May 06, 2009 — By lending them a gene normally reserved for other classes of animals,
researchers have shown they can rescue flies from their
Parkinson’s-like symptoms, including movement defects and excess free
radicals produced in power-generating cellular components called
mitochondria. The gene swap also protects healthy flies’ mitochondria,
and to a large extent the flies themselves, from the damaging effects
of cyanide and other toxins, the team reports in the May issue of Cell
Metabolism, a Cell Press publication.
key gene (single-subunit alternative oxidase or AOX) in essence acts as
a bypass for blockages in the so-called oxidative phosphorylation
(OXPHOS) cytochrome chain in mitochondria. Howard Jacobs, who led the
study at the University of Tampere in Finland, likens that chain to a
series of waterfalls in a hydroelectric power station. Only, in the
case of mitochondria, it is electrons that flow to release energy that
is captured in molecular form.
that you can take a gene that encodes a single polypeptide and bypass
OXPHOS where it is blocked," said Jacobs, emphasizing that OXPHOS
includes dozens of components and hundreds of proteins. "You may lose
power from one [molecular] ‘turbine,’ but power from the others can be
restored. With a single peptide, you can bypass two-thirds of the
system. That’s the beauty of the idea."
Defects in mitochondrial
OXPHOS are associated with diverse and mostly intractable human
disorders, the researchers said. Therefore, there’s a chance that the
strategy might also prove beneficial in mammals, including humans,
which like arthropods have also lost the AOX gene over the course of
evolution. (Arthropods are represented by insects, spiders, and crabs.)
the other hand, most plants, animals, and fungi do possess an
alternative mitochondrial respiratory chain, which can bypass the
OXPHOS system under specific physiological conditions. In plants, AOX
is thought to be essential for maintaining energy balance under
daylight conditions. In fungi, AOX has been implicated in the control
of longevity and resistance to oxidative stress. In many animals, too,
including annelid worms, mollusks, and urochordates-an underwater
filter-feeding sister group to vertebrates- AOX is present and is
believed to provide resistance to oxidative stress.
previous study, Jacobs and his colleagues tested the idea that AOX
might bypass the consequences of OXPHOS inhibition in human cells. They
introduced the gene into human cells by inserting DNA taken from the
urochordate Ciona intestinalis. Those studies found that the protein
encoded by the Ciona AOX gene made its way to mitochondria, where it
conferred cyanide-resistant respiration and protected against metabolic
acidosis, oxidative stress, and cell death when cells were treated with
OXPHOS inhibitors such as antimycin or cyanide.
shown that the same holds true in a living animal. Importantly,
ubiquitous Ciona AOX activity had no apparent ill effects for the
flies. Quite the contrary, mitochondria taken from AOX-expressing flies
showed significant resistance to cyanide, and the flies partially
resisted both cyanide and antimycin. AOX also rescued the movement
defect and excess production of reactive oxygen species by mitochondria
in flies with a mutant version of a gene known as dj-1b, which is the
fly equivalent to the human Parkinson’s disease gene DJ1.
findings led the researchers to conclude that "AOX appears to offer
promise as a wide-spectrum therapeutic tool in OXPHOS disorders." The
next step is to test whether the findings in flies will also hold true
in mammals, Jacobs said. His hope is that the AOX gene might someday be
delivered to humans via a suitable gene therapy, although he admits
that goal assumes many things will fall into place.
dysfunction is not just a problem in some rare genetic disorders or in
degenerative diseases," he said. It’s an issue in a very large number
of pathologies-and a major cause of tissue damage after heart attack
So, why don’t we have this gene in the first place, one might ask?
said he isn’t entirely sure, but he suspects the gene renders energy
production by mitochondria less efficient under normal circumstances,
which isn’t ideal for running fast to catch prey or avoid predators.
But in today’s world, he said, as people live longer and longer, it
might be better to avoid the consequences of a stroke than to run a