway and affects mitochondrial function, eventually induces cellular senescence. Telomerase catalyzes the removal of subunit TERT stimulated by oxidative stress from the nuclei and locates in mitochondria. This co-localization of TERT and mitochondria protects mitochondrial function by reducing mitochondrial ROS production. :increase; :reduce; ⟝,⟞:inhibition