Mitochondria are the power plants of the cell, vital organelles evolved from symbiotic bacteria that merged with early cellular life to form the first eukaryotes. Every cell contains hundreds of mitochondria, capable of replicating to make up their numbers, as well as fusing together and swapping component parts. Each mitochondrion bears at least one mitochondrial DNA copy, a remnant genome that contains a small number of genes necessary for mitochondrial function. Mitochondrial DNA is more vulnerable to mutational damage and less capable of repair than is the case for DNA in the cell nucleus. It is thought that the accumulation of mitochondrial DNA damage in cells throughout the body contributes to aging via loss of mitochondrial function, but the situation is complicated by selection effects in the mitochondrial population and the operation of mitophagy, a recycling process to clear damaged and dysfunctional mitochondria.
Oocytes are female germline cells, a population that gives rise to egg cells. Oocytes and the cells of their supporting niche have evolved a variety of mechanisms to protect oocyte nuclear DNA from damage; this is fairly well studied. Less well studied is damage that occurs to mitochondrial DNA in oocytes, but it is reasonable to think that oocytes could have evolved the means to minimize mitochondrial DNA damage for all the same reasons that they have evolved ways to better protect nuclear DNA - at least in longer-lived species such as our own. The interesting question is whether any of these evolved mechanisms could usefully be applied to other cells in the body to better maintain their mitochondrial DNA. The first step is to identify these mechanisms, and that is still a work in progress.
Whereas mitochondrial DNA (mtDNA) mutations have been analyzed in human somatic tissues in detail, the direct examination of mtDNA mutations in human oocytes has been challenging due to methodological limitations. Most previous studies either focused on particular mtDNA sites or used sequencing methods with high error rates. Using a low-error duplex sequencing approach, we have recently shown that mutations across the whole mtDNA increase with age in mouse oocytes. Using the same approach, we have demonstrated that mtDNA mutations increase in macaque oocytes until ∼9 years of age and do not increase afterward. Importantly, we still do not know definitively whether the frequency of de novo mtDNA mutations increases with age in human oocytes.
To address this knowledge gap, we analyzed mtDNA substitution mutations in single oocytes, blood, and saliva from women of ages 20 to 42. We used the highly accurate duplex sequencing method, which we had previously modified to generate high-quality mtDNA sequences directly from single oocytes. We obtained a comprehensive set of mutations to study the impact of age on frequencies of germline and somatic mutations, as well as on their distribution across mtDNA.
We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies (≥1%) were less prevalent in coding than non-coding regions, whereas mutations with low allele frequencies (<1%) were more uniformly distributed along mtDNA, suggesting frequency-dependent purifying selection. In somatic tissues, mutations caused elevated amino acid changes in protein-coding regions, suggesting positive or destructive selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations having functional consequences and with aging. These findings are particularly timely as humans tend to reproduce later in life.
View the full article at FightAging
