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Reduced expression of PGC-1α partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex

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Abstract

There is growing evidence that mitochondrial dysfunction and associated reactive oxygen species (ROS) formation contribute to neurodegenerative processes in multiple sclerosis (MS). Here, we investigated whether alterations in transcriptional regulators of key mitochondrial proteins underlie mitochondrial dysfunction in MS cortex and contribute to neuronal loss. Hereto, we analyzed the expression of mitochondrial transcriptional (co-)factors and proteins involved in mitochondrial redox balance regulation in normal-appearing grey matter (NAGM) samples of cingulate gyrus and/or frontal cortex from 15 MS patients and nine controls matched for age, gender and post-mortem interval. PGC-1α, a transcriptional co-activator and master regulator of mitochondrial function, was consistently and significantly decreased in pyramidal neurons in the deeper layers of MS cortex. Reduced PGC-1α levels coincided with reduced expression of oxidative phosphorylation subunits and a decrease in gene and protein expression of various mitochondrial antioxidants and uncoupling proteins (UCPs) 4 and 5. Short-hairpin RNA-mediated silencing of PGC-1α in a neuronal cell line confirmed that reduced levels of PGC-1α resulted in a decrease in transcription of OxPhos subunits, mitochondrial antioxidants and UCPs. Moreover, PGC-1α silencing resulted in a decreased mitochondrial membrane potential, increased ROS formation and enhanced susceptibility to ROS-induced cell death. Importantly, we found extensive neuronal loss in NAGM from cingulate gyrus and frontal cortex of MS patients, which significantly correlated with the extent of PGC-1α decrease. Taken together, our data indicate that reduced neuronal PGC-1α expression in MS cortex partly underlies mitochondrial dysfunction in MS grey matter and thereby contributes to neurodegeneration in MS cortex.

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References

  1. Andrews ZB, Diano S, Horvath TL (2005) Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci 6:829–840

    Article  PubMed  CAS  Google Scholar 

  2. Bouillaud F, Couplan E, Pecqueur C, Ricquier D (2001) Homologues of the uncoupling protein from brown adipose tissue (UCP1): UCP2, UCP3, BMCP1 and UCP4. Biochim Biophys Acta 1504:107–119

    Article  PubMed  CAS  Google Scholar 

  3. Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC (2002) Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson’s disease. J Neurochem 82:615–624

    Article  PubMed  CAS  Google Scholar 

  4. Cadenas E, Boveris A, Ragan CI, Stoppani AO (1977) Production of superoxide radicals and hydrogen peroxide by NADH-ubiquinone reductase and ubiquinol-cytochrome c reductase from beef-heart mitochondria. Arch Biochem Biophys 180:248–257

    Article  PubMed  CAS  Google Scholar 

  5. Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, Howell O, Lassmann H, Turnbull DM, Mahad DJ (2010) Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 69(3):481–492

    Article  PubMed  Google Scholar 

  6. Chen XH, Zhao YP, Xue M, Ji CB, Gao CL, Zhu JG, Qin DN, Kou CZ, Qin XH, Tong ML, Guo XR (2010) TNF-alpha induces mitochondrial dysfunction in 3T3–L1 adipocytes. Mol Cell Endocrinol 328:63–69

    Article  PubMed  CAS  Google Scholar 

  7. Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214

    Article  PubMed  CAS  Google Scholar 

  8. Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG (2004) Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na +/Ca2 + exchanger. Proc Natl Acad Sci U S A 101:8168–8173

    Article  PubMed  CAS  Google Scholar 

  9. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59–69

    Article  PubMed  CAS  Google Scholar 

  10. De Stefano N, Matthews PM, Fu L, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL (1998) Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 121(Pt 8):1469–1477

    Article  PubMed  Google Scholar 

  11. Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478–489

    Article  PubMed  CAS  Google Scholar 

  12. Dutta R, Trapp BD (2007) Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 68:S22–S31

    Article  PubMed  Google Scholar 

  13. Dutta R, Trapp BD (2010) Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol 93(1):1–12

    Article  PubMed  Google Scholar 

  14. Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, Mahad D, Bradl M, Van HJ, Lassmann H (2012) NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 135:886–899

