Bindu Paul Ph.D. is on a roll. A protégé of the pioneering neuroscientist, Solomon Snyder, Paul is an expert in redox signaling who’s written paper after paper on its role in central nervous system diseases. Paul received an invitation to write a review article on redox imbalances and disease for the Proceedings of the National Academy of Sciences (PNAS) journal last year. PNAS, which has been around since 1914, is one of the most respected science journals around. Since PNAS invites only the best to write review articles, getting that invitation was quite an honor. Just this year Paul was also appointed to the tenure track at Johns Hopkins and is starting her own lab.
Happily for us, Paul, who’s been funded by Solve M.E. to study hydrogen sulfide in ME/CFS, chose to focus her PNAS paper on redox reactions in ME/CFS and long COVID. The way Paul came to ME/CFS is worth telling. Marian Lemle’s story will be told elsewhere, but suffice it to say this citizen scientist, and mother of a daughter who had ME/CFS, took her interest in hydrogen sulfide in ME/CFS to such heights that she authored a 2009 hypothesis paper: “Hypothesis: chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism” (Check out Marian’s website).
That was just the beginning. Tony Komaroff advised Lemle to get in touch with the experts in the field, and so off she went, getting in touch with Bindu Paul and Solomon Snyder. Bindu Paul accepted her invitation to attend the NIH Conference on ME/CFS in 2019 and they’ve been communicating and collaborating ever since. They began work on what became the PNAS paper over a year ago. After Tony Komaroff offered up a number of insightful ideas, he was invited to participate.
Bindu Paul has long collaborated with Solomon Snyder. One of the few academics to have had an entire Department named after him (The Solomon H. Snyder Department of Neuroscience ), Snyder reportedly has the highest h-index (productivity/impact rating) and is one of “the 10 most-often cited biologists“. Snyder has received the Lasker Prize, and is regularly rumored to be in the running for the Nobel Prize.
Together, this diverse group has produced a novel slant to ME/CFS and long COVID that could bear real fruit in the future.
There’s no fudging, no question marks, no hedging in the title “Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome“. It doesn’t say a redox imbalance “might” or “could” link the two diseases together; it states that they are linked together in this way. Indeed, Bindu Paul and Marian Lemle told me that they scoured hundreds and hundreds of publications, and even supplementary materials, to arrive at the data in the paper. It’s a solid piece of work that is intended to serve as a roadmap for those interested in this aspect of ME/CFS and long COVID.
The short takeaway is that the same major redox processes and key pathways appear to be dysregulated in both ME/CFS and long COVID.
Redox concerns the transfer of electrons from one molecule to another. During that transfer one compound gains an election (is reduced) while the other loses an electron (is oxidized). (I don’t know why the compound which gains an electron is “reduced“, although it may be because electrons carry a negative charge.)
This movement of a charged electron from one molecule to another is a touchy situation. If that process doesn’t proceed correctly, then free radicals – imbalanced charged atoms or molecules – with unpaired electrons in their outer shells result. In their frenzy to regain their electrical balance, they can rip holes in the lipid coverings of cells, damage proteins and even alter our DNA.
Free radicals are only dangerous, though, when there are too many of them. Our body actually uses free radicals in a number of ways. Our immune cells use them to drill holes into pathogen-infested cells and kill them. They also play a crucial role in many cell signaling processes, and play a key role in aerobic energy production (where NAD+ is reduced to NADH and oxidizing NADH is oxidized to NAD+). In fact, you could think of the mitochondria as a massive free radical generation zone.
Our bodies use antioxidants like glutathione, superoxide dismutase, Vitamin C, Vitamin E, etc. to keep the oxidants (hydroxyl, hydrogen peroxide, superoxide) and nitrogen species (peroxynitrite) our body inevitably produces in check.
Insufficient antioxidant levels, however, can result in a free radical cascade as the damage they cause lets loose more free radicals – which cause more damage – producing more free radicals and on and on. High levels of free radicals have been implicated in many diseases including cancer, stroke, heart attack, diabetes, and ME/CFS.
