10 replies to this topic

[reason]

Mitochondria are the power plants of the cell, generating chemical energy stores used in many cellular processes. A herd of them exists in every cell, dividing like bacteria to keep up their numbers. Mitochondrial damage occurs as a side-effect of the normal operation of metabolism and is an important contribution to degenerative aging, but fortunately there are a wide range of fairly well understood methods by which this issue could be prevented or treated. All that is needed is more funding for research and development.

One possibility is the delivery of replacement mitochondria, and if doing this why not deliver better, more effective mitochondria? Some of the existing mitochondrial haplogroups are objectively better than others, but we could also in theory greatly improve upon what exists based on present knowledge. At the end of this road lies the replacement of mitochondria with optimal synthetic versions, resistant to damage, which influence surrounding cellular mechanisms in beneficial ways, and which minimize the mitochondrial contribution to aging. That isn't a near term prospect, but in the decades ahead it will become very plausible to start replacing more discrete cellular components with designed molecular machinery that is more efficient and less vulnerable, and thus helps to extend healthy life span:

We hypothesize herein that synthetic mitochondria, engineered or reprogrammed to be more energetically efficient and to have mildly elevated levels of reactive oxygen species (ROS) production, would be an effective form of therapeutics against systemic aging. The free radical and mitochondria theories of aging hold that mitochondria-generated ROS underlies chronic organelle, cell and tissues damages that contribute to systemic aging. More recent findings, however, collectively suggest that while acute and massive ROS generation during events such as tissue injury is indeed detrimental, subacute stresses and chronic elevation in ROS production may instead induce a state of mitochondrial hormesis (or "mitohormesis") that could extend lifespan.

Mitohormesis appears to be a convergent mechanism for several known anti-aging signaling pathways. Importantly, mitohormetic signaling could also occur in a non-cell autonomous manner, with its induction in neurons affecting gut cells, for example. Technologies are outlined that could lead towards testing of the hypothesis, which include genetic and epigenetic engineering of the mitochondria, as well as intercellular transfer of mitochondria from transplanted helper cells to target tissues.

Link: http://dx.doi.org/10.1002/cbin.10362

View the full article at FightAging

[corb]

intercellular transfer of mitochondria

Yet another therapy that relies heavily on stem cell therapies making great strides at working in vivo in the near future.

Since you mentioned funding maybe this is where the funding should go for the time being.

[niner]

 

intercellular transfer of mitochondria

Yet another therapy that relies heavily on stem cell therapies making great strides at working in vivo in the near future.

Since you mentioned funding maybe this is where the funding should go for the time being.

 

How does mitochondrial transfer rely on stem cells?  I don't see the connection.

[corb]

Did you read the article?

 

 

as well as intercellular transfer of mitochondria from transplanted helper cells to target tissues.

 

And from an study from pubmed:
 

 

It has been reported that human mesenchymal stem cells (MSCs) can transfer mitochondria to the cells with severely compromised mitochondrial function. We tested whether the reported intercellular mitochondrial transfer could be replicated in different types of cells or under different experimental conditions, and tried to elucidate possible mechanism

 

I'm not familiar with mitochondrial transfer, so I could be misinterpreting the abstracts, but most of the papers I found specifically talk about mesenchymal stem cells.

And it also makes sense, because for a therapy like this you'd want a cell that's mostly everywhere in your body, right?

Again I'm guessing based on the papers I found and my knowledge I could be wrong.

Edited by corb, 05 September 2014 - 11:51 PM.

[niner]

I don't have access to the article, but I think you're right about the mesenchymal stem cells.  I think I was thrown off by the term "synthetic", and was thinking about some sort of engineered mitochondrion.   It seems like a weird function for a cell to have, passing off its mitochondria to a different cell.  I wonder why stem cells would need to do that?

[corb]

 

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.

 

It's very hard to find articles about this because it seems like a novel concept, the first one talking about mitochondria being expelled outside a cell is from 2011 and this one talking about cells swapping mitochondria is from 2014, so I guess this is cutting edge research. Also most of the articles you get when you search the term mitochondrial transfer are about bioethics, a true celebration of chauvinism.

