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A New Link to Mitochondrial Impairment in Tauopathies

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Abstract

Tauopathies like the “frontotemporal dementia with Parkinsonism linked to chromosome 17” (FTDP-17) are characterized by an aberrant accumulation of intracellular neurofibrillary tangles composed of hyperphosphorylated tau. For FTDP-17, a pathogenic tau mutation P301L was identified. Impaired mitochondrial function including disturbed dynamics such as fission and fusion are most likely major pathomechanisms of most neurodegenerative diseases. However, very little is known if tau itself affects mitochondrial function and dynamics. We addressed this question using SY5Y cells stably overexpressing wild-type (wt) and P301L mutant tau. P301L overexpression resulted in a substantial complex I deficit accompanied by decreased ATP levels and increased susceptibility to oxidative stress. This was paralleled by pronounced changes in mitochondrial morphology, decreased fusion and fission rates accompanied by reduced expression of several fission and fusion factors like OPA-1 or DRP-1. In contrast, overexpression of wt tau exhibits protective effects on mitochondrial function and dynamics including enhanced complex I activity. Our findings clearly link tau bidirectional to mitochondrial function and dynamics, identifying a novel aspect of the physiological role of tau and the pathomechanism of tauopathies.

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References

  1. Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT (2009) Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci 3:150–159

    Article  Google Scholar 

  2. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A 11:4051–4055

    Article  Google Scholar 

  3. Dixit R, Ross JL, Goldman YE, Holzbaur EL (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 5866:1086–1089

    Article  Google Scholar 

  4. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 6686:702–705

    Article  Google Scholar 

  5. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 6:815–825

    Article  Google Scholar 

  6. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 13:7737–7741

    Article  Google Scholar 

  7. von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM, Mandelkow E (2001) Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J Biol Chem 51:48165–48174

    Google Scholar 

  8. David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, Ravid R, Drose S, Brandt U, Muller WE et al (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L Tau transgenic mice. J Biol Chem 25:23802–23814

    Article  Google Scholar 

  9. Kuhla B, Loske C, Garcia DA, Schinzel R, Huber J, Munch G (2004) Differential effects of ”Advanced glycation endproducts” and beta-amyloid peptide on glucose utilization and ATP levels in the neuronal cell line SH-SY5Y. J Neural Transm 3:427–439

    Article  Google Scholar 

  10. Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Munch G (2011) Advanced glycation endproducts and their receptor RAGE in Alzheimer’s disease. Neurobiol Aging 5:763–777

    Article  Google Scholar 

  11. Busch KB, Bereiter-Hahn J, Wittig I, Schagger H, Jendrach M (2006) Mitochondrial dynamics generate equal distribution but patchwork localization of respiratory complex I. Mol Membr Biol 6:509–520

    Article  Google Scholar 

  12. Ishihara N, Jofuku A, Eura Y, Mihara K (2003) Regulation of mitochondrial morphology by membrane potential, and DRP1-dependent division and FZO1-dependent fusion reaction in mammalian cells. Biochem Biophys Res Commun 4:891–898

    Article  Google Scholar 

  13. Ono T, Isobe K, Nakada K, Hayashi JI (2001) Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet 3:272–275

    Article  Google Scholar 

  14. Suen DF, Norris KL, Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes Dev 12:1577–1590

    Article  Google Scholar 

  15. Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 11:870–879

    Article  Google Scholar 

  16. Westermann B (2008) Molecular machinery of mitochondrial fusion and fission. J Biol Chem 20:13501–13505

    Article  Google Scholar 

  17. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 7:505–518

    Article  Google Scholar 

  18. Wang X, Su B, Fujioka H, Zhu X (2008) Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol 2:470–482

    Article  Google Scholar 

  19. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 49:19318–19323

    Article  Google Scholar 

  20. Ferrari A, Hoerndli F, Baechi T, Nitsch RM, Gotz J (2003) beta-Amyloid induces paired helical filament-like tau filaments in tissue culture. J Biol Chem 41:40162–40168

    Article  Google Scholar 

  21. Schaeffer V, Patte-Mensah C, Eckert A, Mensah-Nyagan AG (2006) Modulation of neurosteroid production in human neuroblastoma cells by Alzheimer’s disease key proteins. J Neurobiol 8:868–881

    Article  Google Scholar 

  22. Letellier T, Durrieu G, Malgat M, Rossignol R, Antoch J, Deