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

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.

This is a preview of subscription content, access via your institution.

Fig. 1

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

References

  1. Abbracchio MP, Burnstock G (1998) Purinergic signaling: pathophysiological roles. Jpn J Pharmacol 78:113–145

    CAS  PubMed  Google Scholar 

  2. Abcouwer SF, Shanmugam S, Gomez PF, Shushanov S, Barber AJ, Lanoue KF, Quinn PG, Kester M, Gardner TW (2008) Effect of IL-1beta on survival and energy metabolism of R28 and RGC-5 retinal neurons. Investig Ophthalmol Vis Sci 49(12):5581–5592, PMID: 19037001

    Google Scholar 

  3. Ak P, Levine AJ (2010) p53 and NF-kB: different strategies for responding to stress lead to a functional antagonism. FASEB J 24:3643–3652

    CAS  PubMed  Google Scholar 

  4. Allen J, Murrary A, Di Maria C, Newton JL (2010) Chronic fatigue syndrome and impaired peripheral pulse characteristics on orthostasis—a new potential diagnostic biomarker. Physiol Meas 33:231–241

    Google Scholar 

  5. Almeida A, Moncada S, Bolaos JP (2004) Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat Cell Biol 6:45–51

    CAS  PubMed  Google Scholar 

  6. Arnold DL, Bore PJ, Radda GK, Styles P, Taylor DJ (1984) Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion/fatigue syndrome. Lancet 323:1367–1369

    Google Scholar 

  7. Arnold DL, Taylor DJ, Radda GK (1985) Investigation of human mitochondrial myopathies by phosphorus magnetic resonance spectroscopy. Ann Neurol 18:189–196

    CAS  PubMed  Google Scholar 

  8. Arnoult D, Soares F, Tattoli I, Girardin SE (2011) Mitochondria in innate immunity. EMBO Rep 12(9):901–910, PMID: 21799518

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Assaily W, Benchimol S (2006) Differential utilization of two ATP-generating pathways is regulated by p53. Cancer Cell 10:4–6

    CAS  PubMed  Google Scholar 

  10. Bal-Price A, Matthias A, Brown GC (2002) Stimulation of the NADPH oxidase in activated rat microglia removes nitric oxide but induces peroxynitrite production. J Neurochem 80(1):73–80

    CAS  PubMed  Google Scholar 

  11. Barnes PR, Taylor DJ, Kemp GJ, Radda GK (1993) Skeletal muscle bioenergetics in the chronic fatigue syndrome. J Neurol Neurosurg Psychiatry 56(6):679–683, PMID: 8509783

    CAS  PubMed  Google Scholar 

  12. Batthyany C, Souza JM, Durn R, Cassina A, Cervenansky C, Radi R (2005) Time course and site(s) of cytochrome c tyrosine nitration by peroxynitrite. Biogeosciences 44:8038–8046

    CAS  Google Scholar 

  13. Bazzicalupi C, Bencini A, Bianchi A, Danesi A, Giorgi C, Lodeiro C, Pina F, Santarelli S, Valtancoli B (2005) A zinc(II)-based receptor for ATP binding and hydrolysis. Chem Commun (Camb) (20):2630–2632

  14. Behan WM (1992) Muscles, mitochondria and myalgia. J Pathol 166(3):213–214, PMID: 1517878

    CAS  PubMed  Google Scholar 

  15. Behan PO, Behan WM (1988) Postviral fatigue syndrome. Crit Rev Neurobiol 4(2):157–178, PMID: 3063394

    CAS  PubMed  Google Scholar 

  16. Behan WM, More IA, Behan PO (1991) Mitochondrial abnormalities in the postviral Fatigue Syndrome. Acta Neuropathol 83:61–65, PMID: 1792865

    CAS  PubMed  Google Scholar 

  17. Behan WMH, Downie I, More IAR et al (1993) Changes in muscle mitochondria. In: Dawson DM, Sabin TD (eds) Chronic fatigue syndrome. Little, Brown and Co, Boston, pp 131–140

    Google Scholar 

  18. Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, Yücel M, Gama CS, Dodd S, Dean B, Magalhães PV, Amminger P, McGorry P, Malhi GS (2011) Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 35(3):804–817

    CAS  PubMed  Google Scholar 

  19. Berlett BS, Stadtman ER (1997) Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 272(33):20313–20316, PMID: 9252331

    CAS  PubMed  Google Scholar 

  20. Berthiaume F, MacDonald AD, Kang YH, Yarmush ML (2003) Control analysis of mitochondrial metabolism in intact hepatocytes: effect of interleukin-1beta and interleukin-6. Metab Eng 5(2):108–123, PMID: 12850133

    CAS  PubMed  Google Scholar 

  21. Berthold HK, Naini A, Di Mauro S, Hallikainen M, Gylling H, Krone W, Gouni-Berthold I (2006) Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial. Drug Saf 29(8):703–712

    CAS  PubMed  Google Scholar 

  22. Bhagavan HN, Chopra RK (2006) Coenzyme Q10: absorption, tissue uptake, metabolism and pharmacokinetics. Free Radic Res 40(5):445–453

    CAS  PubMed  Google Scholar 

  23. Bhuvaneswar CG, Goetz JL, Stern TA (2008) Multiple neurologic, psychiatric, and endocrine complaints in a young woman: a case discussion and review of the clinical features and management of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke. Prim Care Companion J Clin Psychiatry 10(3):237–244

    PubMed Central  PubMed  Google Scholar 

  24. Bianci MC, Tosetti M, Battini R, Manca ML, Mancuso M, Cioni G, Canapicchi R, Siciliano G (2003) Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic relevance. Am J Neuroradiol 24:1958–1966

    Google Scholar 

  25. Biswal B, Kunwar P, Natelson BH (2011) Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling. J Neurol Sci 301(1–2):9–11

    PubMed Central  PubMed  Google Scholar 

  26. Blanchard DK, Wei S, Duan C, Pericle F, Diaz JI, Djeu JY (1995) Role of extracellular adenosine triphosphate in the cytotoxic T-lymphocyte-mediated lysis of antigen presenting cells. Blood 85:3173–3182

    CAS  PubMed  Google Scholar 

  27. Blough NV, Zafiriou OC (1985) Reactions of superoxide with nitric oxide to form peroxonitrite in alkaline aqueous solution. Inorg Chem 24(22):3502–3504

    CAS  Google Scholar 

  28. Boczkowski J, Lisdero CL, Lanone S, Carreras MC, Aubier M, Poderoso JJ (2001) Peroxynitrite-mediated mitochondrial dysfunction. Biol Signals Recept 10:66–80

    CAS  PubMed  Google Scholar 

  29. Booth NE, Myhill S, McLaren-Howard J (2012) Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med 5:208–220

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Borutaite V, Budriunaite A, Brown GC (2000) Reversal of nitric oxide-, peroxynitrite- and S-nitrosothiol-induced inhibition of mitochondrial respiration or complex I activity by light and thiols. Biochim Biophys Acta 1459(2–3):405–412

    CAS  PubMed  Google Scholar 

  31. Bossy-Wetzel E, Lipton SA (2003) Nitric oxide signaling regulates mitochondrial number and function. Cell Death Diff 10:757–760

    CAS  Google Scholar 

  32. Brilla LR, Haley TF (1992) Effect of magnesium supplementation on strength training in humans. J Am Coll Nutr 11:326–329

    CAS  PubMed  Google Scholar 

  33. Brooks JC, Roberts N, Whitehouse G, Majeed T (2000) Proton magnetic resonance spectroscopy and morphometry of the hippocampus in chronic fatigue syndrome. Br J Radiol 73:1206–1208

    CAS  PubMed  Google Scholar 

  34. Brown GC, Borutaite V (2002) Nitric oxide inhibition of mitochondrial respiration and its role in cell death. Free Radic Biol Med 33(1):1440–1450

