Mitochondrial DNA damage is a contributing cause of aging, and researchers here look at this issue in the context of the aging of heart tissue. Mitochondria are the power plants of the cell, a herd of bacteria-like structures that contain their own small genome, and work to produce the chemical energy store molecule adenosine triphosphate. This is an energetic process that produces oxidative molecules as a byproduct, capable of damaging cellular machinery and requiring maintenance and antioxidant processes as a defense. Mitochondria are destroyed by the quality control mechanism of mitophagy when damaged, and replicate to make up their numbers.

Some forms of mitochondrial DNA damage can subvert quality control and lead to problem cells overtaken by broken mitochondria, exporting harmful reactive molecules into the surrounding tissue. Ways to repair or replace damaged mitochondrial DNA will likely turn back aspects of aging by removing a source of damage and dysfunction, but the various approaches to this challenge are as yet still comparatively early in the development process.

Cardiac aging resulting in defects in cardiac mitochondrial function centers on the mitochondrial DNA (mtDNA) damage. The mechanisms of the alterations in the aging heart mainly involve mitochondrial dysfunction, altered autophagy, chronic inflammation, increased mitochondrial oxidative stress, and increased mtDNA instability.

Reactive oxygen species (ROS) play a pivotal role in healthy cellular and mitochondrial signaling and functionality. However, if unchecked, ROS can mediate oxidative damage to tissues and cells, leading to a vicious cycle of inflammation and more oxidative stress. Meanwhile, mitochondria, the major source of ROS, are thought to be particularly vulnerable to oxidative damage. Because of its richness in mitochondria and high oxygen demand, the heart is at high risk of oxidative damage. The most supportive evidence of the central role of mitochondrial ROS in the aged heart is that overexpression of catalase targeted to mitochondria attenuates cardiac aging.

A growing body of evidence suggests that there is increasing oxidative damage to mitochondrial DNA in cardiac aging. Because of the histone deficiency, limited DNA repair capabilities, and proximity of mtDNA to the site of mitochondrial ROS generation, mtDNA can suffer various types of damage, including mtDNA point mutations, mtDNA point deletions, and decreased mtDNA copy number (mtDNA-CN). The continuous replicative state of mtDNA and existence of the nucleoid structure render mitochondria vulnerable to oxidative damage and mutations.

DNA polymerase gamma (DNA Pol γ) plays a vital role in mtDNA replication. DNA Pol γ has two main functions: mtDNA synthesis and proofreading. Recent studies report that ROS reduces the proofreading ability of Pol γ, causing replication errors. Thus, oxidation aggravating mtDNA mutations causes replication errors, which indirectly cause mtDNA damage. This proves that mtDNA mutations are largely random, and Pol γ oxidation is likely to account for mtDNA mutations in aging. Therefore, mtDNA mutation may be highly associated with heart aging, and the repair of damaged mtDNA provides a potential clinical target for preventing cardiac aging.