Review The power and potential of mitochondria transfer, 2023, Borcherding et al

[hotblack]

The power and potential of mitochondria transfer

Borcherding N, Brestoff JR.

Preface
Mitochondria are believed to have originated through an ancient endosymbiotic process in which proteobacteria were captured and co-opted for energy production and cellular metabolism. Mitochondria segregate during cell division and differentiation, with vertical inheritance of mitochondria (mt) and the mtDNA genome from parent to daughter cells.

However, an emerging body of literature indicates that some cell types export their mitochondria for delivery to developmentally unrelated cell types, a process called intercellular mitochondria transfer. In this Review, we describe the mechanisms by which mitochondria are transferred between cells and discuss how intercellular mitochondria transfer regulates the physiology and function of various organ systems in health and disease.

In particular, we discuss the role of mitochondria transfer in regulating cellular metabolism, cancer, the immune system, maintenance of tissue homeostasis, mitochondria quality control, wound healing, and adipose tissue function. We also highlight the potential of targeting intercellular mitochondria transfer as a therapeutic strategy to treat human diseases and augment cellular therapies.

Link (Nature)
https://doi.org/10.1038/s41586-023-06537-z

 

[hotblack]

A bit of a duplication but thought having this paper posted may be useful

If I’m understanding and summarising correctly, as well as mitochondria being shared from parent to daughter cells, cells can also share mitochondria through intercellular mitochondria transfer, even between different cell types.

This can happen through direct physical contact using micro tubules.

Or indirectly with mitochondria either released in extracellular vesicles (Rab7/GDP status determines if a cell exports) or as free mitochondria. With phagocytosis used by other cells to capture and import them.

So a useful process when all is going well. But this has been shown to be hijacked by some cancers, hence daratumumab being useful, it can stop this sharing.

One possibility after reading this then is, could there be a loop whereby cells under some form of load or metabolic stress will bring in mitochondria from another cell, and if that cell has malfunctioning mitochondria, it hinders rather than helps, so perpetuates the loop.

 

[hotblack]

There’s a whole section on regulation of the immune system which seems potentially interesting too

The abundance of cell-free mitochondria or mtDNA in bronchoalveolar lavage fluid or blood from lung transplant patients directly correlates with early rejection, the severity of lung allograft dysfunction, and concentrations of IL-6, IL-8, IFNγ, and IL1-RA in circulation.

Link

It appears that mitochondria transfer preferentially occurs to CD4+ T cells and induces a regulatory T cell phenotype with enhanced IL-10 expression and immunosuppressive capacities in graft-vs-host disease and arthritis models

Link

And a discussion on metabolic homeostasis which mentions stopping mitochondria transfer in one part of the body maybe being beneficial as it allows mitochondria to be available elsewhere

This article showed that long-chain fatty acids determine whether adipocyte-derived mitochondria are transferred locally to macrophages or diverted into the circulation for delivery to distant organs, and it showed that in vivo administration of purified mitochondria can rescue cell-instrinsic defects in aerobic respiration.

Link

 

[hotblack]

After some more digging there could be a link to Type I Interferons too, which has been of interest to people. We’ve often asked how signals are passed around the body especially as we haven’t seen them. How can this be interferon mediated with no measurable systemic IFN changes? Well what if it’s mitochondria passing the signals around?

@jnmaciuch shared a load of great info on IFN in this thread, which looking at it again seems to cover this!

https://www.mdpi.com/1422-0067/26/7/3069 A review of how mtDNA release leads to a type I interferon signaling response in exercise in healthy people.

So it looks like I’m rediscovering things others have already discovered and possibly even things I’ve already read and consciously forgotten. I have found I keep on forgetting what I learnt not long ago so get the joy of rediscovering things quite frequently!

Has anyone performed analysis of mitochondria in these extracellular vesicles or of free mitochondria in people with ME/CFS vs healthy controls?

 

[jnmaciuch]

Great to see your interest and puzzle-hunting, @hotblack !

