There’s a scientific debate over what damaged mitochondria do to cause premature aging; in this episode of X10, we explore both sides of an interesting and intricate issue.
Our current understanding of biological aging is that it’s the result of different factors that interact with each other in complex ways. Malfunctioning mitochondria – which you can think of as tiny batteries that power your cells – are thought to be one of these factors and this idea has been around for a very long time. But what if mitochondria themselves aren’t really the culprits
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Let’s start with the basics. Mitochondria are organelles – basically, just parts of your cells – and the important thing about them for this video is that they have their own DNA. So there’s nuclear DNA in the nucleus and mitochondrial DNA in the mitochondria, and they don’t necessarily replicate at the same time or speed – each replicates by itself.
Mitochondrial DNA replication is at the core of this story. See, there’s an idea that accumulating mutations in mitochondrial DNA are one of the causes of aging. You can find out more about that in our video on mitochondrial dysfunction as a hallmark of aging.
Scientists have made mutator mice in which the enzyme that copies mitochondrial DNA doesn’t proofread the copy it’s making. This means that their mitochondrial DNA accumulates mutations,and, in keeping with the theory, these mice age prematurely. But a team of researchers in Finland, Sweden, and the US wanted to understand how mitochondrial mutations cause premature aging.
The theory is that the increase in mutations causes problems in the mitochondria, leading to increased production of reactive oxygen species, which cause damage. But the researchers noted that mice that have other kinds of mitochondrial malfunctions or mutations don’t age prematurely. On top of that, there aren’t increased levels of reactive oxygen species in the mature tissues of mutator mice.
That led them to think that reactive oxygen species aren’t the link between mitochondrial mutations and aging, so they set out to find out what’s really going on. When they dug into what’s happening in the cells of mutator mice, they discovered that nuclear DNA replication was stalling for some reason, and there were also signs of increased DNA damage.
It’s not exactly obvious why a lack of proofreading in mitochondrial DNA replication would cause trouble with nuclear DNA replication. The explanation they came up with is actually pretty cool.
Mitochondrial and nuclear DNA copy themselves using building blocks known as dNTPs, and both processes draw on a shared dNTP pool. The researchers found that the common dNTP pool was drawn down in mutator mouse cells. At the same time, the mitochondrial dNTP pool was enriched. In other words, it seems dNTPs are being pulled from the common pool into the mitochondria.
So, the idea is that increased mutations in mitochondrial DNA lead to faster turnover of mitochondrial DNA, which shifts the allocation of dNTPs to favour mitochondria. This means there aren’t enough dNTPs in the common pool when nuclear DNA replication happens, causing it to stall and leading to DNA damage.
In a nutshell, mitochondrial DNA mutations don’t directly cause aging. Instead, they create an imbalance that leads to nuclear DNA damage, which causes aging, but the story doesn’t end there!
A response to this study appeared alongside it. A team of researchers in Sweden used a different technique to measure dNTP pools in mutator mice and found that they were normal. They also point out problems with the method used in the original study and conclude that “changes in dNTP pools are therefore unlikely to explain the premature-ageing phenotype.”
But in a response to the response, the original team defended their case by pointing out that the new measurements were taken using whole embryos of mutator mice. They argue that this isn’t a fair comparison because “it is known that dNTP pools are tightly regulated in a cell-type-, developmental-stage- and cell-cycle-dependent fashion.” In other words, variation between different cell types in the embryo would hide the difference. They say that a fair comparison would use specific cell populations, and they stick by their original conclusions.
Who’s right? We don’t know, and we won’t know until there’s more research. That process is the part of the beauty of science, but it also means learning to reserve judgment. In the meantime, it can be rewarding to discuss these ideas and think about their implications. You can find links to the study, the response, and the response to the response in the description.
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July 14, 2021
First: in posting these please make sure to link to the underlying research:
This finding may have other significance, but isn’t relevant to aging. The kind of mutation that accumulates in aging cells is large deletions, and we already know from many lines of evidence that the way that deletion-bearing mitochondria take over the cell does NOT involve faster replication: it’s generally accepted that it happens by selective avoidance of mitophagy.
Dr. de Grey’s thesis still stands up as one of the very small number of serious contenders to explain the *mechanism* of the peculiar dynamics of mitochondrial mutations in aging:
The #2 contender (after which the field falls far away) is this:
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