The Triad in ME/CFS and long COVID? Antibodies, the Mitochondria, and the Blood Vessels

by Cort Johnson | Mar 28, 2026 | Autoimmune, Connective Tissues, Endothelial Cells, Energy Production, Homepage, Immune, long COVID, Metabolism, Research | 27 comments

Geoff’s Translation

The GIST\

Something in the Blood…

This was another “passive transfer” study where researchers transferred something in the blood – in this case, IgG antibodies- into laboratory cultures and watched what happened. It has ramifications

This study suggests that IgG and the immune complexes associated with it are whacking the mitochondria, impairing blood vessel functioning, and harming the connective tissues. in ME/CFS.

By focusing on IgG antibodies, the mitochondria, and the metabolism. the “Immunoglobulin G complexes from post-infectious ME/CFS, including post-COVID ME/CFS disrupt cellular energetics and alter inflammatory marker secretion” the study hit some hot topics in ME/CFS research. Thanks to Matthias for pointing it out.)

Health Rising’s Quickie Summer Donation Drive is On!

Keeping up with the latest research in ME/CFS, long COVID, fibromyalgia, and allied diseases. Exploring new treatment possibilities. Learning how others have recovered. All in as thoroughly and comprehensively as we can.

Please support Health Rising during our quickie summer donation drive. Our goal is to raise $15,000.

Find out more here.

The mostly German/US study included Bhupresh Prusty, Carmen Scheibenbogen, Charite University, the University of Wurzburg, Stanford, UCSD (Bob Naviaux), and Latvian researchers. It underscored the fact that as ME/CFS, long COVID, etc., researchers dig deeper into these diseases, we can expect some surprises to pop up.

This nice-sized study (n=106) took IgG antibodies – the ones that usually do the mischief in autoimmune diseases – from people with ME/CFS (Canadian Consensus Criteria), long-COVID patients with ME/CFS, multiple sclerosis, and healthy controls, and cultured them with endothelial cells and human foreskin (!) cells. (The foreskin cells were a stand-in for a general cell type. The endothelial cells were chosen because of the apparent blood vessel problems.)

Stressed Mitochondria in…

While the IgG from every group (ME/CFS, MS, and healthy controls) was unable to enter general cells (human foreskin), it readily penetrated endothelial cells. Once the IgG entered the endothelial cells, though, things changed: only the IgG from ME/CFS and long COVID patients caused mitochondrial fragmentation, leaving more small mitochondria.

The GIST

Identifying what the IgG antibodies are attacking could result in targeted treatments and more successful clinical trials.

This is yet another “something in the blood” study in which researchers transfer something in the blood – in this case IgG antibodies – into a lab culture to see what, if anything, those antibodies are doing.
If this study were successful, it would point another arrow at autoimmunity in ME/CFS and/or long COVID. It turned out that it was.
The study found that IgG antibodies from ME/CFS and long COVID patients (but not healthy controls or MS patients) are fragmenting the mitochondria in the endothelial tissues that line the blood vessels in a substantial subset of patients. Mitochondrial fragmentation typically occurs when the mitochondria are under stress and start splitting off damaged sections.
Interestingly, mitochondrial ATP production was not significantly affected, but the mitochondria were left in a damaged, hunkered-down, protective state that the authors believe likely affected blood flows.
Further analyses suggested that the antibodies were inhibiting mitochondrial functioning but that the entire immune complex traveling with the antibodies was necessary to fragment them.
An analysis of these immune complexes suggested that they damaged connective tissues (including blood vessels) in ME/CFS and led to increased clotting in long COVID.
The authors proposed that long COVID presented an earlier form of ME/CFS and that long COVID patients would eventually look like ME/CFS patients; that is, the inflammation and clotting would eventually produce the connective tissue issues present in ME/CFS.
The potential treatment ramifications of these findings are substantial. For one, the study suggests that a significant subset of ME/CFS/Long COVID patients (with mitochondrial fragmentation) might be more amenable to treatments that remove or block IgG and/or which improve blood vessel functioning. Identifying that subset should lead to more targeted and successful treatment trials.
Because this was a lab study, it will be important to move into human studies that assess the effects of mitochondrial fragmentation on blood flows, symptoms, etc. and are able to identify patients that could benefit from treatments.. Identifying what the antibodies target will be critical to determining which treatments can stop them, and many options are available. Treatments that increase blood flows could be helpful as well.
In short, this study identified a possible autoimmune process that causes mitochondria in the cells lining blood vessels to fragment, thereby affecting blood flows and opening potential treatment options if the findings are validated.

