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The GIST

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THE GIST

  • Many studies suggest something is up with the mitochondria in diseases like chronic fatigue syndrome (ME/CFS) and long COVID but the question remains: if the mitochondria are not functioning well how did they get that way? While we don’t have the answer to that, recent studies are providijng some clues.
  • When muscle tissues (apparently from healthy controls (?)) were exposed to serum from ME/CFS and long COVID patients for 48 hours, the muscles switched from producing energy using the mitochondria (i.e. using aerobic energy production) to producing energy anaerobically.
  • High levels of mitochondrial and non-mitochondrial oxygen consumption capacity indicated that the serum caused the mitochondria to work really hard. As time went on, though, the mitochondria began to fade and break up and the muscle tissues became highly fatigued.
  • The authors hypothesized that a “stress-induced hypermetabolic state” ultimately resulted in “severe deterioration of muscle function”.
  • These are not the first authors to suggest that an initial burst of hypermetabolism permanently affected the ability of ME/CFS and long COVID patient’s cells to produce energy.
  • Earlier this year a study examining the effects of the Tick-borne Crimean-Congo hemorrhagic fever virus found that energy demands soared in the early stages of the infection – again creating a “hypermetabolic state”.
  • Some of the patient’s mitochondria wilted under the stress and began to produce energy using the anaerobic energy pathways to generate energy. Thirty days later – long after the pathogen had been vanquished – their immune cells still remained in a state of “metabolic insufficiency”.
  • Similarly, several studies suggest that the energy production systems of B-cells have become ‘overstressed” in ME/CFS.  This appears to prevent many B-cells from maturing – leaving an important part of the immune system hobbled when fighting off pathogens.
  • Indeed, Avindra Nath has proposed that a lack of B-cell maturation may be the primary driver causing ME/CFS.
  • Other studies have found evidence of exhausted and overly stressed T-cells that could be tied to an inability to produce sufficient energy.
  • All in all these studies suggest when the mitochondria of people with ME/CFS and/or long COVID are put into a highly stressed state such as during an infection, they become exhausted and are not be able to recover.
  • Bob Naviaux’s Cell Danger Response model proposes that the hypermetabolic to hypometabolic switch is operative in ME/CFS. He believes our cells become supersensitive to danger signals such as ATP when it is released from a cell when it becomes stressed.
  • He believes that antipurinergic drugs like Suramin will ultimately be able to return both the cells and the patient to health.
  • Once again the hypersensitivity theme shows up. From the overly sensitive glial cells in the brain to the hypersensitive pain processes found in the central nervous system, the spine, and nerves in fibromyalgia, finding ways to calm things down will surely play a role in overcoming these complex diseases.

Many studies suggest something is up with the mitochondria in chronic fatigue syndrome (ME/CFS) and long COVID but the question remains: if the mitochondria are not functioning well how did they get that way?

Recent studies provide some clues. The latest came from a fascinating abstract “571P Muscular metabolic plasticity in 3D in vitro models against systemic stress factors in ME/CFS and long COVID-19” from the 2024 Neuromuscular Disorders conference (thanks, Jutta for the tip! With its focus on the mitochondria and the muscles this Spanish study really hit some hot spots.

When muscle tissues (apparently from healthy controls (?)) were exposed to serum from ME/CFS and long COVID patients for 48 hours, a bunch of bad things happened.

The fact that the serum from both the ME/CFS and long COVID (LC) patients produced the same result suggested that the kind of trigger (SARS-CoV-2 virus – LC; multiple possibilities – ME/CFS) didn’t matter – the same core dysfunction was present in both. It brought to mind Akiko Iwasaki’s admonition to stop focusing so much on the spike protein in long COVID and look to core abnormalities that pervade all these diseases.

The ability of the muscle to contract; i.e. produce force (muscles produce force by contracting) was “severely compromised” suggesting that these muscle tissues were probably pretty much dead in the water.

At the same time that was happening, enhanced levels of glycolytic enzymes suggested that the muscle tissue’s ability to generate lots of energy via the aerobic energy production pathway had pooped out – causing them to rely on the less efficient anaerobic energy production.

