Int J Clin Exp Med
2012;5(3):208-220
www.ijcem.com /ISSN:1940-5901/IJCEM1204005
Original
Article
Mitochondrial dysfunction
and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS)
Norman E Booth1, Sarah
Myhill2, John McLaren-Howard3
1Department
of Physics and Mansfield College, University of Oxford, Oxford UK; 2Sarah
Myhill Ltd, Llangunllo, Powys
UK;
3Acumen, Tiverton, Devon UK
Received April 26, 2012;
accepted May 21, 2012; Epub June 15, 2012; Published June 30, 2012
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.
Discussion and conclusions
Diagnosis
of ME/CFS
The ATP profile is a test which
provides numerical values of 6 biomedical quantities
regarding
energy provision by the mitochondria
in neutrophils, the main effectors of the innate
immune
system. The ATP Profile is an
objective test of ME/CFS and clearly shows that this
illness has
a physical basis. Individually and
collectively the biomedical quantities select patients
whose
symptoms are the direct result of
mitochondrial dysfunction. These quantities also
reflect the
severity of the illness and, together
with one or more additional tests such as
Cell-free DNA they
demonstrate that it is not just
neutrophils that are dysfunctional but also other
biological systems.
In some cases there may be a co-morbid
psychiatric disorder but it hardly seems necessary
to
perform a psychiatric diagnosis as a
matter of course, as has been proposed [30].
Many accompanying mental symptoms can be explained as resulting from the long period of
physical
disability endured by many sufferers.
Pathophysiology
of ME/CFS
Our results clearly show mitochondrial
dysfunction in all 138 patients of Cohort 2 and
also the
61 patients of Cohort 1 [3]. A major
factor in the dysfunction is partial blocking of the
translocator
protein TL, and this has not been
investigated in any other study of ME/CFS or in
most
other studies of illnesses with
mitochondrial dysfunctions of various types [9].
We also find that lack of substrate or
essential co-factors contributes to the
mitochondrial dysfunction
of some patients, particularly those with super-normal values of TL IN
(sub-group A2).
Another feature that we have uncovered
is that there are at least two alternative
processes that
cells and their mitochondria use in
order to partially compensate for the dysfunction. This
division
into 2 distinct groups, A and B,
appears to correlate with the 2 groups observed
in some
exercise studies [21, 23]. Future
exercise studies coupled with tests like the ATP
Profile are
needed to confirm this correlation.
Our measurements of Cell-free DNA show
that ME/CFS patients have abnormally high
levels of
damaged and necrotic cells and that
there is strong correlation with the measured
mitochondrial
dysfunction. Taken together, these
measurements show that ME/CFS is a serious illness
which may affect
every cell in the body.
