November 21, 2016 by Lori Dajose
Mitochondrial DNA is the small circular chromosome found inside mitochondria. The mitochondria are organelles found in cells that are the sites of energy production. Credit: http://www.genome.gov/ (CC0)
Researchers from Caltech and UCLA have developed a new
approach to removing cellular damage that accumulates with age. The technique
can potentially help slow or reverse an important cause of aging.
Led by Nikolay Kandul, senior postdoctoral scholar in
biology and biological engineering in the laboratory of Professor of Biology
Bruce Hay, the team developed a technique to remove mutated DNA from
mitochondria, the small organelles that produce most of the chemical energy
within a cell. A paper describing the research appears in the November 14 issue
of Nature Communications.
There are hundreds to thousands of mitochondria per
cell, each of which carries its own small circular DNA genome, called mtDNA,
the products of which are required for energy production. Because mtDNA has
limited repair abilities, normal and mutant versions of mtDNA are often found
in the same cell, a condition known as heteroplasmy. Most people start off life
with some level of heteroplasmy, and the levels of mutant mtDNA increase throughout
life. When a critical threshold level of mutant mtDNA is passed, cells become
nonfunctional or die.
The accumulation of mutant mtDNA over a lifetime is
thought to contribute to aging and degenerative diseases of aging such as
Alzheimer's, Parkinson's, and sarcopenia—age-related muscle loss and frailty.
Inherited defects in mtDNA are also linked to a number of conditions found in
children, including autism.
"We know that increased rates of mtDNA mutation
cause premature aging," says Hay, Caltech professor of biology and biological
engineering. "This, coupled with the fact that mutant mtDNA
accumulates in key tissues such as neurons and muscle that lose function as we
age, suggests that if we could reduce the amount of mutant mtDNA, we could slow
or reverse important aspects of aging."
The team—in collaboration with Ming Guo, the P. Gene
and Elaine Smith Chair in Alzheimer's Disease Research and professor of
neurology and pharmacology at UCLA, and UCLA graduate student Ting
Zhang—genetically engineered Drosophila, the common fruit fly, so that about 75
percent of the mtDNA in muscles required for flight, one of the most energy
demanding tissues in the animal kingdom, underwent mutation in early adulthood.
This model recapitulates aging in young animals. Drosophila grow quickly and
most human disease genes have counterparts in the fly, making it an important
model in which to study human disease-related processes. The researchers chose
to focus on muscle because this tissue undergoes age-dependent decline in all
animals, including humans, and it is easy to see the consequences of loss of
function.
Unlike mutations in the DNA in the nucleus, which can
be corrected through cellular repair mechanisms, mutations in mtDNA are often
not repaired. However, cells can break down and remove dysfunctional
mitochondria through a process called mitophagy, a form of cellular quality
control. What was unclear prior to this work was whether this process could
also promote the selective elimination of mutant mtDNA.
The team found that when they artificially increased
the activity of genes that promote mitophagy, including that of several genes
implicated in familial forms of Parkinson's disease, the fraction of mutated
mtDNA in the fly muscle cells was dramatically reduced. For example,
overexpressing the gene parkin, which is known to specifically promote the
removal of dysfunctional mitochondria and is mutated in familial forms of
Parkinson's disease, reduced the fraction of mutant mtDNA from 76 percent to 5
percent, while the overexpression of the gene Atg1 reduced the fraction to 4
percent.
"Such a decrease would completely eliminate any
metabolic defects in these cells, essentially restoring them to a more
youthful, energy-producing state," notes Hay. "The experiments serve
as a clear demonstration that the level of mutant mtDNA can be
reduced in cells by gently tweaking normal cellular processes."
"Now that we know mtDNA quality control exists
and can be enhanced, our goal is to work with Dr. Guo's lab to search for drugs
that can achieve the same effects," Hay adds. "Our goal is to create
a future in which we can periodically undergo a cellular housecleaning to
remove damaged mtDNA from the brain, muscle, and other tissues. This will help
us maintain our intellectual abilities, mobility, and support healthy aging
more generally."
More information: Nikolay P. Kandul et al. Selective removal of deletion-bearing
mitochondrial DNA in heteroplasmic Drosophila, Nature Communications
(2016). DOI: 10.1038/ncomms13100
Journal reference: Nature
Communications
Provided by: California
Institute of Technology
http://medicalxpress.com/news/2016-11-aging-clock.html
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