 

Anyway, as I said earlier most articles I found talk about EMC stem cells, I don't know if the mechanism is limited to mesenchymal cells, it probably isn't - otherwise they wouldn't be talking about an intercellular therapy, wouldn't be much of a therapy between cells if it only works in one cell type - but there's no way for me to be sure with this lack of information on the subject.

 

And as I said they might be experimenting with EMC cells because they are viable for a theraputic option, because the mesenchymal stem cells are part of every organ and tissue of the body as far as I know. I really cant' say for sure.

Edited by corb, 06 September 2014 - 07:46 AM.

[Logic]

I Googled
mesenchymal stem cells mitochondrial transfer
and got a lot of hits?

"...In the study, the protein Miro1 was shown to regulate the transfer of mitochondria from mesenchymal stem cells to epithelial cells..."
http://www.embo.org/...ng-mitochondria

[Avatar of Horus]

I am too examining this, or similar mechanism: the tunneling nanotube (see the study below), in theory (at present) and for testing/experiment design (in the future).
But not only with mesenchymal stem cells, but also with endothelial progenitor cells, and not only for mitochondrion, but also for dysfunctional lysosomes.
 

Tunneling nanotubes mediate rescue of prematurely senescent endothelial cells by endothelial progenitors: exchange of lysosomal pool
Yasuda et al. 2011.
http://www.ncbi.nlm....pubmed/21705809

Abstract
Although therapeutic effect of adoptive transfer of endothelial progenitor cells (EPC) has been well-substantiated, the actual engraftment is relatively low compared to a robust functional improvement of vasculopathy. Cellular mechanisms governing this action remain elusive. A recently discovered cell-cell communication via tunneling nanotube (TNT) formation is capable of transferring mitochondria and lysosomes between the cells - "organellar diakinesis". Based on the previous demonstration of lysosomal dysfunction in endothelial cells exposed to AGE-modified collagen I, we inquired whether TNT mechanism may be involved in EPC-mediated repair of stressed endothelial cells. Here we demonstrate that EPC selectively and multiplicatively establish TNT communication with stressed endothelia. The guidance cues for the selectivity are provided by exofacially exposed phosphatidylserine moieties. Lysosomal transfer is associated with the preservation of lysosomal pH gradient, functionally reconstituting lysosomal pool of stressed cells and improving endothelial cell viability, reducing premature senescence and apoptosis. In vivo, adoptive transfer of EPC to streptozotocin-diabetic mice results in a TNT-dependent reduction of senescent endothelial cells and correction of endothelium-dependent vasorelaxation. Collectively, these data establish a selective multiplicative effect of TNT between EPC and stressed endothelia, reconstitution of the lysosomal pool, and improved viability and function of stressed endothelia.

 

[Turnbuckle]

Possibly one way of getting new DNA into mitochondria--

 

 

MITO-Porter: A liposome-based carrier system for delivery of macromolecules into mitochondria via membrane fusion

 

 

Abstract

Mitochondria are the principal producers of energy in higher cells. Mitochondrial dysfunction is implicated in a variety of human diseases, including cancer and neurodegenerative disorders. Effective medical therapies for such diseases will ultimately require targeted delivery of therapeutic proteins or nucleic acids to the mitochondria, which will be achieved through innovations in the nanotechnology of intracellular trafficking. Here we describe a liposome-based carrier that delivers its macromolecular cargo to the mitochondrial interior via membrane fusion. These liposome particles, which we call MITO-Porters, carry octaarginine surface modifications to stimulate their entry into cells as intact vesicles (via macropinocytosis). We identified lipid compositions for the MITO-Porter which promote both its fusion with the mitochondrial membrane and the release of its cargo to the intra-mitochondrial compartment in living cells. Thus, the MITO-Porter holds promise as an efficacious system for the delivery of both large and small therapeutic molecules into mitochondria.

 

[Turnbuckle]

And another method, using a virus vector--

 

Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber's hereditary optic neuropathy in a mouse model.

 

...The adenoassociated virus cassette accommodates genes of up to ∼5 kb in length, thus providing a platform for introduction of almost any mitochondrial gene and perhaps even allowing insertion of DNA encompassing large deletions of mtDNA, some associated with aging, into the organelle of adults.

 

 

[Kalliste]

Very interesting to see all the promising work going on around mitochondria. Extra interesting now that I'm reading about MitoQ, C60 and such.