The second of a series of blogs on recent findings on the mitochondria in chronic fatigue syndrome (ME/CFS), long COVID, and fibromyalgia focuses on ME/CFS.

• The Mitochondria in Long COVID Pt. I: Are Core Problems Being Uncovered?

The first ME/CFS mitochondrial study on the docket is “only” a case report – but what a case report! The senior author of the paper was none other than Alan Light, and that deserves a little digression.

Alan Light Returns! 

We can’t just step over the fact that Alan Light has published again on ME/CFS. For those who don’t recognize them, he and his wife, Kathleen Light, are University of Utah pain researchers who, from 2009 to about 2017, produced a series of promising studies on ME/CFS.

Their 2012 paper produced perhaps the most startling graph I’ve seen in ME/CFS yet. It indicated that exercise produced remarkable increases in the expression of the receptors on white blood cells that detect metabolites associated with exercise. In essence, it suggested that exercise was either inducing a lot of damage which the white blood cells were reacting to, and/or that the white blood cells had become hypersensitive to any signs of damage produced by exercise. (Exercise always induces some damage). In either case, it appeared that an exercise-induced immune activation was in full bloom.

Interestingly, given Naviaux’s emphasis on the purinergic metabolites, the paper particularly plucked out the activation of a purinergic receptor (purinergic type 2X4 receptor). The paper also showed that when it came to exercise, people with ME/CFS and another notoriously fatiguing illness, multiple sclerosis (MS), were similar and different.

Exercise did not provoke the white blood cells in MS to go on high alert for exercise-induced metabolites, but it did trigger a spike in adrenergic receptor activity in both ME/CFS and MS patients (but not healthy controls). That suggested exercise dysregulated the sympathetic nervous system in both diseases.

Elucidating the Muscle Fatigue Pathways

Alan Light said he wanted to do for fatigue when had been done for pain (i.e., elucidate the fatigue pathways in the body) and in 2015, he and Markus Amann put their findings together in a review paper, “From Petri dish to human: new insights into the mechanisms mediating muscle pain and fatigue, with implications for health and disease“.

The paper asserted that metabolites produced by muscle activity activated both myelinated and unmyelinated neurons (small nerve fibers) which then sent signals to the central nervous system via the nerve located on the dorsal horn of the spinal cord.

They noted that two sets of receptors designed to interact with these exercise-induced metabolites were present: one subtype responded to relatively low levels of intramuscular metabolites (lactate, ATP and protons), as seen during `normal’ (i.e. freely perfused and aerobic) exercise, while the other responded to higher concentrations of metabolites that were produced during ischemic conditions in which the muscle was in a state of hypoxia; i.e. low oxygen levels.

Over time, studies concluded that protons, ATP, and lactate produced by the muscles induce muscle fatigue and pain, and that neurons with ASIC, P2X, and TRPV1 receptors respond to them. The Lights found that exercise highly upregulated these receptors in ME/CFS. With that, they seemed to be on the road to delineating how muscle activity during exercise could be producing the pain and fatigue in ME/CFS, but the Light’s time with ME/CFS ended in 2017 with Dane Cook’s paper showing that exercise impacted brain functioning.

Inheriting Dysfunction (at the NIH)? The Heritability Study

The Lights also participated in a 2011 paper, “Evidence for a heritable predisposition to Chronic Fatigue Syndrome“, that was remarkable for: a) its conclusion that there was “strong support for a heritable contribution” to ME/CFS (i.e. ME/CFS can run in families), b) its ability to identify a group of “high-risk” family lines, and c) the bizarre fact that it was never followed up on (they tried).

Identifying high-risk family lines was a coup, as researchers typically study families to get clues about what’s going on in a disease. The bizarre part comes from the NIH funding what turned out to be a successful study – and then being unwilling to fund a follow-up. (Why fund the study in the first place?)

What happened to turn off the Lights’ ME/CFS spigot is unclear, but the 2017 paper was the last one from the Lights and ME/CFS until 2024, when Alan Light popped up in an interesting case report.