    CAS  PubMed  Google Scholar 

  35. Brown GC, Borutaite V (2004) Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta 1658(1–2):44–49

    CAS  PubMed  Google Scholar 

  36. Brown GC, Borutaite V (2007) Nitric oxide and mitochondrial respiration in the heart. Cardiovasc Res 75(2):283–290

    CAS  PubMed  Google Scholar 

  37. Brown AM, Ransom BR (2007) Astrocyte glycogen and brain energy metabolism. Glia 55(12):1263–1271

    PubMed  Google Scholar 

  38. Budagian V, Bulanova E, Brovko L, Orinska Z, Fayad R, Paus R, Bulfone-Paus S (2003) Signaling through P2X7 receptor in human T cells involves p56lck, MAP kinases, and transcription factors AP-1 and NF-kappa B. J Biol Chem 278:1549–1560

    CAS  PubMed  Google Scholar 

  39. Burnstock G (1972) Purinergic nerves. Pharmacol Rev 24:509–581

    CAS  PubMed  Google Scholar 

  40. Cai Q, Sheng ZH (2009) Molecular motors and synaptic assembly. Neuroscientist 15(1):78–89

    CAS  PubMed  Google Scholar 

  41. Caldwell SH, de Freitas LA, Park SH, Moreno ML, Redick JA, Davis CA, Sisson BJ, Patrie JT, Cotrim H, Argo CK, Al-Osaimi A (2009) Intramitochondrial crystalline inclusions in nonalcoholic steatohepatitis. Hepatology 49(6):1888–1895, PMID: 19274750

    PubMed  Google Scholar 

  42. Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, Cho RJ, Chen RO, Brownstein BH, Cobb JP, Tschoeke SK, Miller-Graziano C, Moldawer LL, Mindrinos MN, Davis RW, Tompkins RG, Lowry SF (2005) Inflamm and Host Response to Injury Large Scale Collab. Res. Program. A network-based analysis of systemic inflammation in humans. Nature 437(7061):1032–1037

    CAS  PubMed  Google Scholar 

  43. Campello S, Scorrano L (2010) Mitochondrial shape changes: orchestrating cell. pathophysiology. EMBO Rep 11(9):678–684

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Cantoni O, Guidarelli A (2008) Peroxynitrite damages U937 cell DNA via the intermediate formation of mitochondrial oxidants. IUBMB Life 60(11):753–756

    CAS  PubMed  Google Scholar 

  45. Caro AA, Cederbaum AI (2004) Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol 44:27–42

    CAS  PubMed  Google Scholar 

  46. Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S (2011) Myalgic Encephalomyelitis: international consensus criteria. J Intern Med 270(4):327–338

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Cavanagh E, Inserra F, Ferder L (2010) Angiotensin II blockade: a strategy to slow ageing by protecting mitochondria? Oxford Cardiovasc Res J 89(1):31–40

    Google Scholar 

  48. Chang ST, Hsu CH, Cherng SC (2010) Minimal aerobic exercise training improved MELAS demonstrated by 99mTc-ECD brain SPECT. Ann Nucl Med Sci 23:53–58

    Google Scholar 

  49. Chaudhuri A, Condon B, Gow J, Brennan D, Hadley D (2003) Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Brain Imaging 14:225–228

    CAS  Google Scholar 

  50. Chazotte B (2001) Mitochondrial dysfunction in Chronic Fatigue Syndrome. In: Lemasters JJ, Nieminen AL (eds) Mitochondria in pathogenesis. Kluwar Academic/Plenum Publishers, New York, pp 393–411, Chapter 21

    Google Scholar 

  51. Chazotte B, Pettengill M (1999) Using membrane potential to follow cytokinc effects on mitochondria and possible dysfunction in chronic fatigue syndrome. Biophys J 76:A363

    Google Scholar 

  52. Chen JJ, Yu BP (1994) Alterations in mitochondrial membrane fluidity by lipid peroxidation products. Free Radic Biol Med 17(5):411–418

    CAS  PubMed  Google Scholar 

  53. Chuang CS, Lo MC, Lee KW, Liu CS (2007) Magnetic resonance spectroscopy study in basal ganglia of patients with myoclonic epilepsy with ragged-red fibers. Neurol India 55:385–387

    PubMed  Google Scholar 

  54. Ciccone S, Maiani E, Bellusci G, Diederich M, Gonfloni S (2013) Parkinson’s disease: a complex interplay of mitochondrial DNA alterations and oxidative stress. Int J Mol Sci 14(2):2388–2409

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Clay AS, Behnia M, Brown KK (2001) Mitochondrial Disease: a pulmonary and critical-care medicine perspective. Chest 120:634–648

    CAS  PubMed  Google Scholar 

  56. Cohen BH, Gold DR (2001) Mitochondrial cytopathy in adults: what we know so far. Cleve Clin J Med 68(7):625–642

    CAS  PubMed  Google Scholar 

  57. Coll T, Jové M, Rodríguez-Calvo R, Eyre E, Palomer X, Sánchez RM, Merlos M, Laguna JC, Vázquez-Carrera M (2006) Palmitate-mediated downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha in skeletal muscle cells involves MEK1/2 and nuclear factor-kappaB activation. Diabetes 55(10):2779–2787

    CAS  PubMed  Google Scholar 

  58. Corasaniti MT, Turano P, Bilotta A, Malorni W, Stringaro AR, Nisticò R, Finazzi-Agró A, Bagetta G (2001) Evidence that increases of mitochondrial immunoreactive IL-1beta by HIV-1 gp120 implicate in situ cleavage of pro-IL-1beta in the neocortex of rat. J Neurochem 78(3):611–618

    CAS  PubMed  Google Scholar 

  59. Corriden R, Insel PA, Junger WG (2007) A novel method using fluorescence microscopy for real-time assessment of ATP release from individual cells. Am J Physiol Cell Physiol 293:C1420–C1425

    CAS  PubMed  Google Scholar 

  60. Crane FL (2001) Biochemical functions of coenzyme Q10. J Am Coll Nutr 20(6):591–598

    CAS  PubMed  Google Scholar 

  61. De Becker P, McGregor N, De Meirleir K (2001) A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. J Intern Med 250:234–240

    PubMed  Google Scholar 

  62. Di Filippo M, Chiasserini D, Tozzi A, Picconi B, Calabresi P (2010) Mitochondria and the link between neuroinflammation and neurodegeneration. J Alzheimers Dis 20(Suppl 2):S369–S379

    PubMed  Google Scholar 

  63. Dominguez L, Barbagallo M, Lauretani F, Bandinelli S, Bos A, Corsi AM, Simonsick EM, Ferrucci L (2006) Magnesium and muscle performance in older persons: the InCHIANTI study. Am J Clin Nutr 84(2):419–426

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Donnino MW, Cocchi MN, Salciccioli JD, Kim D, Naini AB, Buettner C, Akuthota P (2011) Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock. Crit Care 15(4):R189

    PubMed  Google Scholar 

  65. Eckert GP, Franke C, Nöldner M, Rau O, Wurglics M, Schubert-Zsilavecz M, Müller WE (2010) Plant derived omega-3-fatty acids protect mitochondrial function in the brain. Pharmacol Res 61(3):234–241

    CAS  PubMed  Google Scholar 

  66. Eckert GP, Lipka U, Muller WE (2012) Omega-3 fatty acids in neurodegenerative diseases: focus on mitochondria. Prostaglandins Leukot Essent Fat Acids 88(1):105–114

    Google Scholar 

  67. Ericsson A, Arias C, Sawchenko PE (1997) Evidence for an intramedullary prostaglandin-dependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1. J Neurosci 17(18):7166–7179

    CAS  PubMed  Google Scholar 

  68. Ernster L, Dallner G (1995) Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta 1271(1):195–204

    PubMed  Google Scholar 

  69. Ernster L, Forsmark P, Nordenbrand K (1992) The mode of action of lipid-soluble antioxidants in biological membranes: relationship between the effects of ubiquinol and vitamin E as inhibitors of lipid peroxidation in submitochondrial particles. Biofactors 3(4):241–248

    CAS  PubMed  Google Scholar 

  70. Escartin C, Valette J, Lebon V, Bonvento G (2006) Neuron-astrocyte interactions in the regulation of brain energy metabolism: a focus on NMR spectroscopy. J Neurochem 99(2):393–401

    CAS  PubMed  Google Scholar 

  71. Escartin C, Won SJ, Malgorn C, Auregan G, Berman AE, Chen PC, Deglon N, Johnson JA, Suh SW, Swanson RA (2011) Nuclear Factor Erythroid 2-Related Factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression. J Neurosci 31(20):7392–7401