    Article  PubMed  Google Scholar 

  15. Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis–the plaque and its pathogenesis. N Engl J Med 354:942–955

    Article  PubMed  CAS  Google Scholar 

  16. Garcia-Vallejo JJ, Van DW, van Het HB, Van DI, Engelse MA, Van HV, Gringhuis SI (2006) Activation of human endothelial cells by tumor necrosis factor-alpha results in profound changes in the expression of glycosylation-related genes. J Cell Physiol 206(1):203–210

    Article  PubMed  CAS  Google Scholar 

  17. Hock MB, Kralli A (2009) Transcriptional control of mitochondrial biogenesis and function. Annu Rev Physiol 71:177–203

    Article  PubMed  CAS  Google Scholar 

  18. Jin F, Wu Q, Lu YF, Gong QH, Shi JS (2008) Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats. Eur J Pharmacol 600:78–82

    Article  PubMed  CAS  Google Scholar 

  19. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179

    Article  PubMed  CAS  Google Scholar 

  20. Kooi EJ, Prins M, Bajic N, Belien JA, Gerritsen WH, Van HJ, Aronica E, van Dam AM, Hoozemans JJ, Francis PT, Van DV, Geurts JJ (2011) Cholinergic imbalance in the multiple sclerosis hippocampus. Acta Neuropathol 122(3):313–322

    Article  PubMed  CAS  Google Scholar 

  21. Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267–276

    Article  PubMed  CAS  Google Scholar 

  22. Lucchinetti C, Bruck W, Noseworthy J (2001) Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment. Curr Opin Neurol 14:259–269

    Article  PubMed  CAS  Google Scholar 

  23. Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, Serafini B, Aloisi F, Reynolds R (2010) A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 68:477–493

    Article  PubMed  CAS  Google Scholar 

  24. 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

    Article  PubMed  Google Scholar 

  25. Mao W, Yu XX, Zhong A, Li W, Brush J, Sherwood SW, Adams SH, Pan G (1999) UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett 443:326–330

    Article  PubMed  CAS  Google Scholar 

  26. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273

    Article  PubMed  CAS  Google Scholar 

  27. Nakase T, Yoshida Y, Nagata K (2007) Amplified expression of uncoupling proteins in human brain ischemic lesions. Neuropathology 27:442–447

    Article  PubMed  Google Scholar 

  28. Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Bruck W, Bishop D, Misgeld T, Kerschensteiner M (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17:495–499

    Article  PubMed  CAS  Google Scholar 

  29. Pacelli C, De RD, Signorile A, Grattagliano I, Di TG, D’Orazio A, Nico B, Comi GP, Ronchi D, Ferranini E, Pirolo D, Seibel P, Schubert S, Gaballo A, Villani G, Cocco T (2011) Mitochondrial defect and PGC-1alpha dysfunction in parkin-associated familial Parkinson’s disease. Biochim Biophys Acta 1812:1041–1053

    Article  PubMed  CAS  Google Scholar 

  30. Pandit A, Vadnal J, Houston S, Freeman E, McDonough J (2009) Impaired regulation of electron transport chain subunit genes by nuclear respiratory factor 2 in multiple sclerosis. J Neurol Sci 279:14–20

    Article  PubMed  CAS  Google Scholar 

  31. Reijerkerk A, Lakeman KA, Drexhage JA, van Het HB, van WY, van der Pol SM, Kooij G, Geerts D, De Vries HE (2011) Brain endothelial barrier passage by monocytes is controlled by the endothelin system. J Neurochem 121(5):730–737

    Article  PubMed  Google Scholar 

  32. Remels AH, Gosker HR, Schrauwen P, Hommelberg PP, Sliwinski P, Polkey M, Galdiz J, Wouters EF, Langen RC, Schols AM (2010) TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia? FASEB J 24:5052–5062

