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Geoff’s Narration

The GIST

The Blog

 

(The GIST is on the bottom right of the blog today)

The “Oxidative Stress is a shared characteristic of ME/CFS and Long COVID” preprint is an example of how a small but well-done study can still reach very deeply into the biology of ME/CFS. Health Rising covered Mark Davis’s presentation on the effort in the Dec 2023 NIH ME/CFS Conference, but the preprint that was just published includes long COVID and has new findings.

Vishnu Shankar

Vishnu Shankar, an enterprising graduate student, turned a struggling NIH grant on T-cells into a win.

Some people may remember that Health Rising reported that becoming obsessed with the energy problems found in ME/CFS, Vishnu Shankar, a PhD. Stanford student, engineered a study that assessed energy production in ME/CFS patients’ immune cells.

Shankar focused on immune cells because their energy needs are so high. It turns out that protecting the body from pathogens is quite an energy-intensive project. Even when it’s not fighting off an infection, the immune system uses about 15-20% of our energy. (When it is fighting off an infection, the body will devote about 25% of its total energy expenditure to the immune system.)

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

The Study

This study did something fairly simple: it assessed both mitochondrial activity and oxidative stress in immune cells (PBMCs) in 16 healthy controls, 15 ME/CFS and 15 LC donors. While doing so, it opened up a world of possibilities.

Mitochondrial Breakdown

While this study did not find reductions in mitochondrial mass or mitochondrial membranes in ME/CFS or long COVID, it did find reduced production of a considerably more important factor – ATP production. The immune cells in the ME/CFS/Long-COVID patients weren’t pumping out as much energy as the healthy controls cells – suggesting they were damaged and possibly exhausted.

Because damaged mitochondria aren’t just bad at producing energy but can become free radical-producing machines, they took a look at oxidative stress (free radical) levels. (Just as a damaged automobile engine produces more exhaust than a well-functioning one, damaged mitochondria spew out more toxins; i.e. free radicals.)

Elevated Oxidative Stress Levels 

Immune cells have to switch their after-burners on to get the energy to go after pathogens. Producing that energy comes at a cost, though, in the form of increased levels of reactive oxygen species oxidative stress (free radicals). (Note the key word – reactive oxygen species – these are unbalanced oxygen molecules which try to achieve balance by ripping electrons from other molecules; hence the word “reactive”.)

These reactive oxygen species, or free radicals, are a normal byproduct of aerobic energy production, and our systems have evolved to handle them. But not so well, apparently, in ME/CFS and long COVID. Various studies that have found low levels of antioxidants and increased levels of oxidative stress suggest that antioxidant systems in ME/CFS are not up to the task.

From the study. Note the dramatically increased levels of reactive oxygen species in B and T-cells in ME/CFS patients in particular (ME/CFS – red, LC – green, healthy controls – blue).

Indeed, in this study, dramatically higher levels of reactive oxygen species were found in both the ME/CFS and long-COVID patients’ immune cells compared to the healthy controls. (ME/CFS patients had the highest levels).

A closer look revealed, however, that the reactive oxygen species were almost wholly centered in the immune cells from female ME/CFS patients. Their levels were 2-4x’s higher than the healthy controls. The immune cells from the male ME/CFS and male long-COVID patients did not have significantly increased reactive oxygen species.

Both male ME/CFS and long-COVID patients did, however, exhibit elevated glutathione levels – indicating that their immune cells were also dealing with increased oxidative stress levels – which have triggered the production of the master antioxidant in our cells – glutathione.

Altogether, multiple pathways that deal with oxidative stress (glutathione, superoxide dismutase, lipid oxidative damage, etc.) appear to have been overwhelmed in the immune cells in these diseases.  That’s not such a surprise given what we know about oxidative stress and ME/CFS.

Could a Free Radical Explosion Be Causing ME/CFS and Long COVID?