At first glance, the myotube hypertrophy (increased incidence of immature muscle cells) found suggested that muscle cells were simply gearing up for activity. The fused mitochondrial networks, though, suggested that adding the ME/CFS/Long COVID serum to the muscle tissue put the mitochondria under severe stress and the myotube enhancement was a compensatory mechanism.

Mitochondria

Serum from ME/CFS and long COVID patients caused the mitochondria in the muscle cells to become highly stressed and ultimately dysfunctional.

Indeed, both mitochondrial and non-mitochondrial oxygen consumption capacities were elevated – suggesting that the serum caused the mitochondria to work really hard. As time went on, though, the mitochondria began to fade, and break up and the muscle tissues became highly fatigued.

The authors hypothesized that a “stress-induced hypermetabolic state” ultimately resulted in “severe deterioration of muscle function”. In this scenario, something in the serum caused the muscle cells to get revved up – and exhaust themselves – resulting in the exercise intolerance in ME/CFS and long COVID.

An “Energy Maladjustment”

These are not the first authors to suggest that an initial burst of hypermetabolism permanently affected the ability of ME/CFS and long COVID patient’s cells to produce energy.

Earlier this year a study examining the effects of the Tick-borne Crimean-Congo hemorrhagic fever virus found that energy demands soared in the early stages of the infection – again creating a “hypermetabolic state”.  The ATP upregulation, the turn towards an increased use of amino acids, and the increased fatty acid oxidation suggested the immune cells scrambling to keep up the fight against the virus.

That made sense. We know that during an infection immune cells have to dramatically rev up their engines.

There was a catch, though. Some of the patient’s mitochondria wilted under the stress and began to produce energy using the anaerobic energy pathways (glycolysis/pyruvate metabolism) to generate energy. These patients had a more difficult time fighting off the virus – indicating that the ability to produce energy plays a crucial role in being able to fight off the virus.

Then came the post-infectious clincher. Thirty days later – long after the pathogen had apparently been vanquished – their immune cells still remained in a state of “metabolic insufficiency”.

Indeed, the vast majority of patients (83%) were experiencing fatigue strong enough to inhibit their daily activities leading the authors to conclude they were in a postviral fatigue state. Besides fatigue, musculoskeletal pain (75%), anorexia (50%), weight loss (50%), headache (38%), palpitation (38%), and sweating (38%) were found.

The authors declared that an “energy maladjustment” had occurred and concluded that “metabolic rewiring during the recovery phase potentially leads to postviral fatigue”.

Energy Drain: Could an African Virus Tell Us Much about ME/CFS, Long COVID and other Postviral Illnesses?

Immune Cells

The B-cell Bust in ME/CFS

Several studies suggest that B-cells’ energy production systems may have also become ‘overstressed” in these diseases.

Studies that have been tracking down why so many “naïve” or immature B-cells are present in ME/CFS have found that these B-cells have also turned to anaerobic energy production. The lower levels of mitochondria and the higher levels of lactate associated with them provided a reason why these immature B-cells may be having trouble making it to maturity.

These immature cells have also been associated with a breakdown in autophagy; the ability to safely recycle the cells contents including the mitochondria. Autophagy-deficient cells are associated with, guess what, high levels of inflammation. The Simmaron Research Foundation has found evidence of autophagy problems in ME/CFS.

Cleaning Crisis? Defective Mitochondrial Cleanup In ME/CFS May Be Impairing Energy Production

Since antibody-producing B-cells play a major role in fighting off infections, having a bunch of immature B-cells hanging around the immune systems of ME/CFS patients would not be much help.

Interestingly, Avinda Nath believes immature B-cells constitute “the primary defect” (in ME/CFS). The inability of these cells to mature leads to “immune exhaustion and activation of innate immune responses”; i.e. the adaptive (later) immune response that the B-cells participate in punks out leaving the early and more inflammatory innate immune response to kick in.

