Mitochondrial DNA Heteroplasmy in the Aging Heart

Every cell contains hundreds of mitochondria, bacteria-like structures that carry their own small genome, the mitochondrial DNA. Mitochondria replicate like bacteria to maintain their population size, and are destroyed when worn and damaged by the quality control mechanism of mitophagy. The primary task undertaken by mitochondria is the generation of chemical energy store molecules (adenosine triphosphate, ATP) to power the cell, but they also play many other roles in fundamental cell processes. Mitochondrial DNA is poorly protected and repaired in comparison to nuclear DNA, and accumulates mutational damage over time. It is argued that this damage contributes to loss of mitochondrial function, and thus faltering tissue function, particularly in energy-hungry organs such as the heart.

The most common aging-associated diseases are cardiovascular diseases which affect 40% of elderly people. It is well accepted that the origin of aging-associated cardiovascular diseases is mitochondrial dysfunction. Mitochondria have their own genome (mtDNA) that is circular and double-stranded. There are between 500 to 6000 mtDNA copies per cell, depending on tissue type. As a by-product of ATP production, reactive oxygen species (ROS) are generated which damage proteins, lipids, and mtDNA.

ROS-mutated mtDNA co-existing with wild type mtDNA is called mtDNA heteroplasmy. The progressive increase in mtDNA heteroplasmy causes progressive mitochondrial dysfunction leading to a loss in their bioenergetic capacity, disruption in the balance of mitochondrial fusion and fission events (mitochondrial dynamics, MtDy) and decreased mitophagy. This failure in mitochondrial physiology leads to the accumulation of depolarized and ROS-generating mitochondria. Thus, besides attenuated ATP production, dysfunctional mitochondria interfere with proper cellular metabolism and signaling pathways in cardiac cells, contributing to the development of aging-associated cardiovascular diseases.

In this context, there is a growing interest to enhance mitochondrial function by decreasing mtDNA heteroplasmy. Reduction in mtDNA heteroplasmy is associated with increased mitophagy, proper MtDy balance and mitochondrial biogenesis; and those processes can delay the onset or progression of cardiovascular diseases. This has led to the development of mitochondrial therapies based on the application of nutritional, pharmacological, and genetic treatments, seeking to have a positive impact on mtDNA integrity, mitochondrial biogenesis, dynamics, and mitophagy in old and sick hearts.



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