Supporting Evidence for Mitochondrial Transfer as Therapy
Bacteria-like mitochondria are the cell's power plants, and they become damaged with age. This damage spirals out to create a small but significant population of cells that export harmful reactive compounds into surrounding tissues and the circulatory system, contributing to a range of age-related conditions. One possible approach to address this issue involves destroying existing damaged mitochondria and replacing them with undamaged versions. Simply introducing new undamaged mitochondria is an easier proposition but probably not sufficient, as the damaged versions overtake cells because they have an advantage in replication: diluting their numbers won't last very long.
Here researchers provide more evidence to show that simply introducing new mitochondria into a tissue environment is probably sufficient to see them taken up into cells and used. This is great news for work on inherited genetic mitochondrial disorders, where supplying new unmutated mitochondria should be a cure, but it is only a part of any potential treatment for the mitochondrial damage of aging based on mitochondrial replacement:
Mitochondria play an essential role in eukaryotes, and mitochondrial dysfunction is implicated in several diseases. Therefore, intercellular mitochondrial transfer has been proposed as a mechanism for cell-based therapy. In addition, internalization of isolated mitochondria cells by simple coincubation was reported to improve mitochondrial function in the recipient cells. However, substantial evidence for internalization of isolated mitochondria is still lacking, and its precise mechanism remains elusive.We tested whether enriched mitochondria can be internalized into cultured human cells by simple coincubation using fluorescence microscopy and flow cytometry. Mitochondria were isolated from endometrial gland-derived mesenchymal cells (EMCs) or EMCs stably expressing mitochondrial-targeted red fluorescent protein (EMCs-DsRed-mito), and enriched by anti-mitochondrial antibody-conjugated microbeads. They were coincubated with isogeneic EMCs stably expressing green fluorescent protein (GFP).
Live fluorescence imaging clearly showed that DsRed-labeled mitochondria accumulated in the cytoplasm of EMCs stably expressing GFP around the nucleus. Flow cytometry confirmed the presence of a distinct population of GFP and DsRed double-positive cells within the recipient cells. In addition, transfer efficiency depended on mitochondrial concentration, indicating that human cells may possess the inherent ability to internalize mitochondria. Therefore, this study supports the application of direct transfer of isogeneic mitochondria as a novel approach for the treatment of diseases associated with mitochondrial dysfunction.
This is an interesting potential delivery mechanism for advanced synthetic biology treatments. Mitochondria can act as cell cycle gatekeepers, so specially designed "mitochondria" that are easily taken up by cells could influence cell fate in all sorts of ways in accordance with their design.
But can the new Mitochondria be seeded (presumably by intermuscular injection) in sufficient quantity in humans to reproduce and outnumber native mitochondria in less than a year? I doubt it.
Nuclear expression of mitochondrial genes and the import of their proteins into mitochondria seems like a more permanent solution. Although you'd have to transfect every cell in the body. Is this possible with gene therapy?
I hope to be able to undergo some treatment like this. It would be nice if it turned out you could create new mitochondria relatively easy and then inject them in large numbers. Until that day I will stick with targeted antioxidants for what it's worth.
I don't think you would need to transfect every cell in the body, only cells that are long lived. If a cell dies the mitochondria is gone with the cell.
"Simply introducing new undamaged mitochondria is an easier proposition but probably not sufficient, as the damaged versions overtake cells because they have an advantage in replication: diluting their numbers won't last very long."
I wonder what is meant by "their numbers won't last very long"? Does anyone know how long would they last and be effective? Because if they can last long enough till the patient undergoes another infusion of new mitochondria then that would presumably be sufficient. Or perhaps the newly introduced mitochondria could just be altered in some way to give them a slight selective advantage over the damaged ones.
I'm just saying if it's relatively easy to introduce new mitochondria this approach shouldn't necessarily be abandoned for more complex interventions.
@Cosmicalstorm: "what it's worth" is, unfortunately, nothing ;) .
@Jim: transfecting every cell (or rather, as my Didymus says, every long-lived cell) would be very challenging today, which is why Dr. de Grey has had stuff on improving delivery systems on his site from since before SENS Research Foundation even existed. However, (a) by the time we have allotopic expression ready for rollout to normal, otherwise-healthy aging people, gene therapy will surely be much better than it is today (anyone attending RB2014 got a glimpse of some quite astonishing unpublished material on progress in using CRISPR), and (b) one can of course put people through multiple rounds of transfection over time.
@Jen: no one is quite sure what the rate of "takeover" of postmitotic cells by deletion-bearing mitochondria is. All we know is that we essentially never see cells in tissues in any kind of transitional, "heteroplasmic" state with a mixture of deletion-bearing and non-deletion-bearing mitochondria: they're either homoplasmic for deletion-bearing mitos, or have wild-type mitos or mitos bearing small point mutations. This is unlike people with inherited mitochondriopathies, whose single-gene mutated mitochondrial genomes often coexist in heteroplasmy with healthy ones, with the balance between the two determining whether the cell is functional or not.