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11(1):81–128

    CAS  PubMed  Google Scholar 

  73. Eu JP, Liu L, Zeng M, Stamler JS (2000) An apoptotic model for nitrosative stress. Biogeosciences 39(5):1040–1047

    CAS  Google Scholar 

  74. Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E (2012) Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci 322(1–2):254–262

    CAS  PubMed  Google Scholar 

  75. Fernández-Checa JC, Kaplowitz N, García-Ruiz C, Colell A (1998) Mitochondrial glutathione: importance and transport. Sem Liver Dis 18(4):389–401

    Google Scholar 

  76. Fetrow CW, Avila JR (2001) Professional’s handbook of complementary & alternative medicines, 2nd edn. Springhouse, Springhouse, pp 211–215

    Google Scholar 

  77. Fields RD, Burnstock G (2006) Purinergic signaling in neuronglial interactions. Nat Rev Neurosci 7:423–436

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Fink M (1997) Cytopathic hypoxia in sepsis. Acta Anaesthesiol Scand Suppl 110:87–95

    CAS  PubMed  Google Scholar 

  79. Fink MP (2001) Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. Crit Care Clin 17:219–237

    CAS  PubMed  Google Scholar 

  80. Freeman R, Komaroff AL (1997) Does the Chronic Fatigue Syndrome involve the autonomic nervous system? Am J Med 102:357–364

    CAS  PubMed  Google Scholar 

  81. Fulle S, Pietrangelo T, Mancinelli R, Saggini R, Fano G (2007) Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis. J Muscle Res Cell Motil 28:355–362

    CAS  PubMed  Google Scholar 

  82. Gaby AR (2002) Intravenous nutrient therapy: the “Myers’ cocktail”. Alternat Med Rev 7(5):389–403

    Google Scholar 

  83. Gardner PR, Costantino G, Szabo C, Salzman AL (1997) Nitric oxide sensitivity of the aconitases. J Biol Chem 272(40):25071–25076

    CAS  PubMed  Google Scholar 

  84. Garrel C, Alessandri JM, Guesnet P, Al-Gubory KH (2012) Omega-3 fatty acids enhance mitochondrial superoxide dismutase activity in rat organs during post-natal development. Int J Biochem Cell Biol 44(1):123–131

    CAS  PubMed  Google Scholar 

  85. Geldof K, Ramboer K, Goethals JM, Verhaeghe L (2007) CT and MRI appearance of mitochondrial encephalopathy. JBR-BTR 90(4):288–289

    CAS  PubMed  Google Scholar 

  86. Genova ML, Pich MM, Bernacchia A, Bianchi C, Biondi A, Bovina C, Falasca AI, Formiggini G, Castelli GP, Lenaz G (2004) The mitochondrial production of reactive oxygen species in relation to aging and pathology. Ann NY Acad Sci 1011:86–100

    CAS  PubMed  Google Scholar 

  87. Gibson H, Carroll N, Clague JE, Edwards RHT (1993) Exercise performance and fatigueability in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry 56:993–998

    CAS  PubMed  Google Scholar 

  88. Ginzberg HH, Shannon PT, Suzuki T, Hong O, Vachon E, Moraes T, Abreu MT, Cherepanov V, Wang X, Chow CW, Downey GP (2004) Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt. Am J Physiol Gastrointest Liver Physiol 287(1):G286–G298

    CAS  PubMed  Google Scholar 

  89. González-Aragón D, Burón MI, López-Lluch G, Hermán MD, Gómez-Díaz C, Navas P, Villalba JM (2005) Coenzyme Q and the regulation of intracellular steady-state levels of superoxide in HL-60 cells. Biofactors 25(1–4):31–41

    PubMed  Google Scholar 

  90. Gottlieb E, Vander Heiden MG, Thompson CB (2000) Bcl-xL prevents the initial decrease in mitochondrial membrane potential and subsequent reactive oxygen species production during tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol 20(15):5680–5689

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Haller RG, Lewis SF, Estabrook RW, DiMauro S, Servidei S, Foster DW (1989) Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency. J Clin Invest 84:155–161

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Hamilton N, Vayro S, Kirchhoff F, Verkhratsky A, Robbins J, Gorecki DC, Butt AM (2008) Mechanisms of ATP- and glutamate-mediated calcium signaling in white matter astrocytes. Glia 56(7):734–749

    PubMed  Google Scholar 

  93. He Y, Leung KW, Zhang YH, Duan S, Zhong XF, Jiang RZ, Peng Z, Tombran-Tink J, Ge J (2008) Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: protection by antioxidants. Investig Ophthalmol Vis Sci 49:1447–1458

    Google Scholar 

  94. Hennet T, Richter C, Peterhans E (1993) Tumour necrosis factor-alpha induces superoxide anion generation in mitochondria of L929 cells. Biochem J 289(Pt 2):587–592

    CAS  PubMed  Google Scholar 

  95. Hill NF, Tiersky LA, Scavalla VR, Lavietes M, Natelson BH (1999) Natural history of severe chronic fatigue syndrome. Arch Phys Med Rehabil 80(9):1090–1094

    CAS  PubMed  Google Scholar 

  96. Hoffman SP, Crouser ED (2007) Mitochondrial mechanisms of organ dysfunction during sepsis. Adv Sepsis 6(1):2–9

    Google Scholar 

  97. Hogen PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17:2205–2232

    Google Scholar 

  98. Hollingsworth KG, Jones DE, Taylor R, Blamire AM, Newton JL (2010) Impaired cardiovascular response to standing in chronic fatigue syndrome. Eur J Clin Investig 40(7):608–615

    Google Scholar 

  99. Howell N (1999) Human mitochondrial diseases: answering questions and questioning answers. Int Rev Cytol 186:49–116

    CAS  PubMed  Google Scholar 

  100. Hwang YS, Jeong M, Park JS, Kim MH, Lee DB, Shin BA, Mukaida N, Ellis LM, Kim HR, Ahn BW, Jung YD (2004) Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells. Oncogene 23(39):6603–6611

    CAS  PubMed  Google Scholar 

  101. Jang B, Han S (2006) Biochemical properties of cytochrome c nitrated by peroxynitrite. Biochimie 88:53–58

    CAS  PubMed  Google Scholar 

  102. Jelin JM, Gregory PJ et al (2009) Natural medicines comprehensive database/compiled by the editors of Pharmacist’s Letter, Prescriber’s Letter, 11th edn. Ther Res Faculty, Stockton, pp 452–457

    Google Scholar 

  103. Jia L, Kelsey SM, Grahn MF, Jiang XR, Newland AC (1996) Increased activity and sensitivity of mitochondrial respiratory enzymes to tumor necrosis factor alpha-mediated inhibition is associated with increased cytotoxicity in drug-resistant leukemic cell lines. Blood 87(6):2401–2410

    CAS  PubMed  Google Scholar 

  104. Jia H, Liu Z, Li X, Feng Z, Hao J, Li X, Shen W, Zhang H, Liu J (2010) Synergistic anti-Parkinsonism activity of high doses of B vitamins in a chronic cellular model. Neurobiol Aging 31(4):636–646

    CAS  PubMed  Google Scholar 

  105. John LJ, Fromm M, Schulzke JD (2011) Epithelial barriers in intestinal inflammation. Antioxid Redox Signal 15(5):1255–1270

    CAS  PubMed  Google Scholar 

  106. Johnson RF, Perkins ND (2012) Nuclear factor-κB, p53, and mitochondria: regulation of cellular metabolism and the Warburg effect. Trends Biochem Sci. 37(8):317–324. doi:10.1016/j.tibs.2012.04.002

    Google Scholar 

  107. Johnson RF, Witzel II, Perkins ND (2011) P53-dependent regulation of mitochondrial energy production by the RelA subunit of NF-jB. Cancer Res 71:5588–5597

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Kagan V, Serbinova E, Packer L (1990) Antioxidant effects of ubiquinones in microsomes and mitochondria are mediated by tocopherol recycling. Biochem Biophys Res Commun 169(3):851–857

    CAS  PubMed  Google Scholar 

  109. Kaur J, Dhaunsi GS, Turner RB (2004) Interleukin-1 and nitric oxide increase NADPH oxidase activity in human coronary artery smooth muscle cells. Med Princ Pract 13(1):26–29

