41 replies to this topic

[Turnbuckle]

As an aside, I wonder how much of the effect seen in heterochronic parabiosis is due to organelle transfer?

 

 

I think it would be hard to avoid at least some transfer and thus some benefit to the older rats (and harm to the younger ones), and probably happens with every blood transfusion--

 

In this study, we demonstrated that isolated mitochondria are internalized into cells by simple co-incubation by using genetically labelled mitochondria. Isolated mitochondria were internalized into homogeneic and xenogeneic cells within a few hours of co-incubation. Furthermore, we observed how mitochondria are engulfed by the recipient cells and how they behave inside the cells after internalization by time-lapse video microscopy. We also showed that optimal mitochondrial internalization significantly improves the mitochondrial function in mtDNA-depleted cells, and that these benefits lasted several days. Finally, we demonstrated the possible involvement of macropinocytosis in this process by using various inhibitors of endocytosis.

 

...

 

We confirmed that human mitochondria are transferred into rat cells as well as human cells. However, a complete set of cognate chromosomes was necessary for the maintenance of mitochondrial genomes and functions [24]. Mitochondria have co-evolved with their host cells for ages, that is supposed to lead to species-specific compatibility [25] . Therefore, we only conducted interspecies mitochondrial transfer to validate the process and investigated the therapeutic potential of the process by using homogeneic mitochondria.

 

In previous studies, exogenous mitochondria were maintained in the recipient cells for longer periods [26, 27]. In contrast, our study demonstrated that the internalized mitochondria disappeared within a week. In addition, transmission electron microscopy showed that some exogenous DsRed-labelled mitochondria were identified in the autophagosomes after mitochondrial transfer within recipient cells (Fig. S6). Exogenous mitochondria may be selectively degraded after mitochondrial transfer.

 

...

 

In this study, the isolated mitochondria-enriched fraction was used for experiments. This fraction also contained various intracellular organelles such as damaged and dysfunctional mitochondria that are proposed to be of no benefit and even harmful to the host cells [34]. A previous study has also indicated that freshly isolated, intact, viable and respiration-competent mitochondria were required to exert a therapeutic effect [13]. Our experiments also revealed that UV-treated mitochondria failed to improve cellular viability in recipient cells.

 

 

http://onlinelibrary...jcmm.12316/full

 

 

 

Edited by Turnbuckle, 14 January 2015 - 01:39 PM.

[pone11]

 

In this study, we demonstrated that isolated mitochondria are internalized into cells by simple co-incubation by using genetically labelled mitochondria. Isolated mitochondria were internalized into homogeneic and xenogeneic cells within a few hours of co-incubation. Furthermore, we observed how mitochondria are engulfed by the recipient cells and how they behave inside the cells after internalization by time-lapse video microscopy. We also showed that optimal mitochondrial internalization significantly improves the mitochondrial function in mtDNA-depleted cells, and that these benefits lasted several days. Finally, we demonstrated the possible involvement of macropinocytosis in this process by using various inhibitors of endocytosis.

 

...

 

We confirmed that human mitochondria are transferred into rat cells as well as human cells. However, a complete set of cognate chromosomes was necessary for the maintenance of mitochondrial genomes and functions [24]. Mitochondria have co-evolved with their host cells for ages, that is supposed to lead to species-specific compatibility [25] . Therefore, we only conducted interspecies mitochondrial transfer to validate the process and investigated the therapeutic potential of the process by using homogeneic mitochondria.

 

In previous studies, exogenous mitochondria were maintained in the recipient cells for longer periods [26, 27]. In contrast, our study demonstrated that the internalized mitochondria disappeared within a week. In addition, transmission electron microscopy showed that some exogenous DsRed-labelled mitochondria were identified in the autophagosomes after mitochondrial transfer within recipient cells (Fig. S6). Exogenous mitochondria may be selectively degraded after mitochondrial transfer.

 

http://onlinelibrary...jcmm.12316/full

 

 

 

Fantastic study.   The only depressing thing there is the host cells may be selectively attacking the exogenous mitochondria.   That suggests that you might have to constantly supplement mitochondria to sustain the raised rates of respiration.

[Turnbuckle]

 

 

 

Fantastic study.   The only depressing thing there is the host cells may be selectively attacking the exogenous mitochondria.   That suggests that you might have to constantly supplement mitochondria to sustain the raised rates of respiration.

 

 

 

It could be that the process of isolating the mitochondria caused them oxidation damage, and thus they would be slated for destruction. And the right antioxidant might have prevented that.

[pone11]

 

 

 

 

Fantastic study.   The only depressing thing there is the host cells may be selectively attacking the exogenous mitochondria.   That suggests that you might have to constantly supplement mitochondria to sustain the raised rates of respiration.

 

 

 

It could be that the process of isolating the mitochondria caused them oxidation damage, and thus they would be slated for destruction. And the right antioxidant might have prevented that.

 

 

Sure.  But the bigger problem seems to me that they were doing this in vitro.   In vivo is probably trickier still.

[resveratrol_guy]

As a follow up to my original post:   I wonder if there is an argument to be made that people should try to get some of their tissues biopsied and frozen cryogenically now, before they are too old, with the idea being that maybe in 30 years someone will be able to take your frozen tissue and mass produce mitochondria from the DNA in those frozen samples.

