Scientists from Caltech and the University of California at Los Angeles have developed a new approach to removing the cellular damage that accumulates with age. This method can potentially help slow down or reverse important aging processes. Under the direction of Nikolay Kandul, an associate professor in the field of biology and biological engineering in the laboratory of biology professor Bruce Hay, scientists have developed a technique for removing mutant DNA from mitochondria, small organelles that produce most of the chemical energy in a cell. A work describing the study was published last week in the journal Nature Communications.
Each cell contains hundreds or thousands of mitochondria, each of which carries its own small circular DNA genome called mtDNA, whose products are necessary for energy production. Since mtDNA has limited repair capabilities, normal and mutant versions of mtDNA are often found in a single cell, and this condition is called heteroplasmy. Most people begin life with some level of heteroplasmy, and mutant mtDNA levels increase throughout their lives. When the critical threshold of mutant mtDNA is overcome, the cells become non-functional or die.
The accumulation of mutant mtDNA throughout life is believed to contribute to aging and the manifestation of degenerative diseases of old age, such as Alzheimer's disease, Parkinson's disease and sarcopenia - age-related loss of muscle strength and fragility. Hereditary defects of mtDNA are also associated with a variety of conditions that are found in children, including autism.
“We know that increasing the rate of the mtDNA mutation causes premature aging,” says Hay, a professor of biology and biological engineering at Caltech. “Combined with the accumulation of mtDNA in important tissues like neurons and muscles, this leads to the loss of important functions. If we could reduce the amount of mutant mtDNA, we could slow down or reverse important aspects of aging. ”
Scientists have changed the fruit flies, the usual fruit fly, with the help of genetic engineering so that about 75% of the mtDNA in the muscles required for flight, which are very demanding of energy in the animal kingdom, underwent mutations in early adulthood. This model means aging in young animals. Drosophila grow quickly, and most genes of human diseases have analogues in flies, so they are important for studying the processes associated with human disease. The researchers decided to focus on the musculature, because its tissues are experiencing degradation associated with aging in all animals, including humans.
Unlike DNA mutations in nuclei, which can be eliminated using cellular repair mechanisms, mutations in mtDNA are often impossible to correct. However, cells can break down and remove poor-quality mitochondria in the process of mitophagy, a kind of control of cellular quality. Prior to this work, it remained unclear whether using this process to selectively get rid of mutant mtDNA.
Scientists have discovered that when they artificially increased the activity of genes that contribute to mitophagy, including several genes associated with hereditary forms of Parkinson's, the proportion of mutant mtDNA in muscle cells of the flies declined dramatically. For example, overexpression of the parkin gene, which in particular leads to the removal of dysfunctional mitochondria and is a mutant familial form of Parkinson's disease, reduced the proportion of mutant mtDNA from 76% to 5%; and overexpression of the Atg1 gene reduced the proportion to 4%.
"This reduction completely eliminates any metabolic defects in these cells, essentially rejuvenates their energy-producing state," says Hay. “Experiments are a clear demonstration that the level of mutant mtDNA in cells can be reduced by carefully adjusting normal cellular processes.”
Now that scientists know that mtDNA quality management is indeed possible and can be improved, it is necessary to create drugs that can lead to the same effects. In the future, scientists intend to create drugs, with the help of which it will be possible to periodically clean the cells, removing the damaged mtDNA from the brain, muscles and other tissues. This will help us to preserve our intellectual abilities, mobility, make healthier as a whole.
The article is based on materials .
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