Given that the immune cells generate oxidative stress to kill pathogens, it’s no surprise that oxidative stress would be increased in acute COVID infections. SARS-CoV-2, though, comes with a special twist: when it enters the ACE-2 receptor by elevating Ang II levels, it produces mitochondrial dysfunction and accumulations of the superoxide radical and other oxygen and nitrogen species.
With over a dozen studies finding a redox imbalance in ME/CFS, high levels of oxidative/nitrosative stress may be the most consistent finding in all of ME/CFS. Interestingly, levels of oxidative/nitrosative stress rise to particularly high peaks after exercise in ME/CFS. Metabolomic studies indirectly suggest the presence of high levels of oxidative stress.
A variety of studies have also found high levels of pro-oxidants – chemicals that either directly produce oxidative stress or impair antioxidant levels – in both ME/CFS and COVID. They include ferritin, free iron, homocysteine, neutrophil extracellular traps, altered levels of nitric oxide and hydrogen sulfide (in COVID), and altered tryptophan metabolism.
We can add an absence of the protective compounds – the antioxidants – which keep these oxidants in check to the list. Low levels of Vitamin E, ascorbic acid, and most importantly glutathione have been found in ME/CFS. Either people with ME/CFS are not producing enough antioxidants or their antioxidant system is getting overwhelmed by protein, lipid, and DNA-damaging free radicals.
The most important player in the redox issue in ME/CFS and COVID may be the mitochondria. The virus directly interferes with the mitochondria to produce an mtDNA-induced inflammasome, which suppresses both our innate and adaptive immunity. SARS-CoV-2 infection of white blood cells results in something which appears very like what we see in ME/CFS – increased rates of glycolysis, high rates of reactive species and lactate levels, and blunted energy production. One study found increasing antioxidant levels actually decreased viral load in COVID-19 patients.
Numerous problems with energy production have been found in ME/CFS. A hypometabolic state characterized by increased glycolysis, reduced ATP production, high blood lactate levels after exercise, elevated lactate levels in the brain, and elevated serum LDH levels (among others) appears to be present.
While it’s not clear what’s causing the mitochondrial problems in ME/CFS, the NLRP3 inflammasome protein complex appears to play a role in the inflammation found in the disease. This intracellular inflammasome reacts to signals (microbe-derived pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs)) generated by the cell to warn of a pathogen attack or damage to the cell. Increased levels of mitochondria-produced free radicals are one of the “danger signals” that activate the NLRP3 inflammasome. Given the mitochondrial issues in both COVID and ME/CFS, it’s likely this inflammasome has been activated.
The authors propose that an infection-triggered mitochondrial breakdown in long COVID and ME/CFS disrupts the redox balance, and produces massive levels of free radicals, which then feed an inflammatory process that impacts the blood vessels, in particular, but also the brain, the muscles, etc.
Over time, in diseases like ME/CFS with reduced antioxidant levels, a positive feedback loop is established: the high levels of mitochondrial-produced reactive oxygen species (oxygen-based free radicals) damage the endothelial cells lining the blood vessels – producing inflammation – which produces more free radicals – which causes more damage, etc. Essentially a fire gets lit that never gets put out.
While the authors focus on redox, they end up in a quite similar place as other hypotheses: inflammation, and mitochondria and blood vessel damage. Those endpoints are coming up again and again.
The redox issue, of course, is not limited to ME/CFS. Paul’s been focusing on redox issues in central nervous system diseases including Alzheimer’s Disease and Huntington’s disease, and has written broad overviews of the subject. Progress with repairing the redox imbalances in those diseases could certainly lead to progress in ME/CFS and allied disorders.
If ME/CFS and long COVID (PASC) are caused by a redox or hydrogen sulfide imbalance that has plunged patients into a kind of hypometabolic state, what is the remedy? Some studies suggest that bucking up the antioxidant systems of COVID patients may help and a large number of redox-boosting agents (glutathione (and glutathione donors), N-acetyl cysteine, sulforaphane, ubiquinol, nicotinamide, melatonin, selenium, vitamin C, vitamin D, vitamin E, melatonin plus pentoxifylline, disulfiram, ebselen, and corticosteroids) are available (including a new one – cysteamine – which Paul recently championed).