You may have already talked about this, but highlighting a quote from the review in case it is relevant to recent discussions on CD38 (edited to remove long embedded links from citations):

Several in vivo studies support this notion. In particular, ischemic neurons and cardiomyocytes can receive and use mitochondria from other cell types to support their survival (49, 63, 65). In the ischemic brain, astrocytes release EVMs in response to CD38-cADPR-Calcium signaling, leading to the transfer of mitochondria to neighboring neurons (Fig. 2a) (49). Inhibiting this process with an anti-CD38 monoclonal antibody was associated with worse outcomes in mice subjected to an ischemic stroke model. Another group showed that intraarterial administration of purified mitochondria shortly after ischemic stroke leads to accumulation of exogenous mitochondria in the infarct zone, restores adenosine triphosphate concentrations locally, and reduces the volume of the infarct (66). Interestingly, extracellular mitochondria are also increased in the cerebrospinal fluid (CSF) of rats and humans after subarachnoid hemorrhage (SAH), and higher membrane potential of CSF cell-free mitochondria is associated with better clinical outcomes in patients 3 months after SAH (67). These studies suggest that cell-free mitochondria may support the metabolism of neurons in both ischemic stroke and SAH.

Has anyone performed analysis of mitochondria in these extracellular vesicles or of free mitochondria in people with ME/CFS vs healthy controls?

2 studies come to mind, though they would each only have a small chance of providing you with an answer. The Hanson lab did a proteomic study in EVs, which in theory could have detected differences in abundance of mitochondrial proteins. However, they used a trypsin digestion, which (if my memory serves, I might be wrong) doesn't do well for proteins embedded in lipid bilayers. Long story short, the protocol could have completely missed mitochondrial proteins.

Thread '[EV] proteomics uncovers energy metabolism, complement system, and [ER] stress response dysregulation postexercise in males with [ME/CFS], 2025,Glass+'

Jun 4, 2025

Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome

Katherine A. Glass, Ludovic Giloteaux, Sheng Zhang, Maureen R. Hanson

[Line breaks added]

Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness characterized by post-exertional malaise (PEM), a worsening of symptoms following exertion. The biological mechanisms underlying PEM remain unclear.

Extracellular vesicles...

• forestglip
• complement endoplasmic reticulum energy metabolism extracellular vesicles giloteaux glass maureen hanson prdx6 study idea
• Replies: 57
• Forum: ME/CFS research

• 

Rob Wüst also measured mtDNA in the circulation after exercise and found no difference (https://www.nature.com/articles/s41467-023-44432-3, in the supplemental figures). Free floating mtDNA is usually found in conditions of cell damage and rupture, so it probably wouldn't be reflective of transfer of intact mitochondria (especially if it was occuring in tissues).

Unfortunately I'm not aware of any studies that would have been well suited to answer your particular question.

 

[hotblack]

Great to see your interest and puzzle-hunting, @hotblack !

Thanks! Well, I got there in the end and am now all aboard the mitochondria and IFN Type I hype trains. Or maybe it’s more accurate to say I have a better appreciation of your interest in these areas than I previously did Today a whole bunch of things you’ve said this year sort of slotted into place for me a bit more.

The Hanson lab did a proteomic study in EVs, which in theory could have detected differences in abundance of mitochondrial proteins

I’ll take a look. I’m not sure if it’s necessarily quantity we’d be looking for, if this is something that goes on all the time as some seem to say, but the quality or makeup of that available or transferred mitochondria.

 

[jnmaciuch]

Thanks! Well, I got there in the end and am now all aboard the mitochondria and IFN Type I hype trains. Or maybe it’s more accurate to say I have a better appreciation of your interest in these areas than I previously did Today a whole bunch of things you’ve said this year sort of slotted into place for me a bit more.

Well I'm happy you considered it worthwhile enough to jump down the rabbit hole. Though don't let my enthusiasm temper your skepticism! I may just as well have missed some important detail or finding that makes my hypotheses less plausible.

I’ll take a look. I’m not sure if it’s necessarily quantity we’d be looking for, if this is something that goes in all the time, but the quality or makeup of that available or transferred mitochondria.

Right, I think anything more specific than abundance of certain molecules would probably require a intentional experimental design, and I don't know of anyone in the ME/CFS field who has been interested in this particular angle.

Perhaps an existing study might have picked up an indirect indicator of a particular mechanism, though. Has your digging led you to a specific functional issue or signaling pathway that you think might be implicated in ME/CFS?