Support Health Rising and Keep the Information Flowing!

Health Rising is not a 501 c (3) non-profit

The fragmentation was concentrated in a subset of ME/CFS patients, but the authors did not state exactly how big the subset is. Suffice it to say, however, that it was a substantial subset and was more evident in women than men.

Mitochondrial fragmentation usually indicates that the mitochondria are under unusual stress. The mitochondria become smaller when they cut off damaged parts of themselves to survive.

…Stressed Endothelial Cells =

Indeed, the increased respiratory rate observed in endothelial cells exposed to ME/CFS IgG suggested that mitochondria were under increased stress. The finding that the endothelial cells in ME/CFS exhibit greater “glycolytic compensation” (i.e., are relying more on glycolysis (anaerobic energy production)) fits with the idea of that something has gone awry with the aerobic energy production system, which may result in more oxidative stress, etc.

The antibody arms attach to the target. The fact that the arms of antibodies from ME/CFS and Long COVID patients affected mitochondrial fragmentation suggested that the antibodies were attacking the mitochondria.

Interestingly, ATP production was not reduced. The fact that it was not may have something to do with how endothelial cells operate. They get most of their basal energy from glycolysis – not aerobic energy production. They use the mitochondria for other activities (blood vessel production, stress response, etc.).

The authors of the paper believe the immune complex associated with ME/CFS and long COVID igG puts the mitochondria in endothelial cells into a “chronic protective stress response” state that sounds very much like Naviaux’s cell danger response.

Next, in an attempt to learn which part of the IgG antibody was affecting the mitochondria, they broke it up into its two major sections – the Fc and Fab regions – and assessed them in culture. The Fab (fragment antigen-binding) regions are represented by the two arms of the antibody. They are what the antibodies use to bind to pathogens, tissues, etc. The Fc region (the stem of the antibody) recruits immune cells and determines the strength of the immune response.

The ability of the Fab region to affect mitochondrial metabolism suggests that antibodies were attacking the mitochondria. Because it points an autoimmune arrow straight at the mitochondria/endothelial cells, this is potentially a big deal in this disease.

The fact that the entire antibody/immune complex was needed to fragment the mitochondria suggests that antibodies plus the immune complexes are needed to complete the picture. Note, though, that this part of the paper is based on a very small sample size.

Stressed Connective Tissue?

The researchers performed proteomic analysis on the immune complexes associated with IgG isolated from ME/CFS and Long COVID ME/CFS patients. Now, the researchers wanted to know what those immune complexes consisted of and if they were having an impact.

Immune complexes can hold the key to what’s going with autoimmunity and IgG because they’re clusters of cells that form when IgG binds to an “antigen” or target. They hold keys not only to what the antibody is attacking but the effects its having.

Look at the clean separation between the healthy controls (red) and the ME/CFS, long COVID ME/CFS, and MS patients’ proteomes. The ME/CFS patients’ proteomes (green) are clustered near but still nicely separated from the long COVID patients’ (purple) and the MS patients (blue).

The results suggested that the immune factors traveling with the antibodies clearly play a role, and they appear to play somewhat different roles in ME/CFS and long-COVID ME/CFS.

The immune complexes associated with the ME/CFS IgG showed increased levels of extracellular‑matrix (ECM)–related proteins, i.e., connective tissue proteins. Note that the blood vessels are connective tissues, and endothelial cells are embedded in an extracellular matrix. The increased levels of extracellular matrix proteins were an intriguing finding, given recent findings suggesting that increased basement membrane production may be preventing blood from flowing to the tissues.

Increased levels of an intriguing protein called SPEG, which plays a major role in muscle development and maintenance, provided another possible lead. Because SPEG is not usually found outside of cells, the increased levels suggested that some sort of muscle injury had occurred, and suggested that autoantibodies to it had been formed. IgG binding to SPEG could result in disturbed muscle calcium handling (aka Wirth and Scheibenbogen?), fatigue, exercise intolerance, and post-exertional malaise. Other proteins that popped up also provided potential leads.

Long COVID + Time = ME/CFS?