Yet, as the authors point out, redox-altering therapies have never resulted in “dramatic improvements” even in conditions with redox imbalances. Given the role redox reactions play in health and disease, the inability to dramatically move the needle on health has undoubtedly puzzled many.
The authors refreshingly point out that no single antioxidant can singlehandedly restore a damaged redox system to health. The fact that the problems in these diseases tend to be bi-directional (i.e. one problem feeds on another and vice versa) suggests that finding the core problem may be an exercise in futility. Instead, whole pathways and systems need to be lifted up together.
- A recent review paper, “Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome“, authored by Bindu Paul, Marian Lemle, Anthony Komaroff and Solomon Snyder, appears in the Proceedings of the National Academy of Sciences.
- Paul, who was recruited to the ME/CFS field by Marian Lemle, received a Ramsay Award grant from Solve M.E. to study hydrogen sulfide in ME/CFS.
- The paper proposes that an imbalanced redox state, characterized by high levels of free radicals, may be causing long COVID and ME/CFS.
- Free radicals occur when molecules have too many or too few electrons in their outer shells, leaving them unbalanced. Unless antioxidants – which rebalance the free radicals – are present, the free radicals will rip electrons from neighboring molecules, causing damage to lipids, proteins or DNA.
- High rates of free radicals (oxidative/nitrosative species) may be the most consistent finding in ME/CFS. Low levels of antioxidants and high levels of prooxidants (free radical enhancing compounds) have also been found. Hi,gh free radicals have also been found in COVID-19.
- The mitochondria are the greatest source of free radicals in the body. The SARS-CoV-2 virus is able to disrupt mitochondrial function via its disruption of the ACE-2 receptor and its upregulation of Ang II. A similar ACE-2/Ang II interaction may be underway in ME/CFS as well.
- The authors propose that an infection-triggered mitochondrial breakdown in long COVID and ME/CFS disrupts the redox balance, and produces massive levels of free radicals, which then feed an inflammatory process that impacts the blood vessels, in particular, but also the brain, the muscles, etc.
- Over time a positive feedback process can result consisting of free radical production which damages tissues – releasing more free radicals – causing more damage and so on.
- While high rates of free radical production are also present in central nervous system and cardiovascular diseases, antioxidant supplementation has only had limited effects. This may be because whole redox pathways need to be enhanced. One way to possibly do that involves using hydrogen sulfide donors. Hydrogen sulfide will be discussed in a future blog.
- While the redox hypothesis focuses on a different system than past long-COVID and/or ME/CFS hypothesis papers, it is, rather encouragingly, circling around some common themes: the ACE-2/Ang II interaction, inflammation, energy production problems involving the mitochondria, and the blood vessels.
- In an interview, Bindu Paul reported that while central nervous system diseases like Alzheimer’s are different from ME/CFS and long COVID, a similar redox situation appears to be present and that treatments targeting that redox situation could benefit all three diseases.
The authors end by focusing on the similarities between ME/CFS and long COVID (redox imbalance, systemic inflammation, neuroinflammation, and impaired ATP production). With perhaps equal numbers of long-COVID patients joining the up to 2 1/2 million people with ME/CFS in the U.S., they declared that it is “imperative that increased research be focused on both long COVID-19 and ME/CFS” and write:
“We suggest that the study of the connections between redox imbalance, inflammation, and energy metabolism in long COVID-19 and in ME/CFS may lead to improvements in both new diagnostics and therapies.”
Bindu Paul Interview
It seems to me that you are saying that redox imbalances can play a major role in disease, yet we’re pretty poor at addressing that imbalance in an effective way. The paper also states “up-regulating pathways that counteract multiple abnormalities and bolster antioxidant defense and balance may be more beneficial.” It appears that instead of targeting specific antioxidants, finding ways to upregulate whole pathways could potentially help. Can you say what those pathways are?
There are several pathways that are protective. As discussed in the study, one of them is the transsulfuration pathway as outlined in the publication. This pathway is responsible for generating cysteine, glutathione and hydrogen sulfide. Cysteine, in turn is utilized for the synthesis of a number of sulfur containing molecules.
