Redox Imbalance Manuscript Review

By Anthony L. Komaroff, MD

ME/CFS is defined exclusively by symptoms—subjective experiences that are hard to verify by objective testing. For that reason, since interest in ME/CFS began to grow in the 1980s, scientists have been looking for evidence of underlying objective abnormalities that might explain the symptoms.

A recent review, published August 24, 2021, in the Proceedings of the National Academy of Sciences USA, summarizes in detail the evidence demonstrating one of the several objective abnormalities in people with ME/CFS and acute COVID-19: redox imbalance. (1) It speculates that redox imbalance may also be present in post-acute COVID-19 syndrome, or “long COVID-19”, although this remains to be studied.

Redox imbalance occurs when the molecules that are oxidants (particularly “free radicals” or reactive oxygen species) exceed the number of molecules that are antioxidants. Essentially, redox imbalance is the same as the more familiar term of “oxidative stress”.

Persistent redox imbalance can damage a body’s cells. Specifically, it can damage the membranes of a cell, and the proteins and DNA within a cell. Redox imbalance is present in many diseases: it is not unique to COVID-19 or ME/CFS.

The review summarizes how redox imbalance is connected to other abnormalities that also have been identified in people with ME/CFS, acute COVID-19 and possibly post-acute COVID-19 syndrome: abnormal function of mitochondria (the sources of cellular energy molecules, or ATP), and chronic inflammation.

Indeed, the connections between these different abnormalities set up the possibility of several vicious cycles.  For example: a) Chronic inflammation leads to redox imbalance, and then redox imbalance causes some cells to die prematurely, leading to chronic inflammation;  b) Abnormal function of mitochondria leads to redox imbalance, and the free radicals present in redox imbalance then damage the mitochondria, impairing their function even more; c) Abnormal function of mitochondria leads to reduced ATP production, which can impair the ability of the immune system to keep viruses that are “asleep” in our body from “reawakening” and multiplying; the viruses then lead to further inflammation, redox imbalance and damage to mitochondria.

The authors of the review are Dr. Bindu Paul, a molecular neuroscientist and faculty member at the Johns Hopkins University School of Medicine; Marian Lemle (the parent of someone who suffered from ME/CFS, who is affiliated with the Solve ME/CFS Initiative); myself (a member of the Center for Solutions for ME/CFS team at Columbia University, and of the faculty of Harvard Medical School); and Dr. Solomon H. Snyder, also from Johns Hopkins. Dr. Snyder is one of the most distinguished and honored neuroscientists in history.

The review had its beginning when Marian Lemle approached me several years ago with the hypothesis that abnormalities in the production of hydrogen sulfide gas, might be one trigger of the symptoms of ME/CFS. Hydrogen sulfide is important in brain and immune function, affects ATP production, and influences redox balance. Ms. Lemle had recently published her hypothesis2, and I was impressed by it. I suggested that she contact Drs. Paul and Snyder, since I knew their laboratories were world-renowned leaders in this field.

The goal of the review is to stimulate the global research community to study the role of redox imbalance in ME/CFS and in post-acute COVID-19 syndrome—as well as the connections between redox imbalance, inflammation, mitochondrial function and impaired energy metabolism.

This theory has implications for treatment. Treatments that reduce redox imbalance, or that reduce the other abnormalities that can lead to redox imbalance, should be considered candidates to study in people with ME/CFS or post-acute COVID-19 syndrome. Since treatments with single antioxidants have not proved very effective in treating various illnesses characterized by redox imbalance, it may require a “cocktail” of several antioxidants and/or anti-inflammatory medications to be successful.

It’s too soon to know whether this hypothesis will prove fruitful. But if it does, it will be because a patient advocate and devoted mother took it upon herself to look for possible scientific explanations for ME/CFS, developed a very plausible hypothesis, wrote an article about the hypothesis that was accepted for publication, and brought the hypothesis to scientists in a position to pursue it. We need more such partnerships.

References

1. Paul BD, Lemle MD, Komaroff AL, Snyder SH.  Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Nat Acad Sci USA 2021;118:e2024358118.

2. Lemle MD. Hypothesis: chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism. Med Hypotheses 2009;72:108-9.