The Power Crisis Behind Long Covid
& ME/CFS Latest Mitochondrial
Research Explained
Feb
21, 2025
This video is part of the recent series of interviews I
posted with Professor Klaus Wirth. It describes how mitochondria work and why their dysfunction
might be the key to understanding Long COVID and ME/CFS - based on Professors Scheibenbogen’s
and Wirth’s most recent paper.
The Central Theory of Mitochondrial Dysfunction
in CFS
Mitochondrial
dysfunction is a central theory in
Myalgic
Encephalomyelitis/Chronic Fatigue
Syndrome
(ME/CFS), explaining severe fatigue,
post-exertional malaise (PEM), and
cognitive issues as impaired cellular
energy production, with studies showing
damaged muscle mitochondria, reduced
ATP, oxidative
stress,
and energy pathway disruptions.
This dysfunction, potentially triggered
by infections, involves a vicious cycle
of poor blood flow, sodium/calcium
overload, and mitochondrial damage,
leading to persistent energy crises and
symptoms like brain fog.
Pacing and treatments targeting
mitochondrial support (like CoQ10,
carnitine) are explored to manage these
cellular energy deficits.
Key Aspects
of Mitochondrial Dysfunction in ME/CFS
Energy
Crisis:
Mitochondria, the cell's powerhouses,
fail to produce enough ATP (energy),
creating a biological bottleneck that
causes overwhelming fatigue.
Post-Exertional Malaise (PEM):
Even minimal exertion damages
mitochondria in muscle, leading to
cycles of damage, insufficient energy,
and prolonged crashes (PEM).
Muscle
Damage:
Skeletal muscle mitochondria show
structural damage, especially after
exercise, and may be related to poor
blood flow (ischemia) causing sodium and
calcium overload.
Oxidative
Stress:
Damaged mitochondria generate more
reactive oxygen species (ROS),
contributing to cellular stress and
further impairing function.
Metabolic
Changes:
Patients show impaired oxidative
phosphorylation,
elevated lactate, and imbalances in
essential compounds like carnitine,
vital for metabolism
Listed below are the articles and published clinical
studies documenting the strong link between Mitochondrial
Dysfunction and Chronic Fatigue Syndrome.
Mitochondrial Dysfunction in Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome
February 17, 2025
Abstract
Myalgic encephalomyelitis/chronic fatigue
syndrome (ME/CFS) is a debilitating multisystem
disorder of unclear etiology that affects many
individuals worldwide. One of its hallmark
symptoms is prolonged fatigue following
exertion, a feature also observed in long COVID,
suggesting an underlying dysfunction in energy
production in both conditions. Here,
mitochondrial dysfunction and its potential
pathogenetic role in these disorders are
reviewed.
Mitochondria in ME/CFS
The mitochondria are best known for oxidizing metabolic
substrates and using oxidative phosphorylation for
generating the high-energy molecule adenosine
triphosphate (ATP), but they also performs many other
activities critical for maintaining cellular homeostasis
(16). The activities of mitochondria are important for
maintaining health, supported by the observation that
>40% of the mitochondrial proteome is linked to human
diseases (17), while its dysfunction can promote
diseases, particularly those associated with aging such
as neurodegeneration and cancer (16). Given the
essential roles of mitochondria in cellular activities,
their dysfunction would likely impair muscle, brain, and
immune cell function, contributing to the hallmark
symptoms of ME/CFS, which include fatigue, cognitive
impairment, and immune system abnormalities (1, 18).
Whether mitochondrial dysfunction in ME/CFS, reported by
numerous groups, is a cause or simply an effect of the
underlying pathogenesis is currently unclear.
Nonetheless, studying the molecular mechanism of the
mitochondrial dysfunction could illuminate interacting
networks that in turn may provide clues to the etiology
of ME/CFS.
Mitochondrial
Dysfunction and Coenzyme Q10 Supplementation in
Post-Viral Fatigue Syndrome: An Overview
January 1, 2024
Abstract
Post-viral fatigue
syndrome (PVFS) encompasses a wide range of
complex neuroimmune disorders of unknown causes
characterised by disabling post-exertional
fatigue, myalgia and joint pain, cognitive
impairments, unrefreshing sleep, autonomic
dysfunction, and neuropsychiatric symptoms. It
includes myalgic encephalomyelitis, also known
as chronic fatigue syndrome (ME/CFS);
fibromyalgia (FM); and more recently
post-COVID-19 condition (long COVID). To date,
there are no definitive clinical case criteria
and no FDA-approved pharmacological therapies
for PVFS. Given the current lack of effective
treatments, there is a need to develop novel
therapeutic strategies for these disorders.
