Stochastic Mutations in Mitochondrial DNA are Commonplace
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Certain forms of mitochondrial DNA damage are one of the causes of aging. Your mitochondria, the cell's power plants, are the remnants of ancient symbiotic bacteria. Most of their original DNA is lost or migrated to the cell nucleus, but a small number of genes remain. This DNA is much more vulnerable to damage and has worse repair mechanisms than nuclear DNA, but if important parts are lost then the outcome can be dysfunctional mitochondria that overtake the cell because they are more resistant to being cleared out by quality control mechanisms. That cell will then cause harm to surrounding tissues by exporting damaged proteins and reactive molecules: this is the modern mitochondrial free radical theory of aging in a nutshell.

Since this is likely an important cause of aging we should expect to see that everyone has an appreciable load of stochastic damage to their mitochondrial DNA, and that this damage grows over time. As the cost of DNA sequencing continues to fall and thousands of human genomes are being sequenced, this data is becoming available:

Mutations in one or more copies of mitochondrial DNA, known as heteroplasmies, are likely to be much more common in healthy people than previously anticipated. Approximately 90 percent of healthy participants in the 1000 Genomes Project harbored at least one heteroplasmy, and 20 percent bore mitochondrial genome mutations implicated in diseases. "It's been known for a long time that lesions in mitochondrial DNA become more prevalent with age. This study offers the intriguing possibility that maybe everybody has a little bit of something wrong with their mitochondrial DNA and that might play a role in aging."

Because a single cell can contain hundreds to thousands of mitochondria, it also carries multiple copies - and, sometimes, variants - of these maternally inherited genomes. Pathogenic mutations can co-exist with healthy mitochondrial DNA (mtDNA) within a cell or group of cells; clinical signs of disease only occur when the frequency of mutations crosses a threshold, which typically ranges from 60 to 85 percent of mitochondria. Severe mtDNA mutations can cause certain myopathies, epilepsy, and other diseases, while less pathogenic variants have been implicated in complex conditions such as type 2 diabetes, aging, and cancer.

Although these results suggest pathogenic mtDNA mutations are more prevalent than previously thought, the low frequency at which they occur is unlikely to have a negative impact on health. However, if the mutations increase in frequency in some fraction of cells as they divide, they could provide a likely source of mitochondrial dysfunction. "The problem is that mitochondrial DNA isn't stable, so there's nothing to say that a 1 percent load of mutation won't blossom into a different level later." Even though a low-frequency mutation "isn't pathogenic in and of itself, it's harder to develop a mutation later if you don't have one, compared to when you start with some level of mutation."


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