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Free-Floating Mitochondria

Here’s a weird one for you – one of those papers that, if it holds up, will make us all wonder about just how much we really know about cell biology. It’s from the IRCM at Montpellier, along with another INSERM lab (Gustav Roussey) and a lab at the Jacques Monod Institute at the Univ. of Paris, and the authors report that they can detect naked mitochondria floating around in blood samples. They appear to be still competent to do cellular respiration, and why they’re out there is anyone’s guess.

People had reported finding extracellular mitochondrial DNA, and it’s been studied as a potential diagnostic marker. That’s a mystery all by itself, because compared to nuclear DNA, mitrochondrial DNA is a much simpler circular species (reflecting its ancient origins from the days when mitochondria were free-living bacteria all their own that took up residence inside early eukaryotic cells). You’d think that it would be pretty rapidly degraded, and this new paper, in fact, started out as a hunt for what sort of structures might be containing it out in the blood. What I don’t think that they expected as an answer was “whole mitochondria, of course”.

You can see these things in plasma samples using dyes such as Mitotracker, and the intact nature of the mitochondria were also confirmed by electron microscopy. At least some of them are still doing their respiratory thing, but from the detection of smaller mitochondrial DNA pieces, it appears that they do get degraded by unknown mechanisms out there as well. This ties in well with the realization in recent years that mitochondria are in fact be transferred from cell to cell under normal conditions. It would appear that this transfer could be taking places over longer distances than anyone realized!

There are clearly implications for cellular communication, for inflammation, and for several other processes as well, but what I’m taking away from this paper is that for decades we have been missing the fact that normal whole blood apparently has ordinary mitochondria floating around in it. As usual when something like this turns out, my thoughts turn to what else we’re missing!

Addendum: since I mentioned the ancient event that brought mitrochondria into the cell, it’s worth nothing that a recent paper describes the first successful culture of an “Asgard” archaea organism (commentary here). It’s quite a feat of microbiology – when you read into the paper, you find that it took around twelve years to establish the culture in the lab. The organism is extraordinarily slow-growing and picky, but then again, it’s a very weird creature (as are the Archaea in general). There’s a good bit of evidence, which this paper is now able to add to greatly, that the very nuclei of eukaryotic cells came about through another such organism fusion. The paper’s figure 5 has a possible mechanism, whereby a bacterial species and an archaeaon fused together in the distant past, with the former eventually becoming the mitochondrion inside a larger eukaryotic cell and the latter becoming a primitive nucleus. When you’re looking at a human cell, you’re looking at the union of things that were once very, very far from humans indeed. . .

16 comments on “Free-Floating Mitochondria”

  1. MattF says:

    One question that occurs to this non-biologist— how do you know that these varied cellular types didn’t arise ‘recently’, i.e., less than a billion years ago?

    1. Icefox says:

      Some of them might have! But, part of the answer is “fossils”: even very simple animals such as sponges are still eukaryotes, and they exist in the fossil record at least to before the Cambrian, 550+ million years ago. Microfossils have been found that are much older than that, but I know a lot less about those.

  2. Charles H. says:

    To me (not working in the field) it seems as if free-floating mitochondria would be expected whenever you have cell lysis happening. It also seems as if they wouldn’t survive very long, as, IIUC, some of their needed DNA has moved inside the cell nucleus. But it’s not clear to me whether “not very long” translates into hours or weeks.

  3. AOM says:

    I’m now extremely curious about this effect with whole blood transfusions. Can these mitochondria reproduce in the blood stream? Can they be reintegrated with a cell? If they can, could someone have mixed mitochondrial DNA?

    1. loupgarous says:

      Might mitochondrial damage within long-lived cells be repaired by culturing healthy mitochondria in vitro and infecting the damaged cells with healthy mitochondria? What happens in a cell which has both its “old”, damaged mitochondria and “new”, fully functional mitochondria? I’m thinking in cases where damage to mitochondria was inflicted by toxins such as fluoroquinolone antibiotics, a cure might be possible.

    2. a. nonymaus says:

      Given that much (perhaps most?) of the DNA coding for mitochondrial proteins has been transferred to the more comfortable environs of the nucleus, reproduction of free mitochondria is almost certainly impossible. Nonetheless, if mitochondria can transfer between cells, absorption of free mitochondria into a cell seems possible. On the other hand, it may be that these free mitochondria are all the produce of a one-way trip on some cell lysis process.
      It is intriguing to wonder about transfusion-induced mitochondrial chimeras. This is even more intriguing to consider possible germ-line chimeras and the resulting errors introduced in attempts to determine the ancestry of the chimera’s progeny.
      Sadly for the monkey-gland crowd (a phrase I don’t say very often), it appears that all xenomitochondrial chimeras so far produced are less good at cellular respiration.

