Destroying Mutant Mitochondrial DNA as a Strategy to Treat Mitochondrial Disease

The herd of bacteria-like mitochondria in each of our cells are vital cellular components, and come equipped with their own small genome, the mitochondrial DNA, one or more copies in each mitochondrion. If that DNA is broken, then harm results. Mitochondrial diseases bear only superficial similarities to the mitochondrial DNA damage that is a root cause of degenerative aging; while it is the case that mitochondrial DNA is mutated in both cases, the distribution of those mutations in cells and tissues is quite different. Nonetheless, it seems a reasonable proposition that a strategy of selectively destroying damaged mitochondrial DNA may work in each situation, though for different reasons.

In inherited mitochondrial disease, there is some split between healthy and damaged copies of mitochondrial DNA in cells. Destroy the bad genome copies and the good ones will hopefully replicate to make up that loss. In aging, just a few cells become entirely overtaken by clones of mitochondria with damaged genomes, but they exert a sizable negative influence on health via generation of oxidative molecules. Destroying all of the mitochondrial DNA in those cells might be expected to kill them, for all of the obvious reasons. Since there are few of them, destroying them is probably the most expedient approach to dealing with the issue. In both cases, effectiveness would be determined by how clean a sweep is made, though one might imagine temporary or partial benefits resulting from removing even half of the damaged mitochondrial genomes.

"Mitochondrial replacement therapy is a promising approach to prevent transmission of mitochondrial diseases, however, as the vast majority of mitochondrial diseases have no family history, this approach might not actually reduce the proportion of mitochondrial disease in the population. One idea for treating these devastating diseases is to reduce the amount of mutated mitochondrial DNA by selectively destroying the mutated DNA, and allowing healthy DNA to take its place."

To test an experimental gene therapy treatment, which has so far only been tested in human cells grown in petri dishes in a lab, the researchers used a mouse model of mitochondrial disease that has the same mutation as some human patients. The gene therapy treatment, known as the mitochondrially targeted zinc finger-nuclease, or mtZFN, recognises and then eliminates the mutant mitochondrial DNA, based on the DNA sequence differences between healthy and mutant mitochondrial DNA. As cells generally maintain a stable number of mitochondrial DNA copies, the mutated copies that are eliminated are replaced with healthy copies, leading to a decrease in the mitochondrial mutation burden that results in improved mitochondrial function.

The treatment was delivered into the bloodstream of the mouse using a modified virus, which is then mostly taken up by heart cells. The researchers found that the treatment specifically eliminates the mutated mitochondrial DNA, and resulted in measures of heart metabolism improving. Following on from these results, the researchers hope to take this gene therapy approach through clinical trials, in the hope of producing an effective treatment for mitochondrial diseases.



If you can target a protein to the mitochondria, could you not just target a full mitchondrial DNA plasmid to the mitochondria at the same time?

You'd need a vector that can carry a large amount of material like Oisin's fusogenix nanoparticles. You couldn't do this with the AAV vectors used in this experiment.

Posted by: Jim at September 26th, 2018 7:14 AM

@Jim: The problem is not so much carrying something to the mitochondria but introducing it on it. MitoSENS proteins are introduced through tiny biochemical gates.

Posted by: Antonio at September 26th, 2018 8:54 AM

If one can use the RNA import complex [RIC] adapted from the parasitic protozoon Leishmania tropica then hell, one could use CRISPR because then there would be a potential way to get the guide RNA that nuclear CRISPR requires, into mitos. But methinks that wouldn't work. There is likely a good reason we keep our RNAs from getting into mitos and it may be foolish to tinker blindly there

Posted by: john at September 26th, 2018 10:14 AM

@antonio - the protein used to edit the DNA inside the mitochondria is a mitchondrially targeted zinc finger nuclease, so I'm assuming the problem of getting this protein inside the mitochondria has been solved by the researchers? I can't read the nature paper yet to check this as it is not yet available on

Posted by: Jim at September 26th, 2018 4:36 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.