A Way to Insert New Mitochondria into Cells

Our mitochondria are responsible for a goodly portion of degenerative aging. Mitochondria are the power plants of the cell, responsible for building the chemical energy stores used to power cellular operations. Each mitochondrion is basically a wrapper membrane that encloses a fluid bag of protein machines, and every cell has a swarm of them floating around inside it. Mitochondria are the evolved descendants of symbiotic bacteria, and they still act much like bacteria in many ways: multiplying by division and promiscuously swapping protein machinery with one another, for example. They also have their own DNA, separate from the DNA in the cell nucleus, that encodes many of the proteins vital to their operation.

This DNA is where the problems start. It's sitting right next door to a power plant that generates all sorts of reactive byproducts - and so mitochondrial DNA is far more prone to harmful mutations than the DNA in the cell nucleus. The DNA repair mechanisms for mitochondria are worse as well.

Now in the case of most significant mitochondrial DNA damage caused this way, the damaged mitochondrion will eventually be broken down, destroyed by the cell's quality control mechanisms, and replaced through fission of a working mitochondrion. Unfortunately there are certain forms of damage that subvert the cell's ability to detect the resulting faulty operation of the mitochondrion - so it is left alone, to divide and create more faulty mitochondria. Once that happens, a cell is doomed to be overtaken by broken mitochondria and then fall into a maladaptive state of operation that exports harmful, reactive compounds into surrounding tissue.

With enough of that going on, real harm starts to accrue to organs and biological systems in the body: i.e. a part of why you become aged is because a small but significant portion of your cells are filled with broken mitochondria, and as a consequence are acting badly and causing damage. Aging is nothing more than an accumulation of damage, after all.

All of this is why research into ways to repair, replace, or otherwise deal with damaged mitochondria is so important. The research community is on the verge of being able to achieve these goals, and any resulting therapy will likely have a large impact on human aging - it will be a concrete step towards rejuvenation of the old, providing a way to remove this one signification contribution to degenerative aging.

Yesterday I was pointed towards some exciting research results in which scientists demonstrate that cells will ingest and adopt appropriately engineered mitochondria, adding them to the existing herd without the need for any intervention beyond placing the engineered mitochondria into the same cell culture. The researchers are calling their process peptide-mediated mitochondrial delivery:

Functional Recovery of Human Cells [via] Peptide-Mediated Mitochondrial Delivery

We explored the feasibility of mitochondrial therapy using the cell-penetrating peptide Pep-1 to transfer mitochondrial DNA (mtDNA) between cells ... Pep-1-conjugated wild-type mitochondria isolated from parent cybrid cells incorporating a mitochondria-specific tag were used as donors for mitochondrial delivery ... Forty-eight hours later, translocation of Pep-1-labelled mitochondria into the mitochondrial regions of [host] cells was observed (delivery efficiencies of 77.48 and 82.96%, respectively). These internalized mitochondria were maintained for at least 15 days in both cell types and were accompanied by mitochondrial function recovery

As you can imagine, this immediately leads one to think in terms of an infusion-type therapy, where a fluid solution containing hordes of mitochondria can be introduced into tissues and be taken up into cells. The mitochondria themselves can be cultivated like bacteria from a sample from the patient, which is gene engineered to fix issues such as genetic diseases caused by mutations in mitochondrial DNA - or they can be from a donor.

In a more liberated, free-wheeling future, this sort of approach might be widely used to swap out the mitochondria you are born with for a better set. It is already the case that some mitochondrial lineages have been shown to be better than others in terms of functionality and durability. Looking further ahead, we might see optimal mitochondria: artificially created biological machines that do the same job, but designed to remove the issues that cause harm and aging in the natural version.

The ability to insert new mitochondria is a viable approach for genetic diseases, where the patient's lineage is damaged. The new fully functional mitochondria will dilute the effects of the established mitochondria, and may largely replace them with time. Thinking on this points out the major issue with wholesale mitochondrial replacement, however: it's not the case that functional mitochondria will necessarily out-compete non-functional mitochondria within a cell over the long haul. Consider that the situation becomes something like competition between bacterial strains in an enclosed environment: whichever strain has the advantage will eventually win out. This picture is complicated by the fact that mitochondria swap components among themselves, but still seems to be a useful model when thinking about results.

For the genetic disease sufferers, it should be comforting to see that the researchers demonstrated repair of cells with broken mitochondria by inserting working mitochondria. For aging, however, the picture is less certain. After all, the problems caused by damaged mitochondria in aging occur because these damaged cellular components have an advantage to survival - they are damaged in a way that evades the surveillance mechanisms designed to weed out broken, harmful mitochondria. So it isn't clear that throwing in a bunch of working mitochondria will help all that much; one might imagine a short-lived benefit, but then you're right back to where you were before.

Which is not to say that people shouldn't try this. I say run up some old flies or nematode worms and infuse them with fresh new mitochondria, see what happens. A study in nematodes in particular should proceed fairly straightforwardly from being able to do this in cell cultures.


I like this approach a lot. But the only viable way I can envision for delivery of the cultured Mito in sufficient volume is via a blood drip type of set up. I have no idea if that would be an effective delivery method.

Posted by: JohnD60 at September 25th, 2012 7:34 AM

Out-competition by broken mitochondria might be a problem for the simplest applications of this method, but it wouldn't pose too much of an obstacle for the advanced applications. One could simply insert functionality into the "new and improved" mitochondria that enables them to impede the replication of or otherwise destroy other mitochondria once they are present in the cell. For instance, they could slowly produce a mitochondrial poison to which they themselves have been rendered specifically immune. As the old mitochondria succumb, the new and improved ones can divide to take their place. This could be seen as a sort of "Roundup ready" strategy for engineered mitochondria. These new mitochondria could even include a convenient "kill switch" feature to ensure that mitochondria 2.0 can be easily replaced by mitochondria 2.1 or 3.0 should that become necessary.

Posted by: José at September 25th, 2012 10:18 AM

Rather than a gene engineered sample from the patient or donor why not just create synthetic DNA from scratch? Once the delivery mechanism is sorted I can imagine the DIY-Bio crowd experimenting on themselves. How about Mitochondria patches, skin cream and bath oils?

Posted by: Wayne at September 26th, 2012 12:10 AM

Fortunately Mitochondria are more than 100 times too large to be absorbed through the skin.

Posted by: JohnD at September 26th, 2012 8:21 PM

Whatever be the method of delivery - whole mitochondria or DNA, how are they going to evade host immune cells and get into target cells?

Posted by: Prakash at November 6th, 2015 1:48 AM

While José's suggestion has merit, it would be better if the introduced mitochondria were to introduce an agent to reverse the broken mitochondria's ability to evade the cell's quality control mechanisms. Alternatively, this agent could be introduced separately to the new mitochondria, but at about the same time. Such an agent might have to be tailored to the specific defect in the broken mitochondria.

This way, any healthy mitochondria would be retained, maximising (healthy) mitochondrial diversity and ensuring that cells with healthy mitochondria survived if for some reason the introduced mitochondria failed.

Posted by: Andrew Hicks at February 2nd, 2017 5:29 PM
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