    PubMed  Google Scholar 

  110. Kawauchi K, Araki K, Tobiume K, Tanaka N (2008) P53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol 10:611–618

    CAS  PubMed  Google Scholar 

  111. Kendall BE (1992) Disorder of lysosomes, peroxysomes and mitochondria. Am J Neuroradiol 13:621–653

    CAS  PubMed  Google Scholar 

  112. Khairallah RJ, Kim J, O’Shea KM, O’Connell KA, Brown BH, Galvao T, Daneault C, Des Rosiers C, Polster BM, Hoppel CL, Stanley WC (2012) Improved mitochondrial function with diet-induced increase in either docosahexaenoic acid or arachidonic acid in membrane phospholipids. PLoS One 7(3):e34402

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Khakh BS, Zhou X, Sydes J, Galligan JJ, Lester HA (2000) State-dependent cross-inhibition between transmitter-gated cation channels. Nature 406(6794):405–410

    CAS  PubMed  Google Scholar 

  114. Kim JV, Dustin ML (2006) Innate response to focal necrotic injury inside the blood–brain barrier. J Immunol 177(8):5269–5277

    CAS  PubMed  Google Scholar 

  115. Kirkinezos IG, Moraes CT (2001) Reactive oxygen species and mitochondrial diseases. Semin Cell Dev Biol 12(6):449–457

    CAS  PubMed  Google Scholar 

  116. Kitajka K, Sinclair AJ, Weisinger RS, Weisinger HS, Mathai M, Jayasooriya AP, Halver JE, Puskás LG (2004) Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proc Natl Acad Sci U S A 101(30):10931–10936

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Komaroff AL, Buchwald D (1991) Symptoms and signs of chronic fatigue syndrome. Rev Infect Dis 13(suppl 1):S8–S11

    PubMed  Google Scholar 

  118. Kon M, Kimura F, Akimoto T, Tanabe K, Murase Y, Ikemune S, Kono I (2007) Effect of Coenzyme Q10 supplementation on exercise-induced muscular injury of rats. Exerc Immunol Rev 13:76–88

    PubMed  Google Scholar 

  119. Kucharska J (2008) Vitamins in mitochondrial function. In: Gvozdjakova A (ed) Mitochondrial medicine. Springer, Netherlands, pp 367–384 http://link.springer.com/chapter/10.1007%2F978-1-4020-6714-3_21#

  120. Kudoh A, Kudoh E, Ishihara H, Matsuki A (1998) ONO-5046, an elastase inhibitor, attenuates liver mitochondrial dysfunction after endotoxin. Crit Care Med 26(1):138–141

    CAS  PubMed  Google Scholar 

  121. L’Her E, Sebert P (2001) A global approach to energy metabolism in an experimental model of sepsis. Am J Respir Crit Care Med 164:1444–1447

    PubMed  Google Scholar 

  122. Lakhan SE, Kirchgessner A (2010) Neuroinflammation in inflammatory bowel disease. J Neuroinflammation 7:37

    PubMed Central  PubMed  Google Scholar 

  123. Landi L, Cabrini L, Fiorentini D, Stefanelli C, Pedulli GF (1992) The antioxidant activity of ubiquinol-3 in homogeneous solution and in liposomes. Chem Phys Lipids 61(2):121–130

    CAS  PubMed  Google Scholar 

  124. Landino LM (2008) Protein thiol modification by peroxynitrite anion and nitric oxide donors. Methods Enzymol 440:95–109

    CAS  PubMed  Google Scholar 

  125. Lane RJM, Burgess AP, Flint J, Riccio M, Archard LC (1995) Exercise responses and psychiatric disorder in chronic fatigue syndrome. Br Med J 311:544–545

    CAS  Google Scholar 

  126. Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R (1998a) Heterogeneity in Chronic Fatigue Syndrome: evidence from magnetic resonance spectroscopy of muscle. Neuromuscul Disord 8:204–209

    CAS  PubMed  Google Scholar 

  127. Lane RJM, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC (1998b) Muscle fibre characteristics and lactate responses to exercise in Chronic Fatigue Syndrome. J Neurol Neurosurg Psychiatry 64:362–367

    CAS  PubMed  Google Scholar 

  128. Lane RJ, Soteriou BA, Zhang H, Archard LC (2003) Enterovirus related metabolic myopathy: a postviral fatigue syndrome. J Neurol Neurosurg Psychiatry 74(10):1382–1386

    CAS  PubMed  Google Scholar 

  129. Lanza IR, Blachnio-Zabielska A, Johnson ML, Coenen-Schimke JM, Jakaitis DR, Lebrasseur NK, Jensen MD, Nair KS, Zabielski P (2013) Influence of fish oil on skeletal muscle mitochondrial energetics and lipid metabolites during high-fat diet. Am J Physiol Endocrinol Metab. doi:10.1152/ajpendo.00584.2012

  130. Lappas M, Permezel M, Georgiou HM, Rice GE (2002) Nuclear factor kappa B regulation of proinflammatory cytokines in human gestational tissues in vitro. Biol Reprod 67(2):668–673

    CAS  PubMed  Google Scholar 

  131. Laszlo A, Ambrus E, Voros E, Svekus A, Kobor J, Bereg E, Palatka J, Pavics L (2009) 99-mTc-HMPAO single photon emission computed tomography examinations in genetically determined neurometabolic disorders. Ideggyogy Sz 62(5–6):168–177

    PubMed  Google Scholar 

  132. Lee FYJ, Li Y, Zhu H, Yang S, Lin HZ, Trush M, Diehl AM (1999) Tumor necrosis factor increases mitochondrial oxidant production and induces expression of uncoupling protein-2 in the regenerating mice [correction of rat] rat liver. Hepatology 29(3):677–687

    Google Scholar 

  133. Lehnhardt FG, Horvath R, Ullrich R, Kracht L, Sobesky J, Moller-Hartmann W, Jacobs AH, Haupt WF (2008) Altered cerebral glucose metabolism in a family with clinical features resembling mitochondrial neurogastrointestinal encephalomyopathy syndrome in association with multiple mitochondrial DNA deletions. Arch Neurol 65(3):407–411

    PubMed  Google Scholar 

  134. Lenaz G (1998) Role of mitochondria in oxidative stress and ageing. Biochim Biophys Acta 1366(1–2):53–67

    CAS  PubMed  Google Scholar 

  135. Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D (2005) White matter involvement in mitochondrial diseases. Mol Genet Metab 84(2):127–136

    CAS  PubMed  Google Scholar 

  136. Li C, Peoples RW, Weight FF (1996) Proton potentiation of ATP-gated ion channel responses to ATP and Zn2+ in rat nodose ganglion neurons. J Neurophysiol 76(5):3048–3058

    CAS  PubMed  Google Scholar 

  137. Li C, Peoples RW, Weight FF (1997) Inhibition of ATP-activated current by zinc in dorsal root ganglion neurones of bullfrog. J Physiol 505(Pt 3):641–653

    CAS  PubMed  Google Scholar 

  138. Li J, Li W, Liu W, Altura BT, Altura BM (2007) Peroxynitrite induces apoptosis and decline in intracellular free Mg with concomitant elevation in [Ca2+]I in rat aortic smooth muscle cells: possible roles of extracellular and intracellular magnesium ions in peroxynitrite-induced cell death. Drug Metab Lett 1(2):85–89

    CAS  PubMed  Google Scholar 

  139. Li C, Liu Q, Li N et al (2008) EAPF/Phafin-2, a novel endoplasmic reticulum-associated protein, facilitates TNF-alpha-triggered cellular apoptosis through endoplasmic reticulum-mitochondrial apoptotic pathway. J Mol Med (Berl) 86(4):471–484

    CAS  Google Scholar 

  140. Li L, Pan R, Li R, Niemann B, Aurich AC, Chen Y, Rohrbach S (2011) Mitochondrial biogenesis and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation by physical activity: intact adipocytokine signaling is required. Diabetes 60(1):157–167

    CAS  PubMed  Google Scholar 

  141. Liang H, Ward WF (2006) PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ 30(4):145–151

    PubMed  Google Scholar 

  142. Lim CH, Dedon PC, Deen WM (2008) Kinetic analysis of intracellular concentrations of reactive nitrogen species. Chem Res Toxicol 21(11):2134–2147

