A General Method for Correcting Mitochondrial Mutations

A therapy that can robustly correct any mitochondrial DNA mutation throughout the body can be turned into a way to rejuvenate the stochastic damage of aging that occurs to the thirteen important mitochondrial genes not replicated in the cell nucleus. If asked to wager, based on the evidence I'd suggest that mitochondrial damage is the largest individual contribution to aging, which is why it's important to see progress on fixing it or making it irrelevant. So this, I think, is a development worth watching: "Researchers [have] identified, for the first time, a generic way to correct mutations in human mitochondrial DNA by targeting corrective RNAs ... I think this is a finding that could change the field. We've been looking to do this for a long time and we had a very reasoned approach, but some key steps were missing. Now we have developed this method and the next step is to show that what we can do in human cell lines with mutant mitochondria can translate into animal models and, ultimately, into humans. ... Gene therapy is often used to express proteins that can treat the cause of a variety of diseases. In this case, [researchers] developed a strategy to target and import specific RNA molecules encoded in the nucleus into the mitochondria and, once there, to express proteins needed to repair mitochondrial gene mutations. First, the research team had to figure out a way to stabilize the reparative RNA so that it was transported out of the nucleus and then localized to the mitochondrial outer membrane. This was accomplished by engineering an export sequence to direct the RNA to the mitochondrion. Once the RNA was in the vicinity of the transport machinery on the mitochondrial surface, then a second transport sequence was required to direct the RNA into the targeted organelle. With these two modifications, a broad spectrum of RNAs were targeted to and imported into the mitochondria, where they functioned to repair defects in mitochondrial respiration and energy production in two different cell line models of human mitochondrial disease. ... This study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence with or without a mitochondrial localization sequence, to provide an exciting, general approach for overcoming mitochondrial genetic disorders."

Link: http://www.sciencedaily.com/releases/2012/03/120312152645.htm

Comments

This seems like a big deal to me, at least the longevity related implications.

Posted by: JohnD60 at March 13th, 2012 11:26 AM

This study went over my head. Are they proposing not correcting the mtDNA and just transporting specific RNA programmed by gene therapy in the nucleus to the mitochondria (where translation would occur)? It seems like an awful complicated strategy to selectively move nuclear RNA to mitochondria if I'm getting the gist of it.

Posted by: Patrick at March 13th, 2012 3:35 PM

Stellar work of course. The next step will be to use these techniques to localise all 13 mitochondrial genes in the nucleus so the nucleus' repair machinery can protect them; by sending fresh RNA to mitochondria there is no need to send repair machinery as well. Although some added repair redundancy might be worthwhile?

Posted by: Mark Bruce at March 13th, 2012 4:28 PM

@Patrick: Yes, that is my understanding - don't fix the mutational damage, but port RNA to create the required protein on site. Other, similar strategies have been demonstrated in recent years, and the SENS approach of placing a working copy of the mitochondrial gene in the nucleus still requires that the protein get ported back to the mitochondria, which is actually the hard part of the problem.

The advance here is that this technique is general; it isn't completely specific to the one gene/protein in question, as prior methods have been. So that should make building therapies based on this foundation for any given set of mitochondrial genes much cheaper than via alternative methods.

Given that it's been a slow gene-by-gene grind to produce the basis for a working fix for each one so far, this is good news.

Posted by: Reason at March 13th, 2012 4:54 PM

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