A point to be noted is that excessive levels of antioxidants may counteract essential processes such as autophagy. So, caution should be exercised while using single antioxidants.
Bindu, you’ve published quite a paper on redox imbalances in Alzheimer’s and neurodegenerative diseases and have proposed that hydrogen sulfide donors might be helpful. ME/CFS is obviously not Alzheimer’s disease (AD), but do you believe that some of the underlying processes might be present in both diseases?
Yes, redox imbalance plays a central role in the pathogenesis of AD, ME/CFS and COVID, based on the scientific evidence. There are common pathways which are affected in both neurodegeneration and in COVID-19 and ME/CFS. Both familial and sporadic AD are characterized by accumulation of plaques and tangles, both of which affect redox balance, especially in the brain.
ME/CFS is usually triggered after an infection. Although the causes for developing ME/CFS and AD are very different, they end up with elevated oxidative damage. The combination of the mutations in key proteins (Tau, APP, Presenilin and others) in AD in conjunction with the oxidative damage can elicit disease-specific effects. Regardless of the actual cause of the disease, preventing oxidative and nitrosative damage can be beneficial.
Might some treatments that attempt to alter the redox state in Alzheimer’s disease help with ME/CFS and other central nervous system disorders?
That is certainly possible.
Why might people with ME/CFS be susceptible to a redox imbalance triggered by an infection? Bad mitochondria? Insufficient antioxidant production? Genetic issues?
All or either of the above. As we discuss in the article, there are bidirectional connections between oxidative stress, mitochondrial function and inflammation. Excessive inflammation can trigger oxidative damage and mitochondrial dysfunction, which in turn causes inflammation, forming several vicious cycles that feed into each other.
Are there commercially available tests that can accurately assess the state of the redox system in ME/CFS?
There are tests to measure levels of individual antioxidants.
If you were planning a major effort to assess the role a redox imbalance plays in ME/CFS and long COVID what would it involve?
Measuring the status of redox signaling as a function of disease progression. There are of course multiple ways to study redox balance. It is important to classify patients in terms of severity of the disease. Patients exhibiting mild symptoms may have a different redox profile as compared to those with severe disease. When oxidative damage, inflammation and mitochondrial dysfunction crosses a certain threshold, that is when the disease progresses to the severe stage. Additional funding would greatly facilitate these studies.
This PNAS review paper presents another intriguing possibility for chronic fatigue syndrome (ME/CFS) and long COVID (PASC). The authors are not alone in believing that a redox imbalance plays a crucial role in COVID-19. Another recently published hypothesis paper proposed that a similar scenario:
“We here consider COVID-19 as a redox disease…An inflammation-driven “oxidative storm” alters the redox landscape, eliciting epithelial, endothelial, mitochondrial, metabolic, and immune dysfunction, and coagulopathy.”
Like Paul et. al. they believe the endothelium – the cells that line the blood vessels – which they call the “gatekeeper of vascular health” plays a critical role in COVID-19.
The paper circles around a bunch of common themes found in other ME/CFS hypotheses; inflammation, ACE-2/Ang II, mitochondrial, and energy production problems, possible blood vessel damage.
The main source of free radicals (oxidative and nitrosative species) in the body – the mitochondria – are where the problem starts. While studies have failed to consistently pinpoint a specific problem in the mitochondria in ME/CFS virtually all the ME/CFS mitochondrial studies have found that something’s gone awry. Oxidative stress studies have produced probably the most consistent results in the ME/CFS literature: it’s clear that free radical levels are high, antioxidant levels – particularly in the brain – are low, and as the authors note levels of prooxidants appear to be high.
With regards to COVID-19 numerous studies and papers have focused on redox issues and treatment approaches are being proposed and tried. While we don’t have data on mitochondrial problems in long COVID many studies have assessed the effects COVID-19 has on the mitochondria and new treatment approaches are being proposed as well.
The authors propose that a fire gets lit in these diseases that never gets put out. Redox imbalances have been found in central nervous system disorders, cardiovascular diseases, ME/CFS, long COVID, and others yet effective treatments have not yet been found. That could be changing with the introduction of hydrogen sulfide treatments, and it’s to hydrogen sulfide that an upcoming blog will focus on.
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