Mitochondria, the cellular organelles
responsible for tissue energy production, have
recently garnered attention in research into
PVFS due to their crucial role in cellular
bioenergetic metabolism in these conditions. The
accumulating literature has identified a link
between mitochondrial dysfunction and low-grade
systemic inflammation in ME/CFS, FM, and long
COVID. To address this issue, this article aims
to critically review the evidence relating to
mitochondrial dysfunction in the pathogenesis of
these disorders; in particular, it aims to
evaluate the effectiveness of coenzyme Q10
supplementation on chronic fatigue and pain
symptoms as a novel therapeutic strategy for the
treatment of PVFS.
WASF3 disrupts
mitochondrial respiration and may mediate
exercise intolerance in myalgic
encephalomyelitis/chronic fatigue syndrome
August 22, 2023
Abstract
Myalgic encephalomyelitis/chronic fatigue
syndrome (ME/CFS) is characterized by various
disabling symptoms including exercise
intolerance and is diagnosed in the absence of a
specific cause, making its clinical management
challenging. A better understanding of the
molecular mechanism underlying this apparent
bioenergetic deficiency state may reveal
insights for developing targeted treatment
strategies. We report that overexpression of
Wiskott-Aldrich Syndrome Protein Family Member 3
(WASF3),
here identified in a 38-y-old woman suffering
from long-standing fatigue and exercise
intolerance, can disrupt mitochondrial
respiratory supercomplex formation and is
associated with endoplasmic reticulum (ER)
stress. Increased expression of WASF3
in transgenic mice markedly decreased their
treadmill running capacity with concomitantly
impaired respiratory supercomplex assembly and
reduced complex IV levels in skeletal muscle
mitochondria. WASF3 induction by ER stress using
endotoxin, well known to be associated with
fatigue in humans, also decreased skeletal
muscle complex IV levels in mice, while
decreasing WASF3 levels by pharmacologic
inhibition of ER stress improved mitochondrial
function in the cells of the patient with
chronic fatigue. Expanding on our findings,
skeletal muscle biopsy samples obtained from a
cohort of patients with ME/CFS showed increased
WASF3 protein levels and aberrant ER stress
activation. In addition to revealing a potential
mechanism for the bioenergetic deficiency in
ME/CFS, our study may also provide insights into
other disorders associated with fatigue such as
rheumatic diseases and long COVID.
A SWATH-MS
analysis of Myalgic
Encephalomyelitis/Chronic Fatigue
Syndrome peripheral blood mononuclear
cell proteomes reveals mitochondrial
dysfunction
September 24, 2020
Abstract
Background:Myalgic
Encephalomyelitis/Chronic Fatigue
Syndrome (ME/CFS) is a serious and
complex physical illness that affects
all body systems with a multiplicity of
symptoms, but key hallmarks of the
disease are pervasive fatigue and
'post-exertional malaise', exacerbation
after physical and/or mental activity of
the intrinsic fatigue and other symptoms
that can be highly debilitating and last
from days to months. Although the
disease can vary widely between
individuals, common symptoms also
include pain, cognitive deficits, sleep
dysfunction, as well as immune,
neurological and autonomic symptoms.
Typically, it is a very isolating
illness socially, carrying a stigma
because of the lack of understanding of
the cause and pathophysiology.
Mitochondrial
dysfunction in a family with psychosis
and chronic fatigue syndrome
May 2017
Abstract
Mitochondrial
impairment is hypothesized to be
involved in chronic fatigue syndrome
(CFS) and schizophrenia. We performed a
clinical, genetic and functional
mitochondrial study in a family
consisting of a female presenting
schizophrenia in addition to CFS
symptoms and her mother and older
sister, both presenting with CFS. The
three family members showed higher blood
lactate levels, higher mitochondrial
mass, lower mtDNA content and overall
lower mitochondrial enzymatic activities
and lower oxygen consumption capacities
than healthy women. This family
presented mtDNA depletion; however, no
mutation was identified neither in the
mtDNA nor in the nuclear genes related
with mtDNA depletion, even though
C16179A and T16519A variants should be
further studied.
Mitochondrial
Myopathy in Follow-up of a Patient With
Chronic Fatigue Syndrome
September 24, 2015
Abstract
Introduction.
