Taking a Look at Mitochondrial Repair Research

Mitochondria are the power plants of our cells, tiny organelles churning away to turn food into ATP, the molecule used to transport energy used in cellular processes. Mitochondria were once symbiotic bacteria, way back in the dim and distant evolutionary past, and one remnant of that origin is that they contain their own DNA, separate from the DNA within the cellular nucleus. Unfortunately for us - and all other species that depend upon mitochondria - the operating processes of these organelles gradually damages their DNA, which in turn leads to a chain of consequences and further cellular damage, spreading and accelerating over the years to produce a large faction of what we know as degenerative aging.

Aging is nothing more than accumulated biochemical damage, and our mitochondria produce more than their fair share of that damage.

You will recall that DNA is essentially a blueprint for proteins, and that the proteins produced from these blueprints through the process of gene expression are components in biological machinery vital to the operation of a cell - or of a mitochondrion. If a section of mitochondrial DNA is knocked out by damage, then that mitochondrion is no longer capable of full functionality. It can no longer produce one or more of the proteins it needs, a state of affairs which causes all sorts of issues.

If, however, scientists could employ modern biotechnology to repair or work around mitochondrial DNA damage and the consequent loss of important proteins, then the medical community could build a therapy to completely alleviate this aspect of aging. We know that it takes a few decades of life for the effects of accumulated mitochondrial DNA damage to even start to become significant (given that most thirty year olds are in good shape), so a repair therapy for mitochondria would only have to be applied once every twenty or thirty years at worst.

How are researchers approaching the development of a fix for mitochondrial DNA damage, however? Over at the SENS Foundation, Michael Rae summarizes the options:

A number of credible proposals have been advanced for rejuvenation biotechnology to restore youthful mitochondrial function [to cells overtaken by damaged mitochondria]. The lead candidate approach, first proposed by SENS Foundation Chief Scientific Officer de Grey, is the placement of functioning "backup copies" of the protein-coding mtDNA genes in the cell nucleus ("allotopic expression" (AE)). There has been substantial progress in this area since then, and in recent years SENS Foundation has prioritized funding of AE research beginning with early work by Mark Hamalainen in Ian Holt's lab at Cambridge, and later in both the SENS Foundation Research Center and in the lab of Dr. Marisol Corral-Debrinski at the Institut de la Vision at Pierre and Marie Curie University, Paris. Active investigation of AE is soon to resume in the latter two centers.

But other potential routes to mitochondrial rejuvenation do exist and should also be developed, including the wholescale intraorganellar replacement of mtDNA using "protofection" and the delivery of allotopic RNA to the organelle. The latter possibility was highlighted by work targeting tRNA human cell mitochondria with the transgenic use of the transfer RNA import complex adapted from the parasitic protozoon Leishmania tropica. Working with Newcastle University's Dr. Robert Lightowlers and others, UCLA's Carla Koehler and Michael Teitella have now identified and begun to characterize a mammalian-specific mitochondrial system for the import of nuclear-encoded RNA, which could well be exploited to meet this biomedical challenge.

...

And of course, in principle there is no exclusivity between AE of protein and AE of mRNA: provided that at minimum the mitochondrial tRNAs can be allotopically expressed and imported, regenerative engineers could deliver some fully-translated AE proteins and some mRNA precursors, depending on the facility and efficiency of either approach for a given protein, and on the burden on the relevant import machinery.

Delivering RNA is an option because the process of gene expression - of turning the DNA blueprint into the protein end result - uses RNA as an intermediate stage. Genetic transcription is the first step in gene expression, wherein RNA is formed from the DNA blueprint. So if you can deliver the right RNA to the right place in a cell, you don't need the original DNA: it could be damaged or missing, and the desired protein would still be produced.

That there are at least three options under serious consideration for mitochondrial rejuvenation is a good sign for the future of this field. Competition is the lifeblood of progress, and the more of it the better.

Comments

Are there any lab projects to show or prove any of the theory expressed here.

Posted by: David Robinson at December 11th, 2012 7:30 AM
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