 

[hotblack]

You may have already talked about this,

Not explicitly no. There’s so much in there. It’s really useful to see what someone more familiar with all this sees as relevant or important.

Has your digging led you to a specific functional issue or signaling pathway that you think might be implicated in ME/CFS?

Yes and no. More potential fragments of mechanisms or involved pathways. Probably all a bit hand wavy!

 

[hotblack]

I’m very much in learning things, seeing possibilities and throwing stuff at the wall and seeing what sticks territory. Which is very fun. But find piecing it together into something cohesive or articulating it is much trickier.

I’ve made some notes though. So they’re not fully formed or referenced but in broad terms..

There’s other ideas about triggers and effects in different parts of the body, including neurons and signalling. But one piece that’s often missing is spread throughout the body.

Mitochondria transfer seems like a great hidden way of moving (immune activating) information around in a way we may not have observed. And the fact that daratumumab appears to inhibit it seems relevant.

Basic steps:

• Mitochondria is under stress or damaged (maybe load from physical activity, infection, etc)
• So releases mitochondrial DNA into the cytoplasm
• The cell responds by creating type I interferons (or maybe even type II)
• Now what if this mitochondria is exported? (Maybe the cleanup mechanism isn’t working, so it is exported rather than degraded)
• Other cells elsewhere pick this up when they need mitochondria
• Now in this cell the mitochondria is still releasing mtDNA
• So now this cell also responds by creating interferons

That’s the basic process I have learnt. To add some sprinkling of possibilities…

• It seems T cells like gobbling up mitochondria (and glycolysis plays is an important part in their lifecycle/behaviour). And if T cells are involved there could be a bit of a type II (interferon gamma) enhancing element here. It’s also been shown that good fit healthy mitochondria absorbed by T cells dampen down interferon gamma production, so the opposite must also be true.
• I’ve also been reading that mitochondria transfer influences T cell differentiation and can push them more towards becoming T reg cells.
• That the paper has some mention of astrocytes releasing mitochondria through this method and macrophages transferring mitochondria to sensory neurons when there’s inflammatory signalling is also of interest.
• Some reading on other diseases or illness describes macrophages, endothelial and glial cells actimg as donors for these mitochondria and macrophages, T cells and neurons as recipients, which could fit nicely.

I don’t have enough of an understanding of it all, but the idea that only certain cells would pick up the mitochondria, or would be more likely to seems possible. Some cells seem to do or depend on this process more than others. Or that as this is a process which normally happens, things could be knocked a bit out of whack by the balance of unhappy mitochondria to normal healthy mitochondria being available changes. Exactly what a complete mechanism is or what is perpetuating it longer term I’m not sure, possibly some particular cell groups, maybe immune again. It could work nicely for activity and PEM too.

But the thing that seems clearer to me is that bridge between immune and metabolic states. In mitochondria transfer we have a process which would allow what was a localised immune signal or state to be spread without systemic immune signals or states being present.

I’ll try and post some more papers or thoughts later if I can or things become clearer in my head. I think I’ve fried my brain a bit over recent days. Hopefully someone with more of an understanding of all this sees something interesting or relevant though.

 

[Jonathan Edwards]

I’m very much in learning things, seeing possibilities and throwing stuff at the wall and seeing what sticks territory. Which is very fun. But find piecing it together into something cohesive or articulating it is much trickier.

It seems so. I am concerned that we do not have any obvious venue for this going on in ME/CFS where we might expect to see some tissue effects. And mitochondrial transfer seems unlikely to be providing critical immune signals for T cells. It might be a way of speeding up a T cell's response but there needs to be a reason for the response in the first place.

 

[jnmaciuch]

It would be difficult to explain spreading of an interferon response across the body via this mechanism—it seems like all the examples of this phenomenon are primarily occurring in cells in proximity with each other, whether that’s neurons sharing with other neurons, or mitochondria being transferred to immune cells at the site of infection/injury. The chances of this transfer happening to immune cells in the circulation are small, though maybe some occurrences are happening in NETs.

In order to implicate T cells in this theory there would need to be a reason for them to be in a specific location.

