21 replies to this topic

[mag1]

Mitochondrial transplantation: From animal models to clinical use in humans.

PMID: 28342934

 

 

"Our results show that 10 min following mitochondrial transplantation myocardial function is significantly enhanced as compared to hearts receiving injection of respiration media (vehicle) alone and that this function remains enhanced for at least 28 days–the end point of our studies ...

 

The methodology for the isolation of mitochondria for use in mitochondrial transplantation is simple and rapid and can be performed in under 30 min. The freshly isolated tissue is homogenized using a commercial automated homogenizer ..."

 

Replacing mitochondria has substantial potential to treat a wide range of human illnesses and to possibly increase life span.

 

Considering how technically easy this appears to be, this might become part of clinical sooner than might usually be expected.

 

Comments please!   

[mag1]

"Five pediatric patients in critical condition who were unable to be weaned off extracorporeal membrane oxygenation (ECMO) support due to myocardial dysfunction  .. were treated with autologous mitochondria.

 

... all 5 patients had significant improvement in their myocardial systolic function. All but one patient were successfully weaned off ECMO support by the 2nd day ... Ventricular function improved to normal systolic function with no regional hypokinesia detected in any patient at 10 days"

Edited by mag1, 14 May 2017 - 03:34 PM.

[mag1]

Wouldn't this have substantial implications for mortality, perhaps in a range of diseases? For example, 600,000+ passed away from heart disease in the US in 2014. mt Replacement could also help in cancer, dementia, and others. And it appears very technically easy. Could always do some CRISPRing. Might want to add in a few new genes.

 

mt R could become a universal gene editing vector.   

 

Edited by mag1, 14 May 2017 - 03:43 PM.

[mag1]

Mitochondria organelle transplantation: introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity

 

..." In conclusion, the introduction of normal mammary mitochondria into human breast cancer cells inhibits cancer cell proliferation and increases the sensitivity of the MCF-7 human breast cancer cell line to doxorubicin, Abraxane, and carboplatin. These results support the role of mitochondrial dysfunction in cancer and suggest the possible use of targeted mitochondria for cancer therapeutics."

 

[mag1]

"Here we found that mitochondria isolated from human hepatoma cell could naturally enter human neuroblastoma SH-SY5Y cell line, and when the mitochondria were intravenously injected into mice, all of the mice were survived and no obvious abnormality appeared. The results of in vivo distribution suggested that the exogenous mitochondria distributed in various tissues including brain, liver, kidney, muscle and heart, which would benefit for multi-systemically mitochondrial diseases. In normal mice, mitochondrial supplement improved their endurance by increase of energy production in forced swimming test; and in experimental Parkinson's disease (PD) model mice induced by respiratory chain inhibitor MPTP, mitochondrial replacement prevented experimental PD progress through increasing the activity of electron transport chain, decreasing reactive oxygen species level, and preventing cell apoptosis and necrosis."

 

PMID:28242362

[mag1]

Heart disease, cancer, stroke, Alzheimer's, Parkinson's, ALS, aging, ...

 

"The methodology for the isolation of mitochondria for use in mitochondrial transplantation is simple and rapid and can be performed in under 30 min."

 

What is the traffic flow at the border into Mexico now?

Edited by mag1, 14 May 2017 - 05:34 PM.

[mag1]

Would love to hear suggestions about how mtR could be used to treat cancer.

 

Start with vanilla mtR.

Might then try mtR with CRISPR to correct variants in the mtDNA.

Could then try for some enhancements in OXPHOS etc.

Add in some nuclear genes to correct in correct signaling from the nucleus?

Have a built in off switch in case anything goes wrong.

 

Increase the mitochondrial membrane potential perhaps by 100 mv.

This would enormously increase the homing ability of mitocans to these mitochondria.

 

Include an engineered independent oxygen producing mechanism and improved method

of energy extraction. Allowing the mt to avoid switch to glycolysis.

 

A sensor that would check that the cell was not behaving in a cancerous way.

If it were launch apoptosis.

 

[HaplogroupW]

I'm just a lay person so please excuse my ignorance. Are they saying you can just dump mitochondria into the blood stream and they get incorporated into cells? Wut?