Mitochondrial Calcium

Increased levels of mitochondrial calcium – which can drive the production of reactive oxygen species (ROS) in the mitochondria – provided another potential explanation for the increased levels of oxidative stress. Indeed, mitochondrial calcium levels were highly associated with low antioxidant levels (SOD2) in both ME/CFS and long COVID.

Check out the dramatically elevated mitochondrial calcium levels in the ME/CFS patients (red) in particular (healthy controls- blue, long COVID - green). Also notice the reduction in the SOD2 antioxidant but the dramatic elevation the ME/CFS patients glutathione levels - indicating that an upramping of the antioxidant system has occurred

From the study. Check out the dramatically elevated mitochondrial calcium levels in the ME/CFS patients (red), in particular (healthy controls – blue, long COVID – green). Also notice the reduction in the SOD2 antioxidant but the dramatic elevation in the ME/CFS patients’ glutathione levels – indicating that an up-ramping of the antioxidant system has occurred.

That was a very interesting finding given Wirth’s and Scheibenbogen’s 2021 hypothesis that calcium overload in the mitochondria could explain ME/CFS.

“The consequences of that were potentially vast. The high sodium levels turned the tables on the calcium pump, causing calcium to be imported into the cell instead of getting exported out of it. That calcium overload then impaired the mitochondria and other metabolic parts of the cell from working properly and with that – bam! – a new hypothesis (calcium overload) explaining the fatigue, post-exertional malaise, and inability to exercise, think well, etc. was born.”

ME/CFS Muscle Study Results in Drug Company Startup

Klaus Wirth’s Mitodicure startup now has a nice website. Wirth believes a drug called MDC002 will be able to stop the mitochondrial calcium buildup found in the skeletal muscles in people with ME/CFS and similar fatiguing diseases.

Metabolomics

The study also took a deep dive into metabolomics, which assesses the metabolic activity of the cells. The difference between this study and others – which looked at a broad array of cells – was its precision: this part of the study was focused entirely on T-cells.

Would the metabolic activity of T-cells mirror the metabolic activity of other cells? It did – suggesting a systemic metabolic problem may be present. Perhaps to no one’s surprise (at this point) problems with lipid metabolism popped out. Lipids are fatty compounds that provide a dense energy source for our cells, protect our cells, regulate the production of hormones, help with signaling, etc.

Note the increased lipid peroxidation in ME/CFS and long COVID patients (red/green )(lower score = more lipid peroxidation) and dramatically reduced levels of lipid droplets which mop up damaged lipids in the ME/CFS group in particular.

From the study. Note the increased lipid peroxidation in ME/CFS and long-COVID patients (red/green) (lower score = more lipid peroxidation) and dramatically reduced levels of lipid droplets which mop up damaged lipids in the ME/CFS group, in particular. The authors proposed that long COVID is an intermediate form of ME/CFS.

