21 August 2023 Episode 344 Long COVID and mitochondria

Mon, 08/21/2023 - 21:52

Episode 344 : Is there a relation between long COVID, post-septicemia and chronic fatigue syndrome and mitochondrial function?

Dear colleagues,

The syndromes in the title are “annoying” and frustrating medical issues, because we know they exist, but we do not understand the pathogenesis and therefore we have no rationally designed treatment.

Some very recent papers suggest a link between long COVID and chronic fatigue with the “powerhouse” of our cells, the mitochondria, which seems intuitively likely, but how strong is the evidence?


Par 1 Revisiting the “semiology” of long COVID (thanks to colleague EF)

Ep 344-1: Kieran Quinn JAMA June 2023: Comparison of Medical and Mental Health Sequelae over 1 year Following Hospitalization for COVID-19, Influenza, and Sepsis


Forest plot of the adjusted risk of incident cardiovascular, neurologic, and mental health conditions and rheumatoid arthritis within 1 year among adults who survived hospitalization for COVID-19 compared with those who survived hospitalization for influenza and sepsis in Ontario, Canada, between January 1, 2014, and October 31, 2021.


Clearly, largely similar sequelae in the three conditions, with the exception of

  • Higher incidence of venous thromboembolism in COVID patients.
  • Lower of some other cardiovascular diseases in COVID e.g. heart failure, hypertension, stroke.


However: this study looked only at hospitalized and older patients (mean age = 75).  

  • Thus not representative for long COVID in younger subjects after mild-moderate disease.
  • Symptoms not investigated like anosmia/ageusia, “brain fog”, gastro-intestinal issues, respiratory problems, incident type 2 diabetes etc.    


Therefore, the conclusion may rather be: if an elderly population is hospitalized for a life-threatening infectious condition, many of the long-term consequences are rather similar, irrespective of the underlying pathogen…


Ep 344-2: Michael Gottleib Open Forum Infect Dis May 2023 present an attempt to objectively classify acute and post-COVID symptoms, using “latent class analysis”  (= a way to uncover hidden groupings in data, using a statistical model in which individuals can be classified into mutually exclusive and exhaustive types, or latent classes, based on their pattern of answers on a set of (categorical) measured variables i.e. symptoms)


As could be expected, COVID-positive participants had higher occurrence of loss of taste/

smell and cognition problems as compared to COVID-negative subjects.

However: there was substantial class-switching over time:


Acute symptoms were  NOT predictive for the longer term and patients showed different symptoms at different times.

CONCLUSION from Par 1:

  1. Long COVID shares many characteristics with post-influenza or post-sepsis syndromes in severe (hospitalized) patients .
  2. There are some distinctive symptoms, such as smell/taste loss and “brain fog” I long COVID, but classifying long COVID into discrete syndrome remains enigmatic.  

Par 2: Very long COVID and related syndromes

Ep 344-3: Eric Topol Ground Truth 21 August

  1. Sequelae of COVID


  1. Impressive study by Zyad Al: During the second years after COVID, still new complications appear, both in non-hospitalized and hospitalized patients, but with almost 10 X higher frequency in the latter



Disability adjusted life years (DALY’s) still increase during the second year after acute episode.


Death (1.39 X) and (repeat) hospitalization (2.57 X) remained significantly elevated for the hospitalized group

This is a very large study: nearly 140,000 people who had Covid, compared with almost 6 million people non-infected controls, but 90 % men with mean age of 61 years.  While long COVID is known to be also frequent in younger women.   


  1. Theodore Iwahina in JAMA Int J: mortality in Veterans with COVID over 2 years = 8.7 %, which is double that of non-infected controls (4.1 %).  Mainly concentrated in first 6 months and hospitalized subjects.


  1. Increased risk of auto-immune disease (Rheumatoid Arthritis, Multiple Sclerosis, Graves, Psoriasis and Spondylarthritis) after COVID in several studies


  1.  Increased risk of type 2 diabetes: meta-analysis demonstrated more than 60% increased risk after COVID, or at the population level an excess 3 to 5%. Very substantial reduction by previous vaccination




B Increased risk of Parkinson after Influenza in Denmark





Par 3 Studies by Carolyn Bramante on effect of Metformin versus Ivermectin and Fluvoxamine) on severity of acute and incidence of long COVID:

  • No clear-cut effect on severe acute COVID
  • Only Metformin is beneficial in preventing long COVID
  • Only Metformin has a direct anti-SARS-CoV-2 effect


Ep 344-4: NEJM August 2022: Effect on severe COVID disease:

Adults between 30 and 85 years, with recent confirmed COVID and overweight or obesity.

Complex set-up: Metformin, Ivermectin and Fluvoxamine alone,  combinations of Metformin + Ivermectin and Metformin + Fluvoxamine, compared to placebo.


Results :

  • No effect of either medication on “primary composite endpoint”  (hypoxemia, emergency department

visit, hospitalization, or death)


  • However: Metformin seems to decrease hospitalization and emergency department visits:  more pronounced when Metformin was started earlier.