Symptoms of mitochondrial diseases and
chronic fatigue syndrome (CFS)
frequently overlap and can easily be
mistaken. Methods. We report the case of
a patient diagnosed with CFS and during
follow-up was finally diagnosed with
mitochondrial myopathy by histochemical
study of muscle biopsy,
spectrophotometric analysis of the
complexes of the mitochondrial
respiratory chain, and genetic studies.
Results. The results revealed 3%
fiber-ragged blue and a severe
deficiency of complexes I and IV and
several mtDNA variants. Mother, sisters,
and nephews showed similar symptoms,
which strongly suggests a possible
maternal inheritance. The patient and
his family responded to treatment with
high doses of riboflavin and thiamine
with a remarkable and sustained fatigue
and muscle symptoms improvement.
Conclusions. This case illustrates that
initial symptoms of mitochondrial
disease in adults can easily be mistaken
with CFS, and in these patients a
regular reassessment and monitoring of
symptoms is recommended to reconfirm or
change the diagnosis.
Mitochondrial dysfunction and the
pathophysiology of
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS)
Abstract
The objectives of this study
are to test the hypothesis that the fatigue and
accompanying symptoms of Chronic Myalgic
Encephalomyelitis/Fatigue Syndrome are in part due to
defects in energy provision at the cellular level, and
to understand the pathophysiology of the defects so that
effective medical intervention can be implemented. We
performed an audit of 138 patients (ages 18-65)
diagnosed with ME/CFS and attending a private practice.
The patients and 53 normal, healthy controls had the ATP
Profile test carried out on neutrophils from a 3-ml
venous blood sample. This test yields 6 numerical
factors that describe the availability of ATP and the
efficiency of oxidative phosphorylation in mitochondria.
Other biomedical measurements, including the
concentration of cell-free DNA in plasma, were made. The
results of the audit are compared with the controls and
a previous cohort of 61 patients. We find that all
patients tested have measureable mitochondrial
dysfunction which correlates with the severity of the
illness. The patients divide into two main groups
differentiated by how cellular metabolism attempts to
compensate for the dysfunction. Comparisons with
exercise studies suggest that the dysfunction in
neutrophils also occurs in other cells. This is
confirmed by the cell-free DNA measurements which
indicate levels of tissue damage up to 3.5 times the
normal reference range. The major immediate causes of
the dysfunction are lack of essential substrates and
partial blocking of the translocator protein sites in
mitochondria. The ATP Profile is a valuable diagnostic
tool for the clinical management of ME/CFS.
Targeting mitochondrial dysfunction in the
treatment of
Myalgic Encephalomyelitis/Chronic Fatigue Syndrom(ME/CFS)
- a clinical audit
Abstract
We report on an audit of 138 ME/CFS patients who
attended a private practice and took the ATP Profile
biomedical test. The results revealed that all of these
patients had measureable mitochondrial dysfunction. A
basic treatment regime, based on 1) eating the
evolutionary correct stone-age diet, 2) ensuring optimum
hours of good quality sleep, 3) taking a standard
package of nutritional supplements, and 4) getting the
right balance between work and rest, was recommended for
all patients. Additions to the basic regime were
tailored for each patient according to the results of
the ATP Profile and additional nutritional tests and
clues from the clinical history.
Mitochondrial function is typically impaired in two
ways: substrate or co-factor deficiency, and inhibition
by chemicals, exogenous or endogenous. For the former,
additional nutrients are recommended where there is a
deficiency, and for the latter, improvement of
anti-oxidant status and selective chelation therapy or
far-infrared saunas are appropriate. We show case
histories of nine patients who have taken the ATP
Profile on three or four occasions, and a
before-and-after treatment summary of the 34 patients
who have had at least two ATP Profile tests separated by
some months. Finally, we summarize the results for the
30 patients who followed all aspects of the treatment
regime and compare them with the 4 patients who were lax
on two or more aspects of the treatment regime. All
patients who followed the treatment regime improved in
mitochondrial function by on average a factor of 4.
Patients with chronic fatigue
syndrome performed worse than controls in a controlled repeated exercise
study despite a normal oxidative phosphorylation
capacity
Abstract
BACKGROUND: The aim of this study was
to investigate the possibility that a decreased
mitochondrial ATP synthesis causes muscular and mental
fatigue and plays a role in the pathophysiology of the
chronic fatigue syndrome (CFS/ME).