THE GIST

  • Health Rising reported some time ago becoming obsessed with the energy problems found in ME/CFS. Vishnu Shankar, a PhD. Stanford student, engineered a study that assessed energy production in ME/CFS patients’ immune cells. The study recently appeared in preprint form and includes some new findings – so it’s onto round 2 of this fascinating study.
  • Shankar focused on immune cells because they provide a good test case for assessing energy production. It turns out that protecting the body from pathogens turns is quite an energy-intensive project. Even when it’s not fighting off an infection, the immune system uses about 15-20% of our energy.
  • The study assessed both mitochondrial activity and oxidative stress in immune cells (PBMCs) in ME/CFS patients, long-COVID patients, and healthy controls.
  • The immune cells in the ME/CFS/long-COVID patients weren’t pumping out as much energy as the healthy controls’ cells – suggesting they were damaged and possibly exhausted.
  • Because damaged mitochondria can become free radical-producing machines, they took a look at oxidative stress (free radical) levels. (Just as a damaged automobile engine produces more exhaust than a well-functioning one, damaged mitochondria spew out more toxins; i.e. free radicals.)
  • Immune cells have to switch their after-burners on to get the energy to go after pathogens. Producing that energy comes at a cost, though, in the form of increased levels of reactive oxygen species oxidative stress (free radicals). (Note the key word – reactive oxygen species – these are unbalanced oxygen molecules which try to achieve balance by ripping electrons from other molecules; hence the word “reactive”.)
  • Dramatically higher levels of reactive oxygen species were found in both the ME/CFS and long-COVID patients’ immune cells compared to the healthy controls. (ME/CFS patients had the highest levels). A closer look revealed, however, that the reactive oxygen species were almost wholly centered in the immune cells from female ME/CFS patients.
  • Both male ME/CFS and long-COVID patients did, however, exhibit elevated glutathione levels – indicating that their immune cells were also dealing with increased oxidative stress levels – which have triggered the production of the master antioxidant in our cells – glutathione.
  • Altogether, multiple pathways that deal with oxidative stress (glutathione, superoxide dismutase, lipid oxidative damage, etc.) appear to have been overwhelmed in the immune cells in both ME/CFS and long-COVID patients. In all cases, the ME/CFS patients were worse off than the long-COVID patients – leading the authors to suggest that long COVID was an intermediate condition between health and ME/CFS.
  • Increased levels of mitochondrial calcium – which drive the production of reactive oxygen species (ROS) in the mitochondria – provided another potential explanation for the increased levels of oxidative stress. That was a very interesting finding given that in 2021 Wirth and Scheibenbogen proposed that increased mitochondrial levels of calcium were a core factor in ME/CFS.
  • Once again, damage to the lipids that protect our cells and the organelles in our cells popped out during a metabolomic analysis (of T-cells).  Since reactive oxygen species target lipids this finding make sense and it underscored what big deal lipid issues have become in ME/CFS studies over the past few years.
  • Once again, men and women had different findings. Oxidative stress was worse in women while lipid damage was more extensive in men. Plus, the study suggested that when confronted with high oxidative stress levels, women’s T-cells go on a hyper proliferation binge – potentially sucking more energy from the rest of the body.
  • Trying to reduce the oxidative stress present, they used antioxidants like NAC (increase glutathione), metformin (increase SOD2 expression), and liproxstatin-1 (reduce lipid peroxide levels) in cell cultures and found that NAC and metformin was able to reduce immune activity to some extent. That finding suggested that the right antioxidants might be able to tame the immune activity and improve energy levels.
  • All in all, the authors proposed that long periods of elevated reactive oxygen species damage the mitochondria, producing a long-term problem of energy depletion. Because the immune cells already use up so much energy in the body, and then struggle to produce energy in ME/CFS and long COVID, the authors proposed that immune problems in these diseases produce an energy sink that draws energy from other areas of the body.

 

 

 

 

Because the lipid membranes that protect our cells and the organelles in our cells take the brunt of free radical attacks, the researchers were particularly interested in whether the lipids in the ME/CFS and long-COVID patients showed signs of damage. Substantially increased levels of lipid peroxides were found in the ME/CFS and long-COVID patients.

Next, they assessed “lipid droplets” which are: a) formed to mop up damaged lipids; and b) contribute to acetylcarnitine metabolism – an important part of the energy production. Substantially lower levels of lipid droplets suggested that: a) damaged lipids were not being taken up; and b) that another source of fatty acid metabolism was wanting in the ME/CFS and long-COVID cohorts.  Interestingly, while women showed more evidence of oxidative stress, men showed more evidence of lipid damage.

Once again, the ME/CFS patients appeared to be worse off. The findings suggested that long-COVID patients are in an intermediate state between healthy controls and people with ME/CFS.

Gender Gap Explained?

The finding of greatly increased oxidative stress levels in the women’s immune cells was intriguing given the gender gap (predominantly female) found in these diseases. This study found that as the levels of reactive oxidative species increase, the T-cells in women with ME/CFS go on a proliferation binge that requires 10 x’s as much energy to maintain.