      1. loupgarous says:

        Thanks for the thoughtful response. I had in mind, but didn’t state explicitly, mitochondrial DNA originally finding its way into eukaryotic cells through just such an infection. Instead of devising ways to get healthy mitochondria through an otherwise healthy cell wall, it might be less work to deliver the DNA for healthy mitochondria by CRISPR. Begging the question – “does mitochondrial damage result from epigenetic insults or damage to the affected cell’s DNA for creating mitochondria?”

  4. Andre Brandli says:

    After reading Derek’s post and the abstract of the manuscript, my first take is that these free-floating mitochondria are most likely derived from the lysed cells, which may include platelets. It would be important to determine whether the number of free-floating mitochondria increases in blood samples derived from patients suffering from an acute infection in comparison to healthy persons.

  5. Thoryke says:

    There are a variety of rared diseases associated with mitochondrial disorders. It would be interesting to see if there are free-floating mitochondria in people with one of those disorders, and even more interesting if some of those mitochondria were more functional than others. Or, for that matter, if you could seed in more functional mitochondria and have those picked up by enough of the right cells to make a difference in prognosis…

  6. Ethan Perlstein says:

    Mitochondrial transfusion (of naked mito) is a thing:

    As is mitochondrial augmentation therapy, which involves isolating and expanding a mito disease patient’s CD34+ stem cells and then mixing them with healthy donor mito that enter the cells through nanotunneling. In fact there’s a company (founded in Israel, and they just opened up an office in Boston):

  7. Kaleberg says:

    In mammals, red blood cells don’t have a nucleus or mitochondria. These are ejected at some late stage in the process of a more ordinary cell turning into a red blood cell. Where do the mitochondria go? Perhaps they join the blood stream until they either break down or are absorbed by another cell. Where do the nuclei go? I haven’t a clue, but I’m guessing that they are more likely to cause trouble, so the immune system probably ingests them. Of course, they could be found swimming around in the blood stream too.

    There’s a discussion and a diagram at the link below. I swear that it shows the red blood cell to be puking out its nucleus.

    1. steve says:

      It’s pretty well documented that they get eaten by macrophages in the bone marrow.

  8. Barry says:

    If it’s normal to have mitochondria free in the plasma compartment, they must be non-immunogenic. If you can readily raise antibodies to them, it’s because they’re not normally presented.

  9. Greg says:

    This is not without precedent as was reported in ‘Nature’ in 2017 that Mitochondria can be released from cells/neurons under stress:
    C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress

  10. Paul Brookes says:

    What’s not clear from the paper (I couldn’t really wrap my head around the vague language the authors used) is whether these are single intact mito’s with only 2 membranes (i.e. the outer membrane of these things is the outer mito’ membrane), or they are encased in another layer of membrane (i.e. they’re exosomes with mito’s in). There’s a single sentence in the discussion: “All cell‐free mitochondria in human plasma or cell culture media supernatant as observed by EM were not surrounded by a bi‐ or multi‐layer phospholipid membrane.” But why wouldn’t they have a bi-layer membrane? There are 2 mito’ membranes. So they’re saying these things only have one membrane? If that’s the case they’re not mitos. Confusing.

    As others have noted further up the comment chain, mito proteins and DNA are most definitely recognized as “something other than self” by the immune system (e.g. some evidence that auto-immune diseases such as lupus may include a component involving anti-ATPsynthase antibodies), so I can’t imagine having lots of them floating around in the blood is a good thing.

    The other angle I’d like to see this approached from, is “a mitochondria is not a mitochondria is not a mitochondria.” In other words, there are lots of unique properties that mito’s have in different tissues. For example liver mito’s have a ton of carbamoyl-phosphatesynthetase for the urea cycle, and heart mito’s have a lot of beta-oxidation enzymes for burning fat. There are also tissue-specific isoforms of several mito’ proteins (e.g., adenine nucleotide translocase). Given enough of this material to work with, analysis of their make up should give some clues as to the tissue of origin.

  11. Tom says:

    “when you read into the paper, you find that it took around twelve years to establish the culture in the lab”

    Fun fact: that culture was started before the phylum Asgardarchaea was even established from metagenome datasets. Crazy stuff.

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