DNA damage and mitochondria in cancer and aging

Abstract

Age and DNA repair deficiencies are strong risk factors for developing cancer. This is reflected in the comorbidity of cancer with premature aging diseases associated with DNA damage repair deficiencies. Recent research has suggested that DNA damage accumulation, telomere dysfunction and the accompanying mitochondrial dysfunction exacerbate the aging process and may increase the risk of cancer development. Thus, an area of interest in both cancer and aging research is the elucidation of the dynamic crosstalk between the nucleus and the mitochondria. In this review, we discuss current research on aging and cancer with specific focus on the role of mitochondrial dysfunction in cancer and aging as well as how nuclear to mitochondrial DNA damage signaling may be a driving factor in the increased cancer incidence with aging. We suggest that therapeutic interventions aimed at the induction of autophagy and mediation of nuclear to mitochondrial signaling may provide a mechanism for healthier aging and reduced tumorigenesis.

Figure 1.

Shown below is a diagram displaying the two predominant forms of mitophagy and the general workflow of this quality control mechanism. PINK1/Parkin-mediated mitophagy, as displayed on the lower half of the above mitochondria, is induced by a decrease in mitochondrial membrane potential. This induces the autophosphorylation of PINK1, which is subsequently phosphorylates and activates Parkin. Finally, Parkin polyubiquitinylates mitochondrial membrane proteins and these ubiquitinylated proteins are recognized by LC3-II. Receptor-mediated mitophagy occurs when a stimulus, such as hypoxia, results in the overexpression or activation of receptors on the surface of mitochondria. This results in the recruitment of LC3-II and subsequent autophagosome formation. Finally, lysosomes fuse with autophagosomes to form autolysosomes and the mitochondria are degraded.

Figure 2.

This diagram displays a summary of the mechanisms we have proposed in this review as contributors to the increase in cancer risk with age. In young tissue, robust nuclear DNA repair results in a healthy genome, intact telomeres and abundant NAD⁺ for activation of sirtuins. Additionally, damaged mitochondria are readily recycled through mitophagy. In contrast, in aged tissue, there is increased nuclear DNA damage, leading to constitutive PARP activation and limiting levels of NAD⁺. Nuclear DNA damage results in cytoplasmic chromatin fragments, telomere attrition and nuclear to mitochondrial signaling. Loss of sirtuin activity due to diminished NAD⁺ inhibits mitophagy, resulting in persistent dysfunctional mitochondria. These conditions foster a tumorigenic environment.