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Mitochondrial dysfunctions in Myalgic Encephalomyelitis / chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways

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Abstract

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/cfs) is classified by the World Health Organization as a disorder of the central nervous system. ME/cfs is an neuro-immune disorder accompanied by chronic low-grade inflammation, increased levels of oxidative and nitrosative stress (O&NS), O&NS-mediated damage to fatty acids, DNA and proteins, autoimmune reactions directed against neoantigens and brain disorders. Mitochondrial dysfunctions have been found in ME/cfs, e.g. lowered ATP production, impaired oxidative phosphorylation and mitochondrial damage. This paper reviews the pathways that may explain mitochondrial dysfunctions in ME/cfs. Increased levels of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-α, and elastase, and increased O&NS may inhibit mitochondrial respiration, decrease the activities of the electron transport chain and mitochondrial membrane potential, increase mitochondrial membrane permeability, interfere with ATP production and cause mitochondrial shutdown. The activated O&NS pathways may additionally lead to damage of mitochondrial DNA and membranes thus decreasing membrane fluidity. Lowered levels of antioxidants, zinc and coenzyme Q10, and ω3 polyunsaturated fatty acids in ME/cfs may further aggravate the activated immuno-inflammatory and O&NS pathways. Therefore, it may be concluded that immuno-inflammatory and O&NS pathways may play a role in the mitochondrial dysfunctions and consequently the bioenergetic abnormalities seen in patients with ME/cfs. Defects in ATP production and the electron transport complex, in turn, are associated with an elevated production of superoxide and hydrogen peroxide in mitochondria creating adaptive and synergistic damage. It is argued that mitochondrial dysfunctions, e.g. lowered ATP production, may play a role in the onset of ME/cfs symptoms, e.g. fatigue and post exertional malaise, and may explain in part the central metabolic abnormalities observed in ME/cfs, e.g. glucose hypometabolism and cerebral hypoperfusion.

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Abbreviations

mtDNA:

Mitochondrial DNA

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

NF-κB:

Nuclear factor κB

ATP:

Adenosine-5′-triphosphate

ETC:

Electron transport chain

Coenzyme Q10:

CoQ10

31P:

31phosphorous

NMR:

Nuclear magnetic resonance

ADP:

Adenosine diphosphate

AT:

Anaerobic threshold

CDC:

Centers for Disease Control

FDG-PET:

Fluoro-deoxyglucose positron emission tomography

MRI:

Magnetic resonance imaging

SPECT:

Single-photon emission computed tomography

MRS:

Magnetic resonance spectroscopic

IL:

Interleukin

TNF:

Tumor necrosis factor

O&NS:

Oxidative and nitrosative stress

iNOS:

Inducible NO synthase

PUFA:

Polyunsaturated fatty acids

CCAAT:

Cytidine-cytidine-adenosine-adenosine-thymidine

C/EBPs:

CCAAT-enhancer-binding proteins

Bcl-2:

B-cell lymphoma 2

Bax:

Bcl-2-associated X protein

LPS:

Lipopolysaccharides

p53:

Tumor protein 53

PPAR:

Peroxisome proliferator-activated receptor alpha (

PGC:

PPAR gamma coactivator

GSH:

Glutathione

MDA:

Malondialdehyde

4HN:

4-hydroxynonenal

AMP:

Adenosine monophosphate

NADPH:

Nicotinamide adenine dinucleotide phosphate

TCR:

T cell receptor

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Acknowledgments

The authors would like to thank Victoria Storey and Arial Gerallt Francis Morris for their secretarial services.

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Morris, G., Maes, M. Mitochondrial dysfunctions in Myalgic Encephalomyelitis / chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis 29, 19–36 (2014). https://doi.org/10.1007/s11011-013-9435-x

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