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Lin DD, Crawford TO, Barker PB (2003) Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. Am J Neuroradiol 24(1):33–41

    PubMed  Google Scholar 

  144. Lloyd AR, Gandevia SC, Hales JP (1991) Muscle performance, voluntary activation, twitch properties and perceived effort in normal subjects and patients with the chronic fatigue syndrome. Brain 114(Pt 1A):85–98

    PubMed  Google Scholar 

  145. Lo MC, Lu CI, Chen MH, Chen CD, Lee HM, Kao SH (2010) Glycoxidative stress-induced mitophagy modulates mitochondrial fates. Ann NY Acad Sci 1201:1–7

    CAS  PubMed  Google Scholar 

  146. Logan AC, Wong C (2001) Chronic fatigue syndrome: oxidative stress and dietary modifications. Alternat Med Rev 6(5):450–459

    CAS  Google Scholar 

  147. Lonsdale D, Shamberger RJ, Stahl JP, Evans R (1999) Evaluation of the biochemical effects of administration of intravenous nutrients using erythrocyte ATP/ADP ratios. Alternat Med Rev 4(1):37–44

    CAS  Google Scholar 

  148. Lucas K, Maes M (2013) Role of the Toll Like Receptor (TLR) Radical Cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol 48(1):190–204. doi:10.1007/s12035-013-8425-7

    Google Scholar 

  149. Lukaski HC, Nielsen FH (2003) Dietary magnesium depletion affects metabolic responses during submaximal exercise in postmenopausal women. J Nutr 132:930–935

    Google Scholar 

  150. Maes M, Mihaylova I, Leunis JC (2006) Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuroendocrinol Lett 27:615–621

    CAS  PubMed  Google Scholar 

  151. Maes M, Mihaylova I, Leunis JC (2007a) Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression. Neuroendocrinol Lett 28:861–867

    PubMed  Google Scholar 

  152. Maes M, Coucke F, Leunis J-C (2007b) Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome. Neuroendocrinol Lett 28(6):739–744

    CAS  PubMed  Google Scholar 

  153. Maes M, Kubera M, Leunis JC (2008) The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinol Lett 29(1):117–124

    PubMed  Google Scholar 

  154. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009a) Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuroendocrinol Lett 30:470–476

    CAS  PubMed  Google Scholar 

  155. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009b) Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis / chronic fatigue syndrome. Neuroendocrinol Lett 30(6):715–722

    CAS  PubMed  Google Scholar 

  156. Maes M, Twisk FNM, Kubera M, Ringel K (2011) Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-a, PMN-elastase, lysozyme and neopterin. J Affect Disord. doi:10.1016/j.jad.2011.09.004

    Google Scholar 

  157. Maes M, Twisk FN, Johnson C (2012a) Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res 200:754–760

    PubMed  Google Scholar 

  158. Maes M, Twisk FN, Kubera M, Ringel K, Leunis JC, Geffard M (2012b) Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord 136(3):909–917

    CAS  PubMed  Google Scholar 

  159. Mahad DJ, Ziabreva I, Campbell G, Lax N, White K, Hanson PS, Lassmann H, Turnbull DM (2009) Mitochondrial changes within axons in multiple sclerosis. Brain 132:1161–1174

    PubMed Central  PubMed  Google Scholar 

  160. Mander P, Brown GC (2005) Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration. J Neuroinflammation 2(1):2–20

    Google Scholar 

  161. Marty V, El Hachmane M, Amedee T (2008) Dual modulation of synaptic transmission in the nucleus tractus solitarius by prostaglandin E2 synthesized downstream of IL-1beta. Eur J Neurosci 27(12):3132–3150

    PubMed  Google Scholar 

  162. Masocha W (2009) Systemic lipopolysaccharide (LPS)-induced microglial activation results in different temporal reduction of CD200 and CD200 receptor gene expression in the brain. J Neuroimmunol 214(1–2):78–82

    CAS  PubMed  Google Scholar 

  163. Mathew SJ, Mao X, Keegan KA, Levine SM, Smith EL, Heier LA, Otcheretko V, Coplan JD, Shungu DC (2009) Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study. NMR Biomed 22:251–258

    CAS  PubMed  Google Scholar 

  164. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) P53 regulates mitochondrial respiration. Science 312:1650–1653

    CAS  PubMed  Google Scholar 

  165. Matthews RT, Yang L, Browne S, Baik M, Beal MF (1998) Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci U S A 95(15):8892–8897

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Mauro C, Leow SC, Anso E, Rocha S, Thotakura AK, Tornatore L, Moretti M, De Smaele E, Beg AA, Tergaonkar V, Chandel NS, Franzoso G (2011) NF-KB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat Cell Biol 13:1272–1279

    CAS  PubMed Central  PubMed  Google Scholar 

  167. McCully KK, Natelson BH (1999) Impaired oxygen delivery to muscle in chronic fatigue syndrome. Clin Sci (Lond) 97(5):603–608

    CAS  Google Scholar 

  168. McCully KK, Natelson BH, Iotti S, Sisto S, Leigh JS Jr (1996) Reduced oxidative muscle metabolism in chronic fatigue syndrome. Muscle Nerve 19(5):621–615

    CAS  PubMed  Google Scholar 

  169. McCully KK, Smith S, Rajaei S, Leigh JS Jr, Natelson BH (2003) Blood flow and muscle metabolism in chronic fatigue syndrome. Clin Sci (Lond) 104(6):641–647

    CAS  Google Scholar 

  170. Mehndiratta MM, Agarwal P, Tatke M, Krishnamurthy M (2002) Neurological mitochondrial cytopathies. Neurol India 50(2):162–167

    CAS  PubMed  Google Scholar 

  171. Mehta R, Shangari N, O’Brien PJ (2008) Preventing cell death induced by carbonyl stress, oxidative stress or mitochondrial toxins with vitamin B anti-AGE agents. Mol Nutr Food Res 52(3):379–385

    CAS  PubMed  Google Scholar 

  172. Minko IG, Kozekov ID, Harris TM, Rizzo CJ, Lloyd RS, Stone MP (2009) Chemistry and biology of DNA containing 1, N(2)-deoxyguanosine adducts of the alpha, beta-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chem Res Toxicol 22(5):759–778

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Mitsuishi M, Miyashita K, Muraki A, Itoh H (2009) Angiotensin II reduces mitochondrial content in skeletal muscle and affects glycemic control. Diabetes 58(3):710–717

    CAS  PubMed  Google Scholar 

  174. Molnar MJ, Valikovics A, Molnar S, Tron L, Dioszeghy P, Mechler F, Gulyas B (2000) Cerebral blood flow and glucose metabolism in mitochondrial disorders. Neurology 55(4):544–548

    CAS  PubMed  Google Scholar 

  175. Moon HJ, Ko WK, Han SW, Kim DS, Hwang YS, Park HK, Kwon IK (2012) Antioxidants, like coenzyme Q10, selenite, and curcumin, inhibited osteoclast differentiation by suppressing reactive oxygen species generation. Biochem Biophys Res Commun 418(2):247–253

    CAS  PubMed  Google Scholar 

  176. Morris G, Maes M (2012a) A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis. doi:10.1007/s11011-012-9324-8

  177. Morris G, Maes M (2012b) Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Hypotheses 79(5):607–613

    CAS  PubMed  Google Scholar 

  178. Morris G, Anderson G, Galecki P, Berk M, Maes M (2013) A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior. BMC Med 11(1):64

    CAS  PubMed Central  PubMed  Google Scholar 

  179. Mosqueda Garcia R, Furlan R, Snell M, Jacob G, Harris P (1997) Primary sympathetic hyperadrenergic orthostatic tachycardia syndrome (HOT). Neurology 48:A147

    Google Scholar 

  180. Muravchick S (2008) Clinical implications of mitochondrial disease. Adv Drug Deliv Rev 60(13–14):1553–1560

    CAS  PubMed  Google Scholar 

  181. Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, Nestadt P, Levine SM, Mathew SJ, Shungu DC (2010) Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. NMR Biomed 23:643–650