 

http://www.sciencedi...567724917300053

 

These don't seem like flakes. Department of Cardiac Surgery, Boston Children's Hospital

[corb]

I'm just a lay person so please excuse my ignorance. Are they saying you can just dump mitochondria into the blood stream and they get incorporated into cells? Wut?

 

http://www.sciencedi...567724917300053

 

These don't seem like flakes. Department of Cardiac Surgery, Boston Children's Hospital

 

Yes. That is what they are saying. It's nothing new, it has just taken a good while to get the therapies going.
I remember faintly about posting similar papers one or two years ago.

[mag1]

Without directly engaging in a discussion of the open science movement, here's the article.

 

http://sci-hub.cc/10...ito.2017.03.004

 

This seems too important for humanity not to have this out there in front of a paywall and not behind one.

Edited by mag1, 16 May 2017 - 03:52 PM.

[mag1]

Anyone who might have comments on how this might be used as a cancer therapy would be very much welcomed to the thread.

 

Perhaps CRISPR/gene editing the mitochondria?

Article does not talk about growing mito, though perhaps this could be of help?

 

Genetically engineering the mito so that they would have anti-cancer effect?

Possibly add in a futile ATP cycle into glycolysis that removed 4 instead of 2 ATP in the investment stage?

This would mean that a cell relying on glycolysis such as a cancer cell would create no energy from glycolysis.

I think other non-cancerous cells might be highly glycolytic, though the energy depletion strategy might still be of use.

[Turnbuckle]

Platelets shed mitochondria in the form of microparticles and free mitochondria that can be internalized by cells. While this is a mechanism for inflammation, you have to wonder if it is not also a way of rescuing cells that have gotten dangerously low on functional mitochondria.

 

http://www.bloodjour...ent/124/14/2161

[mag1]

Yeah!!

This is great!

Turnbuckle is a leading mitochondrial N=1 researcher on our forum!

Welcome to the thread!

 

Perhaps could we put an advert on your mito biogenesis mitophagy site to bring the people here?

This recent mito research development is too important not to have the best minds on forum contemplating it!

 

There must be a bunch of researchers now racing to figure out how to amp mito up for therapeutic purposes.

A bit of re-engineering could be of enormous help.

 

TB, in terms of mito research, could they now just take out these mitos, gene edit them and reinsert them?

Also growing them would be nice.

The article says that they only have an hour to before the mito go sour, so they would have to be quick.  

 

I mean the cure for heart disease, cancer, stroke, Alzheimer's, Parkinson's, aging, ....

It's the CURE for everything.

 

Tossing in new mitochondria is literally recharging the cell's powerplant.

Really will like to see what happens when they do some mitoreplacement on seniors.

We might soon start seeing on elders behaving more like teenagers. (Would that be a good thing?)

 

Considering the far reaching importance of this research, I think the current two upvotes that I have for this posting can best be described as paltry.

Edited by mag1, 16 May 2017 - 05:59 PM.

[Turnbuckle]

 

Tossing in new mitochondria is literally recharging the cell's powerplant.

Really will like to see what happens when they do some mitoreplacement on seniors.

We might soon start seeing on elders behaving more like teenagers. (Would that be a good thing?)

 

 

The cell doesn't have just one powerplant; it has a thousand or more. Your cells replace them all the time. It's the failure of the cellular QC and replacement process that leads to a death spiral of individual cells, and then of the organism. Fix that and you remove one of the key causes of aging. 

[mag1]

Hmmm, do mitochondria have telomeres?

 

From what I can see no, no they don't.

Since mito are circular, telomeres would not shorten during replication.

So, mito are immortal?

 

{Haven't seen any geriatric bacteria around lately.}

 

So, if we were to replace these immortal powerplants of the body that can cause all sorts of illnesses when defective, then this should have a fairly important impact on health ...

Edited by mag1, 16 May 2017 - 06:34 PM.

[Turnbuckle]

So, mito are immortal?

 

 

 

It's rather difficult to say what immortality is when it comes to mitochondria since they are always fusing and fissioning. On average a mitochondrion might have 4 loops of mtDNA that are constantly being exchanged with other mitochondria in a random fashion. And unlike nDNA, mtDNA exists in a free radical soup and thus are under constant attack. The 37 genes in mtDNA are all essential, so if only one gets hit the mtDNA loop cannot support ATP production. Thus the cell has a mechanism for identifying that loop and destroying it.