A Viral – Mitochondria Connection?

The case report, “The “Mitochondrial DNA Missense Mutations ChrMT: 8981A > G and ChrMT: 6268C > T Identified in a Caucasian Female with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Triggered by the Epstein–Barr Virus“, involves a 75-year-old woman who had been sick with ME/CFS, triggered by an infectious mononucleosis infection about 20 years earlier.

Her symptoms were primarily mainly neurological and cognitive impairment, and included fatigue, severe PEM, severe dysautonomia, unrefreshing sleep, widespread achiness and tenderness, sporadic dizziness with vertigo, severe orthostatic intolerance, and brain fog.

Standard lab tests, of course, were normal. The NASA lean test, though, revealed that she had neurally mediated hypotension (reduced blood pressure upon standing). Despite taking antivirals (valacyclovir, valganciclovir) for long periods, she at times exhibited moderately high titers of EBV antibodies. Still, neither, her antibody nor a PCR test suggested she had an active infection.

But then there were the mitochondria…

The electron chain complexes where ATP is finally produced are mainly encoded by mitochondrial chromosome DNA (ChrMT DNA, or mtDNA) passed down through the mother. The ChrMT chromosome is also where the first half of the mitochondrial energy production process – the Krebs cycle – where oxidative phosphorylation (OXPHOS) takes place. Because ATP generation produces a lot of oxidative stress (i.e., many free radicals) – picture sitting next to a blast furnace – this part of our DNA is highly susceptible to oxidative damage and has high mutation rates.

A deep dive into her mitochondrial DNA and her mitochondria, however, revealed that she had several mitochondrial DNA mutations (ATP6 (ChrMT: 8981A > G Q152R) and Cox1 (ChrMT: 6268C > T A122V)) including one at a site (ATP6) well known to cause mitochondrial problems.

That ChrMT Cox1 mutation was not just any mutation. For one, it was new to the literature. For two, it occurred in a gene (Cox1) that plays an important role in the later stages of the electron transport chain. The authors believed that a mutation affecting those stages would be particularly devastating and have “progressive effects on ATP production and mitochondrial functions”.

One of those effects was large numbers of dysfunctional extracellular mitochondria. These mitochondria appeared to “protrude” or “secrete” vesicle-like structures similar to those that Gram-negative bacteria produce in stressful conditions (!).

The authors proposed that the extracellular, abnormal mitochondria found in her and other ME/CFS and post-infectious illness patients probably resulted when a batch of malfunctioning mitochondria met up with a virus.

They also proposed that viral-induced reactive oxygen species (free radicals) were at least partly to blame for the mutations in the mitochondrial DNA found.

We’ve seen both of these hypotheses show up. They suggest that dysfunctional mitochondria not only fail to rise to the challenge when a pathogen shows up but break down and start producing large amounts of reactive oxygen species, which then produce more mitochondrial damage.

The authors proposed that people with ME/CFS probably had “dysfunctional mitochondria” that predisposed them to develop ME/CFS after viral infections”. Those dysfunctional mitochondria could either be inherited, or modified by epigenetic changes, and/or by an infection.

With regard to this patient, they believe her mitochondrial mutations probably reflected “accumulated mitochondrial stress” caused at least in part by her exposure to the Epstein-Barr virus at age 52.

Harkening back to the heritability study, they recommended, though, that her family undergo ChrMT DNA sequencing to “help uncover the role that viruses, mitochondrial DNA mutations, and mitochondrial problems play in the disabling fatigue found in post-infectious diseases”.

While we don’t normally associate the mitochondria with viruses, as Dr. Naviaux has explained, and as we saw in a recent blog, the mitochondria play a pivotal role in our viral defenses. Because they do so, they are targeted by viruses which produce large numbers of “virologs” in an attempt to damage the mitochondria and turn down the immune response.

 The Brain-Mitochondria Connection 

Let’s forget infection for a moment though. Could stressful conditions all by themselves lead to mitochondrial breakdown? A recent animal study suggests they can.

