Every cell contains a herd of hundreds of mitochondria, bacterial-like structures that contain a small circular genome, the mitochondrial DNA. Mitochondria replicate to make up their numbers, and are culled by the quality control mechanism of mitophagy when damaged. Their primary task is to conduct the energetic chemistry that packages the energy store molecule adenosine triphosphate, used to power cellular processes. Mitochondrial function declines with age for reasons that are still comparatively poorly understood; damage to mitochondrial DNA is involved, as are changes in the expression of proteins necessary for mitophagy to function correctly.

One crude way to assess the state of mitochondria in cells is to count the number of copies of mitochondrial DNA that are present, a number that changes with aging and disease. While there is plenty of evidence for this to correlate with mitochondrial dysfunction, it doesn’t necessarily directly reflect the most interesting mechanisms in mitochondrial aging, which are all forms of damage to mitochondria and mitochondrial DNA, rather than outright loss of mitochondria. There is a web of damage and dysfunction, and while various different parts of it will tend to be in sync, that doesn’t have to imply direct causal connections.

Thinking outside the nucleus: Mitochondrial DNA copy number in health and disease

Mitochondrial dysfunction, generally characterized as a loss of efficiency in oxidative phosphorylation, is a hallmark of aging and a variety of chronic diseases. Mitochondrial dysfunction results in inefficient cellular energy production and in increased levels of reactive oxygen species (ROS) which may damage lipids, proteins, and nucleic acids. Mitochondrial dysfunction also affects the expression of nuclear genes involved in metabolism, growth, differentiation, and apoptosis. All these changes may explain the contribution of mitochondrial dysfunction to chronic and complex human diseases.

A major limitation to the routine evaluation of mitochondrial dysfunction in clinical practice is the lack of reliable measures of mitochondrial dysfunction available for clinical use. Mitochondrial DNA copy number (mtDNA-CN) is a promising biomarker of mitochondrial dysfunction that has the potential to become widely available in clinical practice. Other measures of mitochondrial dysfunction, including cell culture-based methods are optimized in vitro, do not make use of pre-existing datasets, and cannot be scaled-up for widespread use.

An emerging body of evidence supports roles for mtDNA in the complex underpinnings of a variety of diseases, including a number of cancers and aging-related disorders. A common link in these studies include anti-inflammatory pathways. These mechanisms will be further elucidated as our ability to measure mtDNA-CN from sequencing and microarray technologies expands. As studies increase in power and functional assessment of mechanisms underlying the effect of mtDNA on mitochondrial function and gene expression improve, our understanding of variation in mtDNA-CN as cause or consequence of disease development will rapidly improve.

mtDNA-CN is an especially attractive biomarker because its measurement in blood is both non-invasive and relatively cost-friendly to obtain. The proposed utility of mtDNA-CN as a biomarker for disease has been suggested by the observation that mtDNA content can differentiate healthy controls from patients with cancer and other diseases. In addition, mtDNA-CN has been shown to be relevant for risk reclassification for cardiovascular disease. Currently, these applications are limited by several analytical factors affecting the accurate and reproducible quantification of mtDNA-CN. The recent confirmation that human mtDNA is methylated adds yet another level of complexity to the crosstalk between the nucleus and mitochondrion and its control. We close by suggesting that improved detection techniques for mtDNA-CN as well as greater understanding of the mechanisms underlying individual, cell-type, and tissue-specific variation in mtDNA-CN are essential to determining the direct pathological, therapeutic and/or clinical relevance of this relatively cost-effective and easily measured biomarker.