Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract

Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called "long COVID-19," reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.

Keywords: COVID-19; chronic fatigue syndrome; mitochondria; myalgic encephalomyelitis; redox.

Fig. 1.

Oxidative stress in COVID-19. (A) The ACE2 pathway. SARS-CoV-2 infects cells harboring ACE2 and the protein transmembrane protease, serine 2 (TMPRSS2); together, these molecules prime the viral spike protein S, facilitating its entry by endocytosis. ACE2 converts angiotensin II (Ang II) to angiotensin 1 to 7 (Ang 1–7). This decreases ACE2 and elevates Ang II, which acts through the angiotensin 1 receptors (AT1-Rs), causing accumulation of superoxide radicals (O₂^•−) leading to hypertension and inhibition of vasodilation. Ang 1–7 binds the G-protein–coupled Mas receptor MasR, mediates vasorelaxation, and decreases O₂^•− production. SARS-CoV-2 induces formation of reactive oxygen radicals (ROS) and RNS by eliciting mitochondrial dysfunction and production of proinflammatory cytokines. (B) The NETs. NETs are web-like structures extruded from activated neutrophils, comprising proteins assembled on a scaffold of decondensed chromatin, which target invading pathogens. The component proteins include oxidative and proinflammatory enzymes such as NADPH oxidase (Nox), neutrophil elastase, myeloperoxidase (MPO), NOS, and peptidyl arginine deiminase 4 (PAD4), which deaminates arginine to citrulline, resulting in the formation of citrullinated proteins (such as histone H3, causing its dissociation from DNA). Excessive accumulation of NETs causes inflammation and damage in COVID-19.

Fig. 2.

The interactions between redox imbalance, mitochondrial dysfunction, chronic inflammation, and related symptoms. As explained in the text, redox imbalance, mitochondrial dysfunction, and inflammation are bidirectionally related to each other and may cause some of the symptoms of both long COVID-19 and ME/CFS. The bidirectional connections mean that an initial abnormality in one component can trigger abnormalities in other components and can precipitate a persistent, self-reinforcing pathological process.