Bypassing OXPHOS Damage?

This post is on the topic of mitochondria, their contribution to age-related damage as described by the mitochondrial free radical theory of aging, and the biochemical process of generating fuel for your cells called oxidative phosphorylation (OXPHOS). So you may want to read my explanation for laypeople before continuing:

The synopsis: mitochondria, the power plants of your biology, have several methods of turning food into ATP, the chemical used as fuel by your cells. The primary method is OXPHOS, but this generates free radicals that can sometimes so damage a mitochondrion that it can no longer run the OXPHOS process. It then switches to a secondary (and less efficient) process that has two effects: a) the mitochondrion becomes far less likely to be recycled along with other worn cellular components, so eventually only damaged mitochondria are left in a cell, and b) enough of these damaged mitochondria bring their cell into a state of imbalance that can only be solved by dumping large quantities of free radicals into the surrounding tissue. That in turn causes all sorts of wide-ranging damage to the body's biochemistry, building up over time.

A number of research groups are toiling away at solutions to this portion of the aging process, such as replacing mitochondria entirely, replacing the damaged portions that cause OXPHOS to falter, or moving the critical components of OXPHOS biological machinery elsewhere in the cell such that it will continue to work even if the mitochondria suffers damage.

My attention was directed today to researchers who seem to have a method of bypassing OXPHOS damage via a gene present in some types of animal, but not in insects or mammals:

The key gene (single-subunit alternative oxidase or AOX) in essence acts as a bypass for blockages in the so-called oxidative phosphorylation (OXPHOS) [process] 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.

"This is the first whole organism test for the idea 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."


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.

Now, they've 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.

So they can get OXPHOS partially running even where damaged enough to normally be non-functional - which sounds like it might be a viable partial solution to this form of age-related biochemical damage. I would be interested to see the results of a mouse life span study run with this genetic alteration.


Would be nice to have a motor that never ages, but the shell around that motor ages and looks more and more ugly as the whole body ages.

This discovery may help to keep age related costs down, but will not resolve the problem of decrepitude.

Posted by: Tamea L'Jones at May 6th, 2009 8:39 PM

is it possible to develop interferons / rnai to destroy defective mitochondria?
Also, how does egg destroy/prevent accumulation of defective mitochondria?

Posted by: acci at May 18th, 2009 3:18 PM
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