Ep 344-5: Lancet Infect Dis June 2023:  Positive effect of Metformin on long COVID (but not Ivermectin or Fluvoxamine) 




Conclusion 1:  Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo




Conclusion 2: Apparently better effect of Metformin in women, higher BMI, younger people, non-vaccinated patient and earlier start of Metformin treatment.  


Ep 344-6: MedRxiv June 2023:  Metformin reduces SARS-CoV-2  viral load (Ivermectin or Fluvoxamine no such effect) 


Effect of metformin versus placebo on viral load over time, detectable viral load, and rebound viral load




The magnitude of effect on clinical outcomes was larger when metformin was started earlier = consistent with an antiviral effect, but no statistical association between viral suppression and prevention of long COVID is shown.


CONCLUSION: there may be a trend that Metformin, when given early to some at risk patients reduces hospitalization during the acute phase and long COVID, but these findings require confirmation.


PAR 4 Is there a link between long COVID or chronic fatigue and mitochondrial function?


Ep 344-7: Eric Topol Ground Truth 13 August 2023 Long CIVID and mitochondria


In this hypothetical paper, it is proposed that dysfunctional mitochondria play a key role in long COVID.




Functional mitochondria deliver high quality of energy from ATP, by oxidative phosphorylation.

If this pathway is inhibited, energy production is shifted to glycolysis, which is a much less efficient source of energy.


Two arguments for involvement of dysfunctional mitochondria in long COVID :


  1. Findings of Bramante in Metformin (see above) and known pleiotropic effects of this drug, used as Glucophage® in type 2 diabetes: see Ep 344-8: Apostolova Redox Biology 2020

              Type 2 diabetes is associated with mitochondrial dysfunction



The onset of T2D and its complications can lead to an imbalance in cellular homeostasis such as enhanced oxidative stress levels

due to an increase in ROS production and a decrease in levels of antioxidant defenses. This can promote ER stress, which activates the UPR (unfolded protein response) on the one hand and can increase autophagy on the other hand.

CVD, cardiovascular disease; ER, endoplasmic reticulum; ROS, reactive oxygen species.

Mitochondrial dysfunction is related to the appearance of insulin resistance (IR), reduced sensitivity of tissues to glucose and its uptake, and several related comorbidities, including cardiovascular diseasz


Molecular mechanisms of the mitochondrial action of metformin.




Metformin exerts mild, transient and specific inhibition of complex I (NADH:ubiquinone oxidoreductase) of the respiratory chain (oxidative phosphorylation) , which leads to a change in both AMP/ATP ratio and NAD+/NADH ratio, effects that lead to downregulation of gluconeogenesis.

Metformin also acts as a non-competitive inhibitor of mitochondrial glycerol 3-phosphate dehydrogenase (mGPD), and this inhibition of the glycerolphosphate shuttle can result in impaired respiration, a reduced cytoplasmic NAD+/NADH ratio and undermined glucose production through gluconeogenesis. AMPK, AMP-activated protein kinase; NAMPT, nicotinamide phosphoribosyltransferase.


  1. Recent paper of Joseph Guarnieri in Science Transl Med on reduction of core mitochondrial functions by SARS-CoV-2 (Ep 344-9)  


SARS-CoV-2 was actively synthesizing viral proteins that bind to a wide array of mitochondrial proteins, leading to the inhibition of mitochondrial function: SARS-CoV-2 inhibition of Oxidative Phosphorylation, results in increased mROS (Reactive Oxygen Synthetase), which activates HIF-1a, leading to impaired OXPHOS and increased glycolysis


The irreversible inhibition of visceral (heart, kidney, liver brain…) mitochondrial transcription  was found in autopsies of patients with fatal COVID.


These phenomena could also contribute to the multisystem symptoms of long COVID.


Clearly, however, this paper is rather studying acute and fatal COVID, not long COVID.


Very recent paper on relation between mitochondrial dysfunction and chronic fatigue syndrome


Ep 344-10: Wang PNAS August 2023: WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)


Endoplasmic reticulum (ER) stress–induced increase in WASF3 (Wiskot Aldrich Syndrome Protein Member 3) localizes to mitochondria and disrupts oxidative phosphorylation respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise intolerance.


WASF3 can impair skeletal muscle bioenergetics and may be targetable for treating fatigue symptoms.




  1. Long COVID has some distinctive characteristics, but also many resemblances with post-influenza and post-sepsis syndromes, as well as with chronic fatigue.
  2. The course of long COVID is often irregular and difficult to classify, but it is evident that the consequences are multiple, including thrombo-embolic events, cardiovascular and respiratory disease, mental issues, but also auto-immune disease, type  2 diabetes.  These consequences can even increase during the second year.
  3. Very recently, several lines of evidence suggest a link between impaired mitochondrial function (inhibition of energy production through oxidative phosphorylation) and long COVID as well as chronic fatigue syndrome. Although very preliminary, these findings will inspire a lot of renewed research on pathogenic mechanisms and potential treatments for these “annoying conditions”.


Best wishes,