The Golden Key
The keys to solving the problems of aging are in the mitochondria
Many age-related diseases have a common feature: the mitochondria of cells begin to malfunction. Although not all the reasons for this process have been clarified, experts representing the Buck Institute for Research on Aging have identified one of the mechanisms that disrupt the work of mitochondria. In the future, their discovery may be useful in the development of aging therapy.
"Now that we have a hypothesis about why mitochondrial dysfunction occurs during aging and age—related diseases, we are discovering a completely new way to understand, measure, mitigate and reverse this process," says senior author of the study Chuankai Zhou (Chuankai "Kai" Zhou).
Mitochondria are often called the "powerhouse" of the cell — these bean-shaped structures provide it with energy. They are involved in many important life processes — including the immune response, inflammation and metabolism.
Mitochondrial dysfunction is observed in most chronic diseases, including neurodegenerative disorders, cardiovascular disorders, cancer, diabetes and obesity, Zhou notes. There is growing evidence that such dysfunction contributes to aging in general.
Zhou's team set out to investigate the contribution of mitochondrial biogenesis to the process of mitochondria functioning during aging.
Mitochondrial biogenesis is a cellular process in which new mitochondria are born. It determines both the quality and quantity of mitochondria in cells (which decreases with normal aging).
Over the past couple of decades, scientists have described two main stages of mitochondrial biogenesis: transcriptional activation of mitochondrial protein in the cell nucleus in response to nutritional/metabolic signals and import of these newly synthesized mitochondrial proteins from the cytosol into the mitochondria. However, it was unclear how these two stages of mitochondrial biogenesis coordinate with each other to optimize the synthesis and import of mitochondrial proteins. Zhou's team discovered that a conserved receptor molecule on the surface of mitochondria called Tom70 may be responsible for coordinating these two steps by regulating the transcriptional activity of mitochondrial proteins inside the nucleus.
Earlier it became known that Tom70 facilitates the import of newly synthesized mitochondrial proteins. However, Zhou noted, the amount of protein produced must be fine-tuned to meet the needs and productive capacity of mitochondria. Overproduction of mitochondria is just as dangerous as their deficiency: excess accumulates inside the cell, which damages it and can even kill it.
In the current study, Zhou's team used yeast as a model organism to test whether Tom70 regulates mitochondrial biogenesis by coordinating a complex balance between the production of proteins destined for mitochondria and the rate at which these proteins can be delivered to mitochondria. It turned out that it is.
Figure from the press release Buck Scientist Uncovers Clues to Aging in Mitochondria – VM.
A similar regulatory function of Tom70 is preserved in fruit flies.
An important result of the work is that the level of Tom70 decreases during aging, which is associated with a decrease in mitochondrial biogenesis. Similar reductions in Tom70 levels were observed earlier in elderly fruit flies and rats. It also turned out that increasing the level of Tom70 in yeast delays mitochondrial dysfunction and increases life expectancy. This discovery is related to what has been known for more than a decade: an increase in Tom70 can protect human cells in certain chronic diseases, such as cardiovascular diseases; now it becomes clear why.
"We have discovered a new function of this protein, and we are uncovering the mechanism of how Tom70 can do good things for the cell," says Zhou.
Zhou also explained how new knowledge can point to promising directions in aging research. For example, the Tom70 signaling pathway may be associated with an increase in life expectancy observed with calorie restriction.
"In addition, if our hypothesis is confirmed, it will naturally lead to the appearance of health products — dietary supplements or medicines. It just takes time," Zhou concludes.
The work of Zhou and his colleagues is published in the journal eLife (Liu et al., Volume 70-based transcriptional regulation of mitochondrial biogenesis and aging).
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