Mitochondrial theory in question
Mutations in mitochondria caused breakdowns in the cell nucleus and premature aging of mice
Polina Loseva, N+1
Finnish biologists have discovered the true cause of aging in mutator mice, in which DNA in mitochondria mutates faster than usual. It turned out that the matter is not in the mitochondria themselves, but in the fact that they take most of the nucleotides to fix mutations. When there are not enough nucleotides in the nucleus, cells cannot divide, and this leads to premature aging of animals. The work was published in the journal Nature Metabolism (Hämäläinen et al., Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias).
The mitochondrial theory of aging appeared in 1966. According to her, one of the main causes of aging is free radicals, which cause mutations in mitochondrial DNA. It is believed that as a result of the accumulation of these mutations, mitochondria cease to work fully, cells lack energy for vital processes and this leads to aging – first of the cells, and then of the body as a whole.
To simulate this situation, scientists have developed a special line of mice – they were called mutators, because they have mitochondrial mutations appear more often than usual. This is due to a defect in polymerase, an enzyme that copies DNA in mitochondria. All polymerases make mistakes with one frequency or another – they substitute the wrong nucleotide into the chain under construction. However, most are able to detect and correct their mistakes in time. In mutated mice, the polymerase is defective, and its errors remain in the DNA of mitochondria in the form of mutations.
When researchers started working with mutators, they found that they age prematurely. At the same time, people with mutations that reduce the efficiency of mitochondria do not experience accelerated aging. This means that mutations in mitochondrial DNA affect not only the efficiency of these organelles, but also some other aging processes.
Riikka Hamalainen and colleagues from the University of Eastern Finland suggested that mitochondrial and nuclear mutations are somehow related to each other - judging by the fact that mice that suffer from the accumulation of one or the other develop similar symptoms. To understand this situation, they worked with a culture of induced pluripotent stem cells (that is, adult cells that were turned into germ cells) of mutator mice and compared it with a culture of healthy cells.
Scientists calculated the ratio of cells at different stages of the cell cycle and found that mutator stem cells are more often than usual in the phase of preparation for division or the very beginning of division. The researchers suggested that for some reason the cells "get stuck" at the beginning of reproduction and cannot finish it.
Scientists stained stem cells to examine DNA damage, and saw that there were more markers of double-strand breaks in mutator cells. In addition, the expression of enzymes that are responsible for repairing damage was increased in them. Thus, against the background of mitochondrial mutations, DNA in the nucleus has also accumulated errors.
Researchers have suggested that problems with cell division may arise due to a lack of nucleotides - the building material for DNA. They measured their concentration in cells and found that there are really few of them in the nucleus, but there are many in the mitochondria. The addition of nucleotides from the outside did not save mutator cells: mitochondria take most of them for themselves.
To restore the ability of stem cells to divide, scientists decided to block the copying of mitochondrial DNA. They forced the cells to express the Tfam protein, which works as a packer of mitochondrial DNA and makes it inaccessible to other enzymes. In the presence of Tfam, there were fewer double-strand breaks in the stem cell nucleus.
Based on their data, the researchers recreated the following chain of events in mutator cells: polymerase is wrong, breakdowns accumulate in the DNA of mitochondria, repair proteins require more nucleotides to work, the concentration of nucleotides drops in the cytoplasm and nucleus, the cell cannot complete division, and mutations also accumulate in nuclear DNA. Thus, scientists propose to link the aging of mitochondria with the aging of nuclear DNA.
Recently, other researchers have found that in order for mutator mice to accumulate fewer mitochondrial mutations, it is enough to put a wheel in their cells for voluntary exercises.
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