Note that these studies in these different cell types appear to duplicate the same energy transition that exercise studies indicate has happened: a broken aerobic energy production turns to the less efficient and dirtier anaerobic energy production.

Could it all have begun with overstressed mitochondria?

T-cell Troubles

Vishnu Shankar’s ME/CFS Stanford study (unpublished) suggests it might have. He found that overstressed mitochondria in T-cells were breaking down and releasing high levels of free radicals/reactive oxygen species. Those high levels then damaged the mitochondria – causing even more oxidative stress – and throwing people with ME/CFS into a vicious cycle.

The Vampire: Is the Immune System Sucking the Energy Out of People with ME/CFS? – the NIH ME/CFS Conference Pt. I

Liisa Selin might agree as well. She found exhausted T-cells in ME/CFS were  associated with increased levels of oxidative stress. That made sense given that damaged mitochondria produce a lot of oxidative stress. In a preliminary study she found that a nebulized agent with antioxidant was able to help restore T-cell functioning.

Overtraining Syndrome

While we don’t know if a hypermetabolic state precedes it, it appears that overtrained athletes are stuck in a hypometabolic state as well. Metabolomic studies suggest they are in “procatabolic environment”,  in which their muscles are being broken down to provide energy.

The authors proposed that the “global reduction in metabolic pathways” found, may have been produced to save energy and redirect energy during a state of (energy) starvation; i.e. it suggests that the athlete’s mitochondria, for whatever reason, became overstressed and were unable to provide normal amounts of energy.

Bob Naviaux

Bob Naviaux believes the mitochondria in ME/CFS patients become supersensitive to signs of cellular stress. Anti-purinergic drugs like Suramin could help.

Bob Naviaux’s Take

Indeed, a state of energy starvation or hypometabolism – perhaps akin to Naviaux’s Dauer state where the cells shut down the metabolism – has long been proposed to be present. I asked Bob Naviaux whether this hypermetabolic to hypometabolic switch fit his Cell Danger Response hypothesis and it did.

Yes.  Everyone experiences a transient hypermetabolic state with the beginning of CDR1 and fever during an acute infection. Most people experience this dozens of times in a lifetime. 90% of the time this resolves without any consequences after a few days to weeks, and we recover completely.

Only about 10% of patients have lingering symptoms that last for more than 6 months.  In the patients who develop ME/CFS, Long-COVID, and many other hypometabolic, multi-system, chronic fatigue syndromes, mitochondria and cells enter a chronic, but reversible physiologic state that protects the patient and cells from new injuries and chronic threat, but at the expense of a dramatic decrease in functional capacity.  This occurs because the chronic response to danger (the 3 phases of the CDR) siphons energy and resources away from baseline health for purposes of cellular defense.

Our research suggests that this state is maintained chronically by receptor-mediated hypersensitivity to ATP-signaling.  Very small stresses can trigger setbacks (PEMs) because the body is hypersensitive to small amounts of eATP release that occurs with stress or exertion.

I believe that when ATP signaling sensitivity is restored to normal by a course of suramin treatment, or eventually with other antipurinergic drugs the might one day be taken by mouth, that full recoveries from ME/CFS, Long-COVID, and related disorders will be the norm and not the exception.

Conclusion

A hypermetabolic state that overly stresses the mitochondria early on could be setting the stage for a long term case of hypometabolism; i.e. reduced energy production in diseases like ME/CFS and long COVID. Why the mitochondria might be failing this way in people with these diseases is unclear. Bob Naviaux’s research suggests that the cells have become hypersensitive to stress factors (eATP) produced by the cells and he believes that anti purinergic drugs will ultimately be game-changers.

Once again we see the hypersensitivity theme show up. Jarred Younger believes the glial cells in the brain have become hypersensitive to stimuli in these diseases. With hypersensitive pain processes present in the central nervous system, the spine, and the peripheral nerves in the body, fibromyalgia, of course, is the queen of the hypersensitivity diseases. What’s causing such a twitchy state is unclear but finding ways to calm things down will surely play a role in overcoming these diseases.

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