Though there might be a place for this concept considering the other paper you recently posted about macrophages in sepsis. If mitochondrial transfer to macrophages in tissue is a mechanism of strongly amplifying a local interferon response, it could potentially explain how an interferon response builds in response to mtDNA release during exertion, either in muscle or potentially the brain. This would be in concert with other known mechanisms of interferon spread in tissues, including simple diffusion of interferon itself triggering receptors on neighboring cells, or TLR activation of resident immune cells by extracellular mtDNA.

Once you explain how a local interferon response gets sufficiently amplified locally, we’d need to know if it can result in enough interferon leaking into the circulation to cause systemic symptoms, or if something like pDC recruitment into the tissue could be observed which would amplify interferon production into the circulation. In which case you explain the lack of interferon signature findings in the circulation by the fact that all previous studies have only looked outside of PEM, when a signal might be still be confined to tissues.

If something about either the initial mtDNA release, intracellular interferon response, or transfer of mitochondria was abnormal in ME/CFS, it could explain a hyperexaggerated version of the normal interferon response to exertion. This possibility would align the most with the potential of anti-CD38 therapies being effective for some pwME, since what you’d theoretically be blocking is the amplification preceding PEM (and potentially blocking one part of the feedback loops that maintains an abnormal interferon response).

Still quite a few leaps and assumptions in this amended theory, though perhaps more plausible.

 

[hotblack]

Thanks, the idea of things being a localised amplifier and only ‘spilling over’ in certain circumstances is interesting.

There’s a few things in DecodeME that also showed some genes related to mitophagy and mitochondrial antiviral-signaling protein (MAVS) and how cells respond to RNA that could be involved IIRC. The whole cell cleanup and maintenance side of things.

I’m not sure how convincing it all is but will continue to prod around and post a few bits. It’s certainly helping me learn more about mitochondria beyond being ‘the energy bit’ of a cell.

Thanks for taking a look!

 

[V.R.T.]

there needs to be a reason for the response in the first place.

What kinds of cells/proteins etc could be providing signals that might provoke a T cell response?

 

[V.R.T.]

If something about either the initial mtDNA release, intracellular interferon response, or transfer of mitochondria was abnormal in ME/CFS

In what ways could these processes be abnormal?

 

[hotblack]

In what ways could these processes be abnormal?

Deciding what should be degraded in the cell or ejected from the cell is one area I thought about. And some cells deliberately chuck things out for other cells to take care of for them I believe. But cells which normally take care of their own rubbish may decide not to or have their own internal waste disposal backed up so need to. Or the rubbish/not-rubbish system may be malfunctioning in some way perhaps?

 

[jnmaciuch]

In what ways could these processes be abnormal?

It's a tricky question--theoretically biological systems can go wrong in as many ways as there are players and interactions involved in the process. But biological systems also tend to have built in regulatory mechanisms. The trick would be to look for places where there could be a feedback loop to sustain a long term abnormality which bypasses regulatory mechanisms. Unfortunately that's still a large and vague search space, so it really just comes down to coming up with one specific idea at a time and proving it wrong until you land on something.

 

[Jonathan Edwards]

What kinds of cells/proteins etc could be providing signals that might provoke a T cell response?

Antigen presenting cells presenting antigens or macrophages or dendritic cells producing cytokines in response to specific antigen recognition or innate danger signals.

 

[hotblack]

Once you explain how a local interferon response gets sufficiently amplified locally, we’d need to know if it can result in enough interferon leaking into the circulation to cause systemic symptoms

In my head it was more localised interferon only, with the EV or free mitochondria being the routes for this to travel between separate sites. Precisely because we don’t have or see systemic interferon levels raised.

One of the biggest flaws is probably… if these exported and damaged/interferon triggering mitochondria turn up somewhere else, why are they not just degraded by the new host cell? If the answer is the new host also has a problem degrading damaged mitochondria, well, it wouldn’t need this hidden highway to import any would it.

Either it looks like this isn’t a goer and I have put the puzzle pieces together incorrectly but hopefully some of the pieces themselves will be useful or interesting to others so I’ll post a few more papers. And then move onto some more nonsense and wild speculation! The whole mitochondria-innate immunity angle is really interesting.