 

Is there anyone actually offering this on a commercial basis today?

 

To me that is a much more practical application of cryogenics than freezing an entire body after death.

 

I just did essentially what you asked about above, via stem cell cryopreservation. Details here.

 

@ niner: Testing in vitro prior to in vivo makes good sense and could be done with massive parallelism for cheap. Very good idea. But... organelle transfer? As in, other stuff besides mitochondria or RNA/DNA? Is that possible?

 

[StevesPetRat]

Instead of doing this the hard way through transplants, why not just take a buttload (technical term) of PQQ and then periodically stimulate mitophagy through PINK1 / mild oxidative stress / fasting / other means? Same deal.

I like it specifically because it allows us to ignore the quantum electrodynamics problems of various mitochrondrial failure modes in favor of outright replacement.

I would be intrigued to learn how QED figures meaningfully into mitochondrial function, if you don't mind sharing. +1 point for each Feynman diagram!

[corb]

Instead of doing this the hard way through transplants, why not just take a buttload (technical term) of PQQ and then periodically stimulate mitophagy through PINK1 / mild oxidative stress / fasting / other means? Same deal.
 

I like it specifically because it allows us to ignore the quantum electrodynamics problems of various mitochrondrial failure modes in favor of outright replacement.

I would be intrigued to learn how QED figures meaningfully into mitochondrial function, if you don't mind sharing. +1 point for each Feynman diagram!

 

 

Well, for one because it makes it possible to treat diseases like autism and mitochondrial diabetes.

Another reason is, in the old it might be more efficient to supply them with already formed organelles than to expect their damaged cells to return to a healthy state on their own.

Prevention isn't bad as far as it actually has efficiency.

[resveratrol_guy]

I like it specifically because it allows us to ignore the quantum electrodynamics problems of various mitochrondrial failure modes in favor of outright replacement.

I would be intrigued to learn how QED figures meaningfully into mitochondrial function, if you don't mind sharing. +1 point for each Feynman diagram!

 

My somewhat tongue-in-cheek point was simply that mitochondria are quantum machines which are hard to model, even if we use some classical approximations, so why do that if we can simply forget the question of why it broke, and just replace it? More generally, as corb said, just supply prefabricated organelles and sidestep the complexity of repair. Pragmatically, look at how much computer power (and moreover software engineering dollars) go into targetted drug design, yet how unfruitful it has been compared to basic healthy lifestyle advice.
 

Edited by resveratrol_guy, 18 January 2015 - 04:16 AM.

[pone11]

 

As a follow up to my original post:   I wonder if there is an argument to be made that people should try to get some of their tissues biopsied and frozen cryogenically now, before they are too old, with the idea being that maybe in 30 years someone will be able to take your frozen tissue and mass produce mitochondria from the DNA in those frozen samples.

 

Is there anyone actually offering this on a commercial basis today?

 

To me that is a much more practical application of cryogenics than freezing an entire body after death.

 

I just did essentially what you asked about above, via stem cell cryopreservation. Details here.

 

@ niner: Testing in vitro prior to in vivo makes good sense and could be done with massive parallelism for cheap. Very good idea. But... organelle transfer? As in, other stuff besides mitochondria or RNA/DNA? Is that possible?

 

 

What is the proposed use of those stem cells?  Is the idea that someday in future they will be able to duplicate them easily, and they would use the frozen cells as seed stock for that?

[resveratrol_guy]

 

 

As a follow up to my original post:   I wonder if there is an argument to be made that people should try to get some of their tissues biopsied and frozen cryogenically now, before they are too old, with the idea being that maybe in 30 years someone will be able to take your frozen tissue and mass produce mitochondria from the DNA in those frozen samples.

 

Is there anyone actually offering this on a commercial basis today?

 

To me that is a much more practical application of cryogenics than freezing an entire body after death.

 

I just did essentially what you asked about above, via stem cell cryopreservation. Details here.

 

@ niner: Testing in vitro prior to in vivo makes good sense and could be done with massive parallelism for cheap. Very good idea. But... organelle transfer? As in, other stuff besides mitochondria or RNA/DNA? Is that possible?

 

 

What is the proposed use of those stem cells?  Is the idea that someday in future they will be able to duplicate them easily, and they would use the frozen cells as seed stock for that?

 

 

Well, the main purpose is indeed to use the cells for future maintenance or repair. AFAIK, we already know how to duplicate them into much larger populations in vitro, but of course the question of epigenetic optimization for specific therapeutic targets is still the subject of research. In addition to this prospective use, IMO the procedure itself is therapeutic. But in any event, of course, this also amounts to mitochondrial freezing.
 

Edited by resveratrol_guy, 19 January 2015 - 10:07 PM.

[YOLF]

Moderation - Posts in this topic regarding the use of 3-Bromopyruvate to fight cancer have been moved to this thread.

Edited by PerC, 25 January 2015 - 02:04 AM.

[mag1]

Transplanting healthy mitochondria to people with mitochondrial illnesses seems an attractive and plausible medical therapy.

There are several illnesses caused by mis-functioning mitochondria (e.g. neurodegenerative illnesses etc.).