    CAS  PubMed  Google Scholar 

  182. Myhill S, Booth NE, McLaren-Howard J (2009) Chronic Fatigue Syndrome and mitochondrial dysfunction. Int J Clin Exp Med 2:1–16

    CAS  PubMed Central  PubMed  Google Scholar 

  183. Myhill S, Booth NE, McLaren-Howard J (2013) Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit. Int J Clin Exp Med 6(1):1–15

    PubMed Central  PubMed  Google Scholar 

  184. Nicholson G, Ellithorpe R (2006) Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in Chronic Fatigue Syndrome and other fatiguing illnesses. J Chr Fatigue Synd 13:57–68

    Google Scholar 

  185. Nijs J, De Meirleir K, Meeus M, McGregor NR, Englebienne P (2004) Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Med Hypoth 62(5):759–765

    CAS  Google Scholar 

  186. Nohl H, Jordan W (1986) The mitochondrial site of superoxide formation. Biochem Biophys Res Commun 138(2):533–539

    CAS  PubMed  Google Scholar 

  187. Nozaki T, Sugiyama S, Sugamura K, Ogawa H (2009) Telmisartan enhances mitochondrial biogenesis and protects from endothelial cell damage through peroxisome proliferator-activated receptor-independent pathways. Circulation 120:S1039

    Google Scholar 

  188. O’Shea KM, Khairallah RJ, Sparagna GC, Xu W, Hecker PA, Robillard-Frayne I, Des Rosiers C, Kristian T, Murphy RC, Fiskum G, Stanley WC (2009) Dietary omega-3 fatty acids alter cardiac mitochondrial phospholipid composition and delay Ca2+−induced permeability transition. J Mol Cell Cardiol 47(6):819–827

    PubMed Central  PubMed  Google Scholar 

  189. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87(1):315–424

    CAS  PubMed Central  PubMed  Google Scholar 

  190. Palacios-Callender M, Hollis V, Mitchison M, Frakich N, Unitt D, Moncada S (2007) Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: a possible explanation for hypoxic vasodilation. Proc Natl Acad Sci U S A 104:18508–18513

    CAS  PubMed Central  PubMed  Google Scholar 

  191. Palomer X, Alvarez-Guardia D, Rodríguez-Calvo R, Coll T, Laguna JC, Davidson MM, Chan TO, Feldman AM, Vázquez-Carrera M (2009) TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model. Cardiovasc Res 81(4):703–712

    CAS  PubMed  Google Scholar 

  192. Pankratov Y, Lalo U, Krishtal O, Verkhratsky A (2003) P2X receptor-mediated excitatory synaptic currents in somatosensory cortex. Mol Cell Neurosci 24(3):842–849

    CAS  PubMed  Google Scholar 

  193. Papanicolaou DA, Amsterdamb JD, Levine S, McCann SM, Moore RC, Newbrand CH, Allen G, Nisenbaum R, Pfaff DW, Tsokos GC, Vgontzas AN, Kales A (2003) Neuroendocrine aspects of Chronic Fatigue Syndrome. Neuroimmunomodulation 11(2):65–74

    Google Scholar 

  194. Park LCH, Zhang H, Sheu KFR, Calingasan NY, Kristal BS, Lindsay JG, Gibson GE (1999) Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia. J Neurochem 72(5):1948–1958

    CAS  PubMed  Google Scholar 

  195. Patel RP, Darley-Usmar VM (1996) Using peroxynitrite as oxidant with low-density lipoprotein. Methods Enzymol 269:375–384

    CAS  PubMed  Google Scholar 

  196. Patrick Neary J, Roberts AD, Leavins N, Harrison MF, Croll JC, Sexsmith JR (2008) Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome. Clin Physiol Funct Imaging 28(6):364–372

    CAS  PubMed  Google Scholar 

  197. Paul L, Wood L, Behan WM, Maclaren WM (1999) Demonstration of delayed recovery from fatiguing exercise in Chronic Fatigue Syndrome. Eur J Neurol 6:63–69

    CAS  PubMed  Google Scholar 

  198. Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ (2007) Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55(12):1251–1262

    PubMed  Google Scholar 

  199. Pérez MJ, Cederbaum AI (2003) Metallothionein 2A induction by zinc protects HEPG2 cells against CYP2E1-dependent toxicity. Free Radic Biol Med 34(4):443–455

    PubMed  Google Scholar 

  200. Petty RK, Harding AE, Morgan-Hughes JA (1986) The clinical features of mitochondrial myopathy. Brain 109:915–938

    PubMed  Google Scholar 

  201. Piaceri I, Rinnoci V, Bagnoli S, Failli Y, Sorbi S (2012) Mitochondria and Alzheimer’s disease. J Neurol Sci 322(1–2):31–34. doi:10.1016/j.jns.2012.05.033

    Google Scholar 

  202. Pieczenik SR, Neustadt J (2007) Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 83:84–92

    CAS  PubMed  Google Scholar 

  203. Plioplys AV, Plioplys S (1995) Electron-microscopic investigation of muscle mitochondria in Chronic Fatigue Syndrome. Neuropsychobiol 32:175–181

    CAS  Google Scholar 

  204. Protti A, Singer M (2006) Bench-to-bedside review: potential strategies to protect or reverse mitochondrial dysfunction in sepsis-induced organ failure. Crit Care 10(5):228

    PubMed  Google Scholar 

  205. Puri BK, Counsell SJ, Zaman R, Main J, Collins AG, Hajnal JV, Davey NJ (2002) Relative increase in choline in the occipital cortex in chronic fatigue syndrome. Acta Psychiatr Scand 106(3):224–226

    CAS  PubMed  Google Scholar 

  206. Purohit V, Gao B, Song BJ (2009) Molecular mechanisms of alcoholic fatty liver. Alcohol Clin Exp Res 33(2):191–205

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Purohit V, Rapaka R, Kwon OS, Song BJ (2013) Roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma. Life Sci 92(1):3–9

    CAS  PubMed  Google Scholar 

  208. Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem 266(7):4244–4250

    CAS  PubMed  Google Scholar 

  209. Radi R, Rodriguez M, Castro L, Telleri R (1994) Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys 308(1):89–95

    CAS  PubMed  Google Scholar 

  210. Radi R, Cassina A, Hodara R, Quijano C, Castro L (2002) Peroxynitrite reactions and formation in mitochondria. Free Radic Biol Med 33(11):1451–1464

    CAS  PubMed  Google Scholar 

  211. Ramanathan A, Wang C, Schreiber SL (2005) Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc Natl Acad Sci U S A 102:5992–5997

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Redegeld F, Filippini A, Sitkovsky M (1991) Comparative studies of the cytotoxic T lymphocyte-mediated cytotoxicity and of extracellular ATP-induced cell lysis. Different requirements in extracellular Mg2+ and pH. J Immunol 147:3638–3645

    CAS  PubMed  Google Scholar 

  213. Ren Y, Silverstein RL, Allen J, Savill J (1995) CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis. J Exp Med 181(5):1857–1862

    CAS  PubMed  Google Scholar 

  214. Reynolds NL, Brown MM, Jason LA (2009) The relationship of Fennell phases to symptoms among patients with Chronic Fatigue Syndrome. Eval Health Prof 32(3):264–280

    PubMed  Google Scholar 

  215. Ring S, Enk AH, Mahnke K (2010) ATP activates regulatory T Cells in vivo during contact hypersensitivity reactions. J Immunol 184(7):3408–3416

    CAS  PubMed  Google Scholar 

  216. Riobo NA, Clementi E, Melani M et al (2001) NO inhibits mitochondrial NADH: ubiquinone reductase activity through peroxynitrite formation. Biochem J 359:139–145

    CAS  PubMed  Google Scholar 

  217. Rodríguez-Hernández A, Cordero MD, Salviati L, Artuch R, Pineda M, Briones P, Gómez Izquierdo L, Cotán D, Navas P, Sánchez-Alcázar JA (2009) Coenzyme Q deficiency triggers mitochondria degradation by mitophagy. Autophagy 5(1):19–32

    PubMed  Google Scholar 

  218. Sahlin K, Katz A, Henriksson J (1987) Redox state and lactate accumulation in human skeletal muscle during dynamic exercise. Biochem J 245:551–556