They made a stab at explaining why the gender gap exists. Not surprisingly, it may all come down to sex hormones. It turns out that sex hormones like estradiol regulate the levels of the enzymes (catalase, glutathione peroxidase, SOD2) that trigger antioxidant production. That suggests that reduced estradiol levels in women could predispose them to reduced antioxidant production.

Indeed, a study that used routine lab tests to follow people after a bout of infectious mononucleosis found reduced estradiol levels in the still-sick patients 12 and 24 months after the infection. Estradiol levels recovered after that, but that two-year period of reduced levels may have been enough. The Shankar paper predicted that it might only be a matter of time before the mitochondria in our cells become too battered to return to health.

Treatment

Now that they’d found this oxidative stress/energy production problem in immune cells, they tried to turn it around using antioxidants like NAC (increase glutathione), metformin (increase SOD2 expression), and liproxstatin-1 (reduce lipid peroxide levels) in cell cultures.

The small laboratory trial (5 ME/CFS females/6 healthy controls) found that NAC was able to significantly reduce the T-cell hyperproliferation by about 10%, and metformin by about 6%, but had no effect on healthy controls.

Whether that’s sufficient or not is unclear, but the authors considered that oxidative stress constitutes a “tunable molecular link” that could be controlling the energy-draining T-cell proliferation found: i.e. reducing oxidative stress might be able to “re-tune” the immune system activation, allowing it to return to normal.

The authors proposed that assessing oxidative stress levels in immune cells – apparently not a difficult test to do – could identify people who might benefit from this approach.

The Hypothesis

In the end, the hypothesis goes like this: As the immune cells take their foot on the gas to fight off an infection, levels of reactive oxygen species (ROS) (free radicals) explode. For whatever reason, the inability to rapidly clear the virus leaves these reactive oxygen species elevated for long periods of time, causing damage to the mitochondria.

The authors proposed that the immune system’s flailing about to get more energy is draining energy from the rest of the body. (Edgar Allan Poe, Public domain, via Wikimedia Commons)

The immune system – flailing around for more energy – becomes an energy sink, drawing energy from other parts of the body.

The authors believed the metabolic changes they found “likely” extend to the entire immune system, and “if systemic, could explain the prevalence of fatigue and other symptoms in these two syndromes”.  To put it in plainer terms, they propose that the high levels of oxidative stress and inability of the immune cells to produce proper amounts of energy could explain everything.

Demonstrating the importance that oxidative stress may play in ME/CFS, the study was able, for the first time, the authors said, to directly link increased levels of oxidative stress with reduced mitochondrial functioning in both ME/CFS and long-COVID patients.

A second major takeaway was that the study was able to show the increased oxidative stress particularly affects immune cell activation in ME/CFS/long COVID. Since high levels of oxidative stress appear to cause the T-cells in females to hyperproliferate – which, in turn, potentially produces an energy drag – finding ways to turn down the oxidative stress levels could conceivably help with energy levels.

Moreover, it suggests that at least in females, ROS levels may serve as a tunable link for adjusting T cell proliferation.

Conclusion

Perhaps the most significant outcome of this study was to see a now rather familiar array of themes pop up. The fact that oxidative stress, mitochondrial problems, lipids, fatty acid metabolism, female hormones and gender all showed up suggests the field is getting at some core issues in ME/CFS and long COVID. The increased mitochondrial calcium levels were particularly intriguing given the key role Wirth and Scheibenbogen predicted they play in ME/CFS in 2021, and Wirth has found a drug that he thinks could help. The possibility that relieving oxidative stress could tamp down some of the immune activation found in this illness was intriguing. The question, of course, is how to do that.

While the study opened up some interesting possibilities, it needs to be validated and expanded. The fact that it grew out of a big NIH grant may mean it has a better shot at getting a nice, fat NIH grant that is able to determine if a systemic energy drain is present in the immune system, if it’s affecting the rest of the body, and the best way to address the mitochondrial/oxidative stress issues found.

 

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