The long COVID ME/CFS IgG contained more proteins associated with clots. This might have been expected, as microclots, while present in ME/CFS, appear to be more evident in long COVID. While the end result – poor endothelial functioning – may be the same in ME/CFS and long COVID, it may be produced in different ways. In ME/CFS, the connective tissue is more affected, whereas in long COVID, clotting is a bigger issue.

The authors raised the intriguing idea that the increased inflammatory profile in long-COVID ME/CFS simply reflects an early stage of ME/CFS, which ultimately reverts to a more metabolically challenged state with greater connective tissue damage as the disease progresses.

The treatment ramifications of these findings are substantial. For one, the study suggests that the subset of ME/CFS/Long COVID patients with mitochondrial fragmentation might be more amenable to treatments that remove or block IgG and/or which improve blood vessel functioning. Identifying that subset should lead to more targeted and successful treatment trials. As the last blog pointed out, targeting subsets has become a central theme in ME/CFS and long COVID research.

Conclusion

This was yet another intriguing paper from Prusty and colleagues. This study very nicely potentially tied together two hot topics – IgG antibodies/immune complexes and blood vessel problems – plus, it added a new player to the mix – immune complexes – and boosted the idea that an autoimmune process is present in at least a significant subset of patients.

Increased levels of fragmented mitochondria, which appeared to be hunkered down, suggested the mitochondria in the endothelial cells from ME/CFS and long COVID patients were in a protected, stress-response state.

In the lab, at least, the IgG antibody/immune complexes from ME/CFS and long-COVID ME/CFS patients fragmented the mitochondria, putting them under stress. ATP production was not significantly affected, but the mitochondria were discombobulated and were not working well.

This is the second time, by the way, that Prusty, Naviaux, et al. have been able to fragment ME/CFS mitochondria in the lab. In a small 2023 study, they found that transferring ME/CFS serum in the lab could induce mitochondrial fragmentation in certain cells.

The immune complex analysis – which highlighted coagulation and connective tissue problems – suggested that researchers need to start assessing the immune complexes in which the antibodies are embedded. In fact, it’s possible that immune complexes play a larger role than the antibodies themselves.

Damage to the dynamic endothelial cells that line our blood vessels could translate into, among other things, reduced blood flows (particularly in the microvasculature) and inflammation. The paper identified several proteins that could play a role in these diseases.

The paper had its limitations. Because it was a lab study, it couldn’t provide evidence that its findings – no matter how intriguing – are actually happening. Some of the analyses were also done on very small sample sizes. Some ME/CFS participants’ IgG did not appear to induce high levels of mitochondrial fragmentation.

Next Steps

It also provided some nice leads. Bigger studies are needed to validate and expand its findings. For instance, future studies assessing endothelial cells from other sites in the body (e.g., the brain and skeletal muscle) could determine how widespread this process is.

Getting out of the lab and into human studies is critical. Studies that assess the extent of mitochondrial fragmentation, and its effects on blood flows, inflammation, orthostatic intolerance, handgrip strength, etc., would provide strong validation that mitochondrial fragmentation is playing a major role, and let us know which patients it’s affecting and how it’s affecting them.

Attempting to identify what the IgG antibodies are attacking is a possible next step.

Identifying what the antibodies/proteins are targeting or attacking would play a key role in uncovering treatment options. Once the target is found, many approaches (plasmapheresis/immunoadsorption, IVIG, efgartigimod, complement inhibitors, Rituximab, decoy antigens, etc.) that block those antibodies/proteins from attacking the mitochondria/blood vessels are potentially possible.

Other treatments (statins, ACE inhibitors, ARBs, sildenafil, and more) that attempt to increase blood flows and improve blood vessel health are a possibility. Reports indicating that, in some cases, hyperbaric oxygen therapy (HBOT) has returned some patients to health suggest that, over time, oxygenating tissues might be enough for some. HBOT may be doing this by activating repair programs, creating new, healthier capillaries that increase perfusion, turning off established inflammatory/oxidative stress loops, and even increasing blood flow, thereby promoting neuroplasticity in the brain.

The key will be identifying the patients who are more likely to benefit. Indeed, finding treatable subsets has become the theme of the day. (Thanks to Matthias for the tip about the study.)

Coming up – “Nothing in the Blood”? A validation study fails….

Support Health Rising and Keep the Information Flowing!

Health Rising is not a 501 c (3) non-profit

Health Rising’s Quickie Summer Donation Drive is On!

Please support Health Rising during our quickie summer donation drive. Our goal is to raise $15,000.

Find out more here.

27 Comments