Several researchers have proposed that much of the fatigue in ME/CFS comes from “central fatigue”; i.e. fatigue that’s caused by the brain. In fact, Behan and Chaudhuri’s 2004 tome, “Fatigue in neurological disorders“, which repeatedly cited ME/CFS, was one of the first to make this connection. Their focus on the pathways interconnecting the basal ganglia, thalamus, limbic system, and higher cortical centres still rings true today.

The idea that central fatigue is a big deal in ME/CFS makes a lot of sense in several ways. For one, we know that the symptoms of “sickness behavior” we experience when we have a cold are produced by the brain. Given its typical post-infectious onset, ME/CFS could simply be a cause of chronic, unrelenting “sickness behavior”.

Of course, the big question is how to account for the findings of muscle damage, blood vessel, and mitochondrial problems that have shown up in the periphery in ME/CFS. Does the brain have that far of a reach?

A fascinating study from Daniel Clauw suggested it just might. In another animal study, Clauw found that increasing the activity of the insula – an organ of the brain involved in autonomic nervous system regulation and sensory processing – resulted in the development of small fiber neuropathy and increased pain sensitivity in its limbs (!).

A recent animal model, “Replicating human characteristics: A promising animal model of central fatigue“, set out to understand just how far “central fatigue” might go. It first created a state of central, or brain-induced, fatigue via sleep deprivation and alternate-day fasting. Note that no increases in physical exertion were introduced – whatever happened in the periphery was not the result of exertion.

Even though the mice didn’t exert themselves, their muscles were hit hard. They exhibited reduced grip strength, and endurance, increased lactate levels and energy consumption, and muscle atrophy, including a reduction in slow muscle fiber levels.

And then there were the mitochondria. The mitochondria both in their brain and the muscles got hit even harder. Noting that mitochondrial problems have been found in another fatiguing disease – ME/CFS – the authors reported finding reduced ATP levels, increased levels of oxidative stress, irregularly shaped cells, increased heterochromatin in the nucleus, decreased levels of mitochondria in the cytoplasm, broken or disappeared inner cristae, and ruptured outer membranes.

In the end, the authors proposed that they believed that the fatigue, reduced endurance, and cognitive problems found in the mice with central fatigue were related to mitochondrial damage, problems with energy metabolism, and oxidative stress.

We were back to square one with the mitochondria – and a brain that apparently has a long reach.

Microstructural Mitochondrial Abnormalities

A small but perhaps telling Stanford study from Fereshtah Jahanbani (“Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study“) used transmission electron microscopy (TEM) to dig deep in the microstructures (including the mitochondria) of both unstimulated and stimulated immune cells.

Only four people participated in the study –  a pair of identical twins, one of which had moderate ME/CFS, a person with severe ME/CFS, and another healthy control – but the study produced some intriguing results that will hopefully be followed up on.

Immune activation is not a subtle process. It requires a lot of energy, and thus provides a nice way to test a cell’s energy metabolism. Placid-looking monocytes, for instance, turn into hairy monsters called macrophages, and B and T-cells jack up their energy metabolism as they prepare to clone themselves in great numbers.

Researchers have proposed that all that activity is too much for the puny mitochondria found in people with ME/CFS, causing the immune cells to punk out and either become exhausted (T-cells) or fail to reach maturity (B-cells).

The authors of this small study might agree. Once stimulated, the number of dead and dying T-cells in the ME/CFS patients began to pile up, and the levels of swollen mitochondria – indicative of mitochondrial dysfunction – increased significantly. The authors reported that the two ME/CFS patients “showed remarkably higher numbers of swollen mitochondria.”

The Original Sin – Bad Mitochondria?

Once again we were back to the mitochondria. Whether in the brain or muscles or immune cells, these studies – all of them small, it should be noted – brought us back to what might very well be the original sin in these diseases: dysfunctional mitochondria.

• Coming up: Pt. 3 – the Mitochondria in Fibromyalgia Plus Some Treatment Suggestions

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