[mag1]

Warberg!

 

Yes, if it everything were to go to plan then the cell would be non-viable without mt ATP production.

Enter hyperglycolytic cancer cells.

 

Will be very interested to see what researchers can think up to create the ultimate mitocancer fighter.

There has been a fair amount of interest in CAR-T cells, can't wait for CAR-mitos

[mag1]

Turnbuckle, I am still unsure about whether or not replacing defective mitochondria would have an anti-cancer effect.

My guess would be yes, it would, though I am not aware of any clinical evidence.

 

Has the general mitochondrial mitophagy protocol that you are discussing on your thread been subject to any preclinical

studies in cancer? This could be a simple treatment that people might try to normalize their metabolism.

[mitomutant]

This is great !!

 

In my case this would be great way to counter balance the clonal expansion of my mutant mitochondria. I guess this would be a chronic procedure, maybe once a year.

 

In the isolation process, we would need another step to remove my mutant mitochondria from the pool. Not sure whether this is an easy process. 

[albedo]

Turnbuckle, I am still unsure about whether or not replacing defective mitochondria would have an anti-cancer effect.

My guess would be yes, it would, though I am not aware of any clinical evidence....

I do not want to derail this expert discussion but there is some evidence though I am not sure about the clinical as you rightly point out:

 

"...Elliott et al. [48] have recently used mitochondrial transplantation to enhance drug sensitivity in human breast cancer cells. The authors demonstrated that mitochondria isolated from human immortalized, untransformed mammary epithelia cell line, MCF-12A, and co-incubated with human breast cancer cell lines resulted in the uptake of untransformed cell line mitochondria inhibiting cancer cell proliferation and increasing the sensitivity of the cancer cells to anticancer agents..."

 

Mccully JD, Levitsky S, Del nido PJ, Cowan DB. Mitochondrial transplantation for therapeutic use. Clin Transl Med. 2016;5(1):16.

[Turnbuckle]

 

Turnbuckle, I am still unsure about whether or not replacing defective mitochondria would have an anti-cancer effect.

My guess would be yes, it would, though I am not aware of any clinical evidence....

I do not want to derail this expert discussion but there is some evidence though I am not sure about the clinical as you rightly point out:

 

"...Elliott et al. [48] have recently used mitochondrial transplantation to enhance drug sensitivity in human breast cancer cells. The authors demonstrated that mitochondria isolated from human immortalized, untransformed mammary epithelia cell line, MCF-12A, and co-incubated with human breast cancer cell lines resulted in the uptake of untransformed cell line mitochondria inhibiting cancer cell proliferation and increasing the sensitivity of the cancer cells to anticancer agents..."

 

Mccully JD, Levitsky S, Del nido PJ, Cowan DB. Mitochondrial transplantation for therapeutic use. Clin Transl Med. 2016;5(1):16.

 

 

 

This paper demonstrates how easy it is to transplant them. You just prepare the free-floating mitochondria and cells grab them up. So that suggests this is always going on at a low level as platelets shed them for various reasons. Once incorporated, these will be reproduced and will gradually replace defective mitochondria so long as cellular QC is still functioning. And if not, one can help it along by increasing levels of NAD+. (See Manipulating mitochondrial dynamics.)

 

For the purposes of reducing damage to heart cells, turns out very few mitochondria are necessary. From the paper--

 

Our studies suggest that the number of mitochondria needed for cardioprotection is not a function of the absolute number of mitochondria residing within the cell. In cardiomyocytes the mitochondria constitute 30 % of the total myocardial cell volume; however, only a small fraction of this number appears to be needed for cardioprotection following ischemia and reperfusion.

 

 

 

They break down the process into immediate (10 minutes) and late (>1 hour) phases. Though they don't mention mito fusion in the paper, this is likely the mechanism behind the "late" phase, as when the functional mtDNA is mixed via fusion, the benefits are magnified as the functional mtDNA can make up for the missing proteins for mtDNA that have one or more bad genes. Ultimately, however, you'd want to get rid of as many dysfunctional mtDNA loops as you can.

[adamh]

How do they create the autologous mitos in the first place? Do they culture them in a petrie dish? Do they multiply on their own? Or do they just take them from your own healthy tissue? I saw a part that said they were quickly prepared but this process is very important.