    CAS  PubMed  Google Scholar 

  219. Samavati L, Lee I, Mathes I, Lottspeich F, Hattemann M (2008) Tumor necrosis factor inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. J Biol Chem 283:21134–21144

    CAS  PubMed  Google Scholar 

  220. Saneto RP, Friedman SD, Shaw DW (2008) Neuroimaging of mitochondrial disease. Mitochondrion 8(5–6):396–413

    CAS  PubMed Central  PubMed  Google Scholar 

  221. Scarpulla RC, Vega RB, Kelly DP (2012) Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol Metab 23(9):459–466

    CAS  PubMed Central  PubMed  Google Scholar 

  222. Schenk U, Frascoli M, Proietti M et al (2011) ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci Signal 4(162):ra12

    PubMed  Google Scholar 

  223. Schildknecht S, Pape R, Müller N, Robotta M, Marquardt A, Bürkle A, Drescher M, Leist M (2011) Neuroprotection by minocycline caused by direct and specific scavenging of peroxynitrite. J Biol Chem 286(7):4991–5002

    CAS  PubMed  Google Scholar 

  224. Schmelzer C, Lindner I, Rimbach G, Niklowitz P, Menke T, Doring F (2008) Functions of coenzyme Q10 in inflammation and gene expression. Biofactors 32(1–4):179–183

    CAS  PubMed  Google Scholar 

  225. Sedgwick JD, Ford AL, Foulcher E, Airriess R (1998) Central nervous system microglial cell activation and proliferation follows direct interaction with tissue-infiltrating T cell blasts. J Immunol 160(11):5320–5330

    CAS  PubMed  Google Scholar 

  226. Sharir H, Hershfinkel M (2005) The extracellular zinc-sensing receptor mediates intercellular communication by inducing ATP release. Biochem Biophys Res Commun 332(3):845–852

    CAS  PubMed  Google Scholar 

  227. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, Rentsendorj A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401–414

    CAS  PubMed Central  PubMed  Google Scholar 

  228. Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ (2012) Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed 25(9):1073–1087

    CAS  PubMed Central  PubMed  Google Scholar 

  229. Singer M (2007) Mitochondrial function in sepsis: acute phase versus multiple organ failure. Crit Care Med 35(9 Suppl):S441–S448

    CAS  PubMed  Google Scholar 

  230. Singer M, De Santis V, Vitale D, Jeffcoate W (2004) Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet 364(9433):545–548

    PubMed  Google Scholar 

  231. Smith R, Murphy M (2010) Animal and human studies with the mitochondrial-targeted antioxidant MitoQ. Ann NY Acad Sci 1201:96–103

    CAS  PubMed  Google Scholar 

  232. Smits B, van den Heuvel L, Knoop H, Küsters B, Janssen A, Borm G, Bleijenberg G, Rodenburg R, van Engelen B (2011) Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome. Mitochondrion 11(5):735–738

    CAS  PubMed  Google Scholar 

  233. Sperlagh B, Heinrich A, Csolle C (2007) P2 receptor-mediated modulation of neurotransmitter release-an update. Purinergic Signal 3(4):269–284

    CAS  PubMed Central  PubMed  Google Scholar 

  234. Stadlmann S, Renner K, Pollheimer J, Moser PL, Zeimet AG, Offner FA, Gnaiger E (2006) Preserved coupling of oxidative phosphorylation but decreased mitochondrial respiratory capacity in IL-1beta-treated human peritoneal mesothelial cells. Cell Biochem Biophys 44(2):179–186

    CAS  PubMed  Google Scholar 

  235. Sumbalova Z, Kucharska J, Kristek F (2010) Losartan improved respiratory function and coenzyme Q content in brain mitochondria of young spontaneously hypertensive rats. Cell Mol Neurobiol 30(5):751–758

    CAS  PubMed  Google Scholar 

  236. Suzuki T, Moraes TJ, Vachon E, Ginzberg HH, Huang TT, Matthay MA, Hollenberg MD, Marshall J, McCulloch CA, Abreu MT, Chow CW, Downey GP (2005) Proteinase-activated receptor-1 mediates elastase-induced apoptosis of human lung epithelial cells. Am J Respir Cell Mol Biol 33(3):231–247

    CAS  PubMed  Google Scholar 

  237. Suzuki T, Yamashita C, Zemans RL, Briones N, Van Linden A, Downey GP (2009) Leukocyte elastase induces lung epithelial apoptosis via a PAR-1-, NF-kappaB-, and p53-dependent pathway. Am J Respir Cell Mol Biol 41(6):742–755

    CAS  PubMed  Google Scholar 

  238. Svotelis A, Doyon G, Bernatchez G, Désilets A, Rivard N, Asselin C (2005) IL-1 beta-dependent regulation of C/EBP delta transcriptional activity. Biochem Biophys Res Commun 328(2):461–470

    CAS  PubMed  Google Scholar 

  239. Taivassalo T, De Stefano N, Matthews PM et al (1997) Aerobic training benefits patients with mitochondrial myopathies more than other chronic myopathies [abstract]. Neurology 48:A214

    Google Scholar 

  240. Taivassalo T, De Stefano N, Argov Z et al (1998) Effects of aerobic training in patients with mitochondrial myopathies. Neurology 50:1055–1060

    CAS  PubMed  Google Scholar 

  241. Taivassalo T, Shoubridge EA, Chen J, Kennaway NG, DiMauro S, Arnold DL, Haller RG (2001) Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical and genetic effects. Ann Neurol 50:133–141

    CAS  PubMed  Google Scholar 

  242. Taivassalo T, Abbott A, Wyrick P, Haller RG (2002) Venous oxygen levels during aerobic forearm exercise: an index of impaired oxidative metabolism in mitochondrial myopathy. Ann Neurol 51:38–44

    PubMed  Google Scholar 

  243. Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG (2003) The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain 126(Pt 2):413–423

    PubMed  Google Scholar 

  244. Tak PP, Firestein GS (2001) NF-kB: a key role in inflammatory diseases. J Clin Invest 107(1):7–11

    CAS  PubMed Central  PubMed  Google Scholar 

  245. Tiersky L, DeLuca J, Hill N, Dhar SK, Johnson SK, Lange G, Rappolt G, Natelson B (2001) Longitudinal assessment of neuro- psychological functioning, psychiatric status, functional disability and employment status in chronic fatigue syndrome. Appl Neuropsychol 8:41–50

    CAS  PubMed  Google Scholar 

  246. Tortora V, Quijano C, Freeman B, Radi R, Castro L (2007) Mitochondrial aconitase reaction with nitric oxide, S-nitrosoglutathione, and peroxynitrite: mechanisms and relative contributions to aconitase inactivation. Free Radic Biol Med 42(7):1075–1088

    CAS  PubMed  Google Scholar 

  247. Touyz RM (2004) Reactive oxygen species and Angiotensin II signaling in vascular cells - implications in cardiovascular disease. J Hypertens 37(8):1263–1273

    CAS  Google Scholar 

  248. Uppu RM, Cueto R, Squadrito GL, Salgo MG, Pryor WA (1996) Competitive reactions of peroxynitrite with 2-deoxyguanosine and 7,8-dihydro-8-oxo-2-deoxyguanosine (8-oxodG): relevance to the formation of 8-oxodG in DNA exposed to peroxynitrite. Free Radic Biol Med 21(3):407–411

    CAS  PubMed  Google Scholar 

  249. Uslu R, Bonavida B (1996) Involvement of the mitochondrion respiratory chain in the synergy achieved by treatment of human ovarian carcinoma cell lines with both tumor necrosis factor-alpha and cis-diamminedichloroplatinum. Cancer 77(4):725–732

    CAS  PubMed  Google Scholar 

  250. Valanne L, Ketonen L, Majander A, Suomalainen A, Pihko H (1998) Neuroradiologic findings in children with mitochondrial disorders. AJNR Am J Neuroradiol 19(2):369–377

    CAS  PubMed  Google Scholar 

  251. VanNess J, Snell CR, Stevens SR (2007) Diminished cardiopulmonary capacity during post-exertional malaise. J Chr Fatigue Synd 14:77–85

    Google Scholar 

  252. VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR (2010) Postexertional malaise in women with chronic fatigue syndrome. J Womens Health 19(2):239–244

