Mitochondrial Dysfunction & the Pathophysiology of ME/cfs

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Below you will find the Abstract, the Introduction-,

and Discussion and Conclusions-sections, and (for

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the original version of:

Mitochondrial dysfunction and

the pathophysiology of Chronic

Fatigue Syndrome/Myalgic

Encephalomyelitis (CFS/ME)

which can also be found at: http://bit.ly/MI0DFS

Authors:

Norman E Booth1, Myhill2,

McLaren-3

Affiliation:

1Department of Physics and Mansfield College,

University of Oxford, Oxford UK; 2 Myhill Ltd,

Llangunllo, Powys UK; 3Acumen, Tiverton, Devon

UK

Journal:

Int J Clin Exp Med 2012;5(3):208-220 -

www.ijcem.com /ISSN:1940-5901/IJCEM1204005

Received April 26, 2012; accepted May 21, 2012;

Epub June 15, 2012; Published June 30, 2012

Address correspondence to: Dr. Norman E Booth,

PhD FInstP, Emeritus Professorial Fellow in

Physics, Mansfield College, University of Oxford,

UK E-mail: n.booth1@...

Abstract:

The objectives of this study are to test the

hypothesis that the fatigue and accompanying

symptoms of Chronic Fatigue Syndrome/Myalgic

Encephalomyelitis 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 139 patients (ages 18-65)

diagnosed with CFS/ME 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 CFS/ME.

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Introduction

The devastating illness Myalgic Encephalomyelitis

(M.E.) also called Chronic Fatigue Syndrome

(CFS) is often misunderstood and considered to be

*all in the mind*.

E. D. Acheson (later to become Chief Medical

Officer of England) and others carefully described

the symptom pattern of Myalgic Encephalomyelitis

as long ago as 1959 [1], and the World Health

Organization recognized M.E. as a neurological

illness in 1969.

However these facts are ignored by a substantial

fraction of the medical community, and a patient

can be labeled as having CFS/ME or just M.E. by

just being chronically fatigued.

The most characteristic and disabling symptom of

M.E. is the postexertional malaise following activity

or exercise, either physical or mental, often one to

three days later.

Fortunately, the importance of this key symptom

has been recognized in recent years and

incorporated into the International Consensus

Criteria for Myalgic Encephalomyelitis [2].

In spite of many biomedical studies, there is

inadequate understanding of the biochemical

processes which lead to this malaise and there is

no recognized biomedical test for this illness.

In Section 1 we demonstrate that biochemical tests

such as the ATP Profile do exist that can identify

those patients who have a cellular biological reason

for their symptoms.

In Section 2 we use the results of the various tests

which make up the ATP Profile to unravel the basic

pathophysiology of the mitochondrial dysfunction

and how cellular processes are modified in an

attempt to compensate for the dysfunction.

We also report on the measurement of DNA

fragments in blood plasma (cellfree DNA),

produced as a result of cell damage in CFS/ME.

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Discussion and conclusions

Diagnosis of CFS/ME

The ATP profile is a test which provides numerical

values of 6 biochemical 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 CFS/ME and

clearly shows that this illness has a physical

basis. Individually and collectively the biochemical

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.

Pathophysiology of CFS/ME

Our results clearly show mitochondrial dysfunction

in all 139 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 CFS/ME or

in most other studies of illnesses with

mitochondrial dysfunctions of various types [9].

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

CFS/ME patients have abnormally high levels of

damaged and necrotic cells and that there is

strong correlation with the measured mitochondrial

dysfunction.

Implications for the treatment of CFS/ME

Here we have emphasized the use of biomedical

tests to aid in the diagnosis and to vastly improve

our knowledge of the pathophysiology involved in

this illness.

In addition, these biomedical tests can act as a

valuable guide for medical and therapeutic

interventions. These will be discussed in a paper

which is in preparation.