METHODS: Female patients (n = 15) and
controls (n = 15) performed a cardiopulmonary exercise
test (CPET) by cycling at a continuously increased work
rate till maximal exertion. The CPET was repeated 24 h
later. Before the tests, blood was taken for the
isolation of peripheral blood mononuclear cells (PBMC),
which were processed in a special way to preserve their
oxidative phosphorylation, which was tested later in the
presence of ADP and phosphate in permeabilized cells
with glutamate, malate and malonate plus or minus the
complex I inhibitor rotenone, and succinate with
rotenone plus or minus the complex II inhibitor malonate
in order to measure the ATP production via Complex I and
II, respectively. Plasma CK was determined as a
surrogate measure of a decreased oxidative
phosphorylation in muscle, since the previous finding
that in a group of patients with external
ophthalmoplegia the oxygen consumption by isolated
muscle mitochondria correlated negatively with plasma
creatine kinase, 24 h after exercise.
RESULTS: At both exercise tests the
patients reached the anaerobic threshold and the maximal
exercise at a much lower oxygen consumption than the
controls and this worsened in the second test. This
implies an increase of lactate, the product of anaerobic
glycolysis, and a decrease of the mitochondrial ATP
production in the patients. In the past this was also
found in patients with defects in the mitochondrial
oxidative phosphorylation. However the oxidative
phosphorylation in PBMC was similar in CFS/ME patients
and controls. The plasma creatine kinase levels before
and 24 h after exercise were low in patients and
controls, suggesting normality of the muscular
mitochondrial oxidative phosphorylation.
CONCLUSION: The decrease in
mitochondrial ATP synthesis in the CFS/ME patients is
not caused by a defect in the enzyme complexes
catalyzing oxidative phosphorylation, but in another
factor.
Chronic
fatigue syndrome and mitochondrial dysfunction
Abstract
This study aims to improve the health of patients
suffering from chronic fatigue syndrome (CFS) by
interventions based on the biochemistry of the
illness, specifically the function of mitochondria
in producing ATP (adenosine triphosphate), the
energy currency for all body functions, and
recycling ADP (adenosine diphosphate) to replenish
the ATP supply as needed. Patients attending a
private medical practice specializing in CFS were
diagnosed using the Centers for Disease Control
criteria. In consultation with each patient, an
integer on the Bell Ability Scale was assigned, and
a blood sample was taken for the “ATP profile” test,
designed for CFS and other fatigue conditions.
Each test produced 5 numerical factors which
describe the availability of ATP in neutrophils, the
fraction complexed with magnesium, the efficiency of
oxidative phosphorylation, and the transfer
efficiencies of ADP into the mitochondria and ATP
into the cytosol where the energy is used. With the
consent of each of 71 patients and 53 normal,
healthy controls the 5 factors have been collated
and compared with the Bell Ability Scale. The
individual numerical factors show that patients have
different combinations of biochemical lesions. When
the factors are combined, a remarkable correlation
is observed between the degree of mitochondrial
dysfunction and the severity of illness (P<0.001).
Only 1 of the 71 patients overlaps the normal
region. The “ATP profile” test is a powerful
diagnostic tool and can differentiate patients who
have fatigue and other symptoms as a result of
energy wastage by stress and psychological factors
from those who have insufficient energy due to
cellular respiration dysfunction. The individual
factors indicate which remedial actions, in the form
of dietary supplements, drugs and detoxification,
are most likely to be of benefit, and what further
tests should be carried out.
Treating Chronic Fatigue states as a disease
of the regulation of energy metabolism
Abstract
Chronic Fatigue Syndrome is a physiological
state in which the patient feels high levels of
fatigue without an obvious organic cause, which
affects around 1 in 400 people in the developed
world. A wide range of causes have been
suggested, including immune or hormonal
dysfunction, viral or bacterial infection, and
psychological somatization. It is likely that
several causes are needed to trigger the
disease, and that the triggers are different
from the mechanisms that maintain fatigue over
months or years.
Many treatments have been tested for CFS, with
very limited success - a programme of combined
CBT and graded exercise shows the most effect. I
suggest that patients with CFS have a reduced
ability to increase mitochondrial energy
production when exertion requires it, with fewer
mitochondria that are each more efficient, and
hence nearer to their maximum energy output,
than normal. A range of indirect evidence
suggests that the renin-angiotensin system
stimulates mitochondrial responsiveness and
reduces mitochondrial efficiency: chronic
under-stimulation of this system could
contribute to CFS aetiology.
If correct, this means that CFS can be
successfully treated with RAS agonists (eg
angiotensin mimetics), or adrenergic agonists.
It also suggests that there will be a positive
link between the use of adrenergic- and
RAS-blocking drugs and CFS incidence, and a
negative link between adrenergic agonist use and
CFS.
