Int J Clin Exp Med. 2012 Jun 15.
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.
Int J Clin Exp Med. 2012 Nov 20.
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.
J Transl Med. 2010 Oct 11
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.
Int J Clin Exp Med. 2009
.
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.
|
Med Hypotheses. 2008 Oct
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. |