    Article  PubMed  CAS  Google Scholar 

  33. Rupprecht A, Brauer AU, Smorodchenko A, Goyn J, Hilse KE, Shabalina IG, Infante-Duarte C, Pohl EE (2012) Quantification of uncoupling protein 2 reveals its main expression in immune cells and selective up-regulation during T-Cell proliferation. PLoS One 7(8):e41406

    Article  PubMed  CAS  Google Scholar 

  34. Sanchis D, Fleury C, Chomiki N, Goubern M, Huang Q, Neverova M, Gregoire F, Easlick J, Raimbault S, Levi-Meyrueis C, Miroux B, Collins S, Seldin M, Richard D, Warden C, Bouillaud F, Ricquier D (1998) BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast. J Biol Chem 273:34611–34615

    Article  PubMed  CAS  Google Scholar 

  35. Sattler MB, Bahr M (2010) Future neuroprotective strategies. Exp Neurol 225:40–47

    Article  PubMed  Google Scholar 

  36. Scarpulla RC (2008) Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88:611–638

    Article  PubMed  CAS  Google Scholar 

  37. Schutz B, Reimann J, Dumitrescu-Ozimek L, Kappes-Horn K, Landreth GE, Schurmann B, Zimmer A, Heneka MT (2005) The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J Neurosci 25:7805–7812

    Article  PubMed  Google Scholar 

  38. Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM (2011) PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson’s disease. Cell 144:689–702

    Article  PubMed  CAS  Google Scholar 

  39. Smorodchenko A, Rupprecht A, Sarilova I, Ninnemann O, Brauer AU, Franke K, Schumacher S, Techritz S, Nitsch R, Schuelke M, Pohl EE (2009) Comparative analysis of uncoupling protein 4 distribution in various tissues under physiological conditions and during development. Biochim Biophys Acta 1788:2309–2319

    Article  PubMed  CAS  Google Scholar 

  40. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408

    Article  PubMed  CAS  Google Scholar 

  41. Stys PK (2004) Axonal degeneration in multiple sclerosis: is it time for neuroprotective strategies? Ann Neurol 55:601–603

    Article  PubMed  CAS  Google Scholar 

  42. Trapp BD, Ransohoff R, Rudick R (1999) Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 12:295–302

    Article  PubMed  CAS  Google Scholar 

  43. Trapp BD, Stys PK (2009) Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 8:280–291

    Article  PubMed  CAS  Google Scholar 

  44. Valle I, varez-Barrientos A, Arza E, Lamas S, Monsalve M (2005) PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res 66:562–573

    Article  PubMed  CAS  Google Scholar 

  45. Van Horssen J, Witte ME, Schreibelt G, De Vries HE (2011) Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta 1812:141–150

    Article  PubMed  Google Scholar 

  46. varez-Guardia D, Palomer X, Coll T, Davidson MM, Chan TO, Feldman AM, Laguna JC, Vazquez-Carrera M (2010) The p65 subunit of NF-kappaB binds to PGC-1alpha, linking inflammation and metabolic disturbances in cardiac cells. Cardiovasc Res 87:449–458

    Article  Google Scholar 

  47. Ventura-Clapier R, Garnier A, Veksler V (2008) Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res 79:208–217

    Article  PubMed  CAS  Google Scholar 

  48. Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet S, Sweet IR, Schwartz MW, La Spada AR (2006) Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab 4:349–362

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant from the ‘Dutch MS Research Foundation’; project number (MS 05-581).

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Authors and Affiliations

  1. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    Maarten E. Witte, Philip G. Nijland, Wouter Gerritsen & Paul van der Valk

  2. Department of Molecular Cell Biology and Immunology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands

    Joost A. R. Drexhage, Bert van het Hof, Arie Reijerkerk, Helga E. de Vries & Jack van Horssen

  3. Department of Pediatric Oncology/Hematology, Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands

    Dirk Geerts

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  1. Maarten E. Witte
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Witte, M.E., Nijland, P.G., Drexhage, J.A.R. et al. Reduced expression of PGC-1α partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex. Acta Neuropathol 125, 231–243 (2013). https://doi.org/10.1007/s00401-012-1052-y

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