Mitochondrial DNA and aging
This note quotes a comment on a recent study in which it was demonstrated that the method of weakening mitochondrial function causes an acceleration of the aging process in mice. In a sense, the comment is much more understandable than the article itself, which describes the study. In this case, there is one problem that is universal for all studies in which any of the vital biochemical mechanisms in the animal's body is disrupted, and the result of this looks like an acceleration of the aging process. It lies in the fact that such forms of artificial breakdowns almost never shed light on the processes of normal aging. They create a completely new status of metabolism and extinction of functions.
It is true that normal aging is a process of accumulation of damage and reactions to these injuries. However, it is a specific mixture of damage to certain tissues. These injuries are the consequences of the loss of cellular and tissue functions and, in turn, lead to the appearance of visible and well-known symptoms of aging and age-related diseases. However, almost any form of serious disruption or breakdown of the biochemical process, if it does not occur in the wild, will also lead to the loss of cellular and tissue functions. Very high levels of unrecoverable DNA damage, far exceeding the levels of DNA damage in normal animals, lead to the development of conditions similar to accelerated aging. As a natural example, Hutchinson-Guilford progeria syndrome can be cited. However, it practically does not provide us with information about normal aging, which is characterized by lower levels of nuclear DNA damage.
In the study described here, the mitochondria of mice damaged the ability of mitochondrial DNA polymerase (DNA pol γ) to correct errors during mtDNA replication, after which random mutations began to accumulate in the genomes of mitochondria.
The result of this was very much like accelerated aging. Mitochondria are the energy centers of the cell responsible for the synthesis of chemical energy storage molecules used to power all cellular processes. Progressive extinction of mitochondrial functions is involved in the aging process and the development of many age-related diseases, however, just as in the case of increased levels of nuclear DNA damage, it is not at all obvious that artificial mitochondrial damage provides us with useful information about the contribution of mitochondria to normal aging. This definitely helps us to understand what happens if we damage something, but any other conclusions are very doubtful and strongly depend on the details.
Excerpts from the article "Mitochondrial DNA keeps you young"
(Massimo Bonora & Paolo Pinton, Mitochondrial DNA keeps you young), published in the journal Cell Death & Disease.
"Aging is characterized by the extinction of mitochondrial functions, including a decrease in the concentration of enzymes of the tricarboxylic acid cycle (Krebs cycle), a decrease in respiratory volume, as well as an increase in the production of reactive oxygen species (ROS). This is observed both in animal models and in the human body. The described changes can lead to the appearance of DNA mutations, cell death, the development of inflammation, as well as the extinction of stem cell functions, which contributes to tissue degeneration. Presumably, the driving force of this process is an increase in the number of mutations of mitochondrial DNA, observed both in mouse models and in human cells.
Mitochondrial DNA (mtDNA) is replicated using specialized mitochondrial DNA polymerase. This enzyme was deprived of the ability to edit DNA sequence errors to create a mouse model – the so-called "mitochondrial mutator mice", in whose mitochondrial DNA mutations randomly appear. This model demonstrates a pronounced phenotype of premature aging, including hair loss, graying, and the development of kyphosis. All this is accompanied by a decrease in the activity of the mitochondrial respiratory complex and an increase in oxidative stress.
Recently, researchers have described a new transgenic mouse model with induced mitochondrial DNA depletion – the so-called mtDNA depleter mouse. The DNA of these animals has a mutation that, under the action of the antibiotic doxycycline, induces a mutant DNA polymerase that blocks the replication of mitochondrial DNA. As the expired mitochondrial DNA is removed from the cell as a result of mitophagy, its amount in the cell gradually decreases and after 2 months this decrease reaches 60%. Since mitochondrial DNA encodes the nucleated subunits of mitochondrial respiratory complexes, the activity of the latter is significantly reduced.
At the macroscopic level, mtDNA depleter mice demonstrate accelerated aging, including weight loss and kyphosis, but the skin aging process is especially pronounced, manifested by hyperplastic and hyperkeratous epidermitis, degeneration of hair follicles and the formation of extensive inflammatory infiltrates. Despite the fact that this model needs a detailed additional description, histological examination of sections of other analyzed tissues (considered to have a need for high mitochondrial activity), including the liver, brain and myocardium, did not reveal serious changes.
The question of how mitochondrial DNA depletion affects the aging process remains very interesting. The presence of extensive inflammatory infiltrates indicates that mitochondria can produce reactive oxygen species, as they act as signaling molecules for the activation of inflammosomes. Unfortunately, the author did not provide data on the severity of oxidative stress, however, cells deprived of mitochondrial DNA are usually characterized by reduced oxygen consumption and production of reactive oxygen species. This indicates that oxidative stress does not mediate the development of the aging phenotype described above. At the same time, two serious consequences described below were described in the cellular model of mitochondrial DNA depletion using the same strategy used for depleter mice: (1) a significant restructuring of the histone acetylation profile due to indirect changes in citrate levels and (2) a decrease in cell proliferation activity due to a decrease in membrane potential and destabilization of the transcription factor Hif1a. While the type of epigenetic rearrangements characteristic of aging is unclear, it has been shown that Hif1a depletion leads to the formation of a phenotype of accelerated skin aging in mice.
Another extremely interesting aspect of this study is the restoration of the phenotype. The cessation of doxycycline exposure provided an unexpected and almost complete restoration of the amount of mitochondrial DNA and skin phenotype in 1 month. The restoration of the amount of mitochondrial DNA was predictable, since its original pool was not completely depleted, whereas the restoration of the skin phenotype is much more curious. The mutator mouse model provided important data on how mitochondria can induce the formation of an aging phenotype through the extinction of the ability of hematopoietic and neural stem cells to self-renew. The authors suggest that mitochondrial DNA depletion affects the functions of epidermal stem cells, which leads to skin aging. Despite the fact that for a long time it has been assumed that stem cells do not depend on mitochondrial function (at least for ATP production), additional observations of adult stem cells of other tissues indicate that mitochondria play a fundamental role in the process of self-renewal of stem cells. However, progenitor cells, whose dependence on mitochondrial respiration has been proven for many models, may be more sensitive to mitochondrial DNA depletion and, accordingly, responsible for rapid recovery.
Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Fight Aging!: Commentary on Recent Research into Mitochondrial DNA and Aging.