    Google Scholar 

  253. Vaughan RA, Garcia-Smith R, Bisoffi M, Conn CA, Trujillo KA (2012) Conjugated linoleic acid or omega 3 fatty acids increase mitochondrial biosynthesis and metabolism in skeletal muscle cells. Lipids Health Dis 11:142

    CAS  PubMed Central  PubMed  Google Scholar 

  254. Vercesi AE, Hoffman ME (1993) Methods in toxicology. In: Jones DP, Lash LH (eds) Mitochondrial dysfunction. Vol. 2, Chapter 21. Academic, New York

    Google Scholar 

  255. Vercesi AE, Kowaltowski AJ, Grijalba MT, Meinicke AR, Castilho RF (1997) The role of reactive oxygen species in mitochondrial permeability transition. Biosci Rep 17(1):43–52

    CAS  PubMed  Google Scholar 

  256. Vermeulen RCW, Kurt RM, Visser FC, Sluiter W, Scholte HR (2010) Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med 8:93–100

    PubMed Central  PubMed  Google Scholar 

  257. Vissing J, Galbo H, Haller RG (1996) Exercise fuel mobilization in mitochondrial myopathy: a metabolic dilemma. Ann Neurol 40(4):655–662

    CAS  PubMed  Google Scholar 

  258. Vogt AM, Elsässer A, Pott-Beckert A, Ackermann C, Vetter SY, Yildiz M, Schoels W, Fell DA, Katus HA, Kübler W (2005) Myocardial energy metabolism in ischemic preconditioning and cardioplegia: a metabolic control analysis. Mol Cell Biochem 278(1–2):223–232

    CAS  PubMed  Google Scholar 

  259. Vojdani A, Lambert J (2011) The role of Th17 in neuroimmune disorders: target for CAM therapy. Part II. Evid. Based Complement Alternat Med 2011, 548086

  260. Vorobjev VS, Sharonova IN, Sergeeva OA, Haas HL (2003) Modulation of ATP-induced currents by zinc in acutely isolated hypothalamic neurons of the rat. Br J Pharmacol 139(5):919–926

    CAS  PubMed  Google Scholar 

  261. Wan J, Bae MA, Song BJ (2004) Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of Ogg1 DNA repair enzyme in C6 glioma cells. Exp Mol Med 36(1):71–77

    CAS  PubMed  Google Scholar 

  262. Wang XF, Cynader MS (2000) Astrocytes provide cysteine to neurons by releasing glutathione. J Neurochem 74(4):1434–1442

    CAS  PubMed  Google Scholar 

  263. Wang C, Wang MW, Tashiro S, Onodera S, Ikejima T (2005) IL-1beta acts in synergy with endogenous IL-1beta in A375-S2 human melanoma cell apoptosis through mitochondrial pathway. J Korean Med Sci 20(4):555–561

    CAS  PubMed Central  PubMed  Google Scholar 

  264. Wang H, Zhao X, Yin S (2008) Effects of coenzyme Q10 or combined with micronutrients on antioxidant defense system in rats. Wei Sheng Yan Jiu 37(3):311–313

    CAS  PubMed  Google Scholar 

  265. Wang G, Pierangeli SS, Papalardo E, Ansari GA, Khan MF (2010) Markers of oxidative and nitrosative stress in systemic lupus erythematosus: correlation with disease activity. Arthr Rheum 62(7):2064–2072

    CAS  Google Scholar 

  266. Wariar R, Gaffke JN, Haller RG, Bertocci LA (2000) A modular system for clinical measurement of impaired skeletal muscle oxygenation. J Appl Physiol 88:315–325

    CAS  PubMed  Google Scholar 

  267. Wei H, Desouki MM, Lin S, Xiao D, Franklin RB, Feng P (2008) Differential expression of metallothioneins (MTs) 1, 2, and 3 in response to zinc treatment in human prostate normal and malignant cells and tissues. Mol Cancer 7:7

    PubMed Central  PubMed  Google Scholar 

  268. Witte ME, Bo L, Rodenburg RJ, Belien JA, Musters R, Hazes T, Wintjes LT, Smeitink JA, Geurts JJ, De Vries HE, van der Valk P, van Horssen J (2009) Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol 219(2):193–204

    PubMed  Google Scholar 

  269. Wong R, Lopaschuk G, Zhu G, Walker D, Catellier D, Burton D, Teo K, Collins-Nakai R, Montague T (1992) Skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy. Chest 102:1716–1722

    CAS  PubMed  Google Scholar 

  270. Woolf K, Manore MM (2006) B-vitamins and exercise: does exercise alter requirements? Int J Sport Nutr Exerc Metabol 16(5):453–484

    CAS  Google Scholar 

  271. Wu X, Hill HS, Garvey WT (2006) A role for C/EBP-delta in mitochondrial dysfunction and insulin resistance in skeletal muscle. Abstract Number: 1298-P. Category: Signal Transduction. 66th Scientific Sessions. http://professional.diabetes.org/Abstracts_Display.aspx?TYP=1&CID=48159

  272. Wu I-C, Ohsawa I, Fuku N, Tanaka M (2010) Metabolic analysis of 13C-labeled pyruvate for noninvasive assessment of mitochondrial function. Ann NY Acad Sci 1201:111–120

    CAS  PubMed  Google Scholar 

  273. Wynne AM, Henrt CJ, Godbout JP (2009) Immune and behavioral consequences of microglial reactivity in the aged brain. Integr Comp Biol 49(3):254–266

    CAS  PubMed  Google Scholar 

  274. Xiong K, Peoples RW, Montgomery JP, Chiang Y, Stewart RR, Weight FF, Li C (1999) Differential modulation by copper and zinc of P2X2 and P2X4 receptor function. J Neurophysiol 81(5):2088–2094

    CAS  PubMed  Google Scholar 

  275. Xu M, Dai W, Deng X (2002) Effects of magnesium sulfate on brain mitochondrial respiratory function in rats after experimental traumatic brain injury. Chin J Traumatol 5(6):361–364

    CAS  PubMed  Google Scholar 

  276. Yamamoto Y, Komuro E, Niki E (1990) Antioxidant activity of ubiquinol in solution and phosphatidylcholine liposome. J Nutr Sci Vitaminol (Tokyo) 36(5):505–511

    CAS  Google Scholar 

  277. Yang X, Zhu J, Tang Z (2007) Interventional effect of magnesium sulphate on nitric oxide synthase activity after acute craniocerebral injury. Neural Reg Res 2(4):251–253

    CAS  Google Scholar 

  278. Zell R, Geck P, Werdan K, Boekstegers P (1997) TNF-alpha and IL-1 alpha inhibit both pyruvate dehydrogenase activity and mitochondrial function in cardiomyocytes: evidence for primary impairment of mitochondrial function. Mol Cell Biochem 177(1–2):61–67

    CAS  PubMed  Google Scholar 

  279. Zeyda M, Stulnig TM (2006) Lipid Rafts & Co.: an integrated model of membrane organization in T cell activation. Prog Lipid Res 45:187–202

    CAS  PubMed  Google Scholar 

  280. Zhang G, Lu X, Kimura S, Nishiyama A (2007) Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation. Cardiovasc Res 76:204–212

    CAS  PubMed  Google Scholar 

  281. Zhou S, Kachhap S, Singh KK (2003) Mitochondrial impairment in p53-deficient human cancer cells. Mutagenesis 18:287–292

    CAS  PubMed  Google Scholar 

  282. Zimmermann H (2006) Nucleotide signaling in nervous system development. Pflugers Arch 452:573–588

    CAS  PubMed  Google Scholar 

  283. Zsembery A, Fortenberry JA, Liang L, Bebok Z, Tucker TA, Boyce AT, Braunstein GM, Welty E, Bell PD, Sorscher EJ, Clancy JP, Schwiebert EM (2004) Extracellular zinc and ATP restore chloride secretion across cystic fibrosis airway epithelia by triggering calcium entry. J Biol Chem 279(11):10720–10729

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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

Conflict of interest

The authors do not report conflicts of interests.

Role of funding source

No specific funding was obtained for this specific research.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michael Maes.

Additional information

This paper has been “Ithenticated”.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Keywords

  • ME
  • Chronic fatigue syndrome
  • Mitochondria
  • Inflammation
  • Oxidative and nitrosative stress