Evidence for a Mechanism that Operates in Oocytes to Reduce Mitochondrial DNA Mutation Rate

Researchers here show that, in primates, oocyte cells are more protected from mutations to mitochondrial DNA in later life. This suggests that one or more mechanisms are operating to produce this outcome. Given that mitochondrial DNA mutations are implicated in age-related loss of mitochondrial function and other aspects of aging, the existence of protective mechanisms is potentially interesting. It is not as interesting as the ability to repair or replace damaged mitochondrial DNA, of course. Mechanisms that can only produce sizable differences by operating over long periods of time are a poor foundation upon which to build rejuvenation therapies.

New mutations occur at increasing rates in the mitochondrial genomes of developing egg cells in aging rhesus monkeys, but the increases appear to plateau at a certain age and are not as large as those seen in non-reproductive cells, like muscle and liver. A new study using an accurate DNA sequencing methodology suggests that there may be a protective mechanism that keeps the mutation rate in reproductive cells relatively lower compared to other tissues in primates, a fact that could be related to the primate - and therefore human - propensity to reproduce at later ages.

Mitochondria are cellular organelles - often called the powerhouse of the cell because of their role in energy production - that have a genome of their own separate from the cell's nuclear genome. Researchers sequenced the mitochondrial genome from muscle cells, liver cells, and oocytes - precursor cells in the ovary that can become egg cells - in rhesus macaques that ranged in age from one to 23 years. This age range covers almost the entire reproductive lifespan of the monkeys. Tissues for the study were collected opportunistically over the course of several years from primate research centers when animals died of natural causes or were sacrificed because of diseases not related to reproduction. Oocytes, and not sperm cells, were used because mitochondria are inherited exclusively through the maternal line.

Overall, the researchers saw an increase in the mutation frequency in all of the tested tissues as the macaques aged. Liver cells experienced the most dramatic change with a 3.5-fold increase in mutation frequency over approximately 20 years. The mutation frequency in muscle increased 2.8-fold over the same time span. The mutation frequency in oocytes increased by 2.5-fold up to age nine, at which point it remained steady. Our results suggest that primate oocytes might have a mechanism to protect or repair their mitochondrial DNA, an adaptation that helps to allow later reproduction. The precise mechanism leading to the plateau in mutation frequency in oocytes remains enigmatic, but it might act at the level of elimination of defective mitochondria or oocytes."

Link: https://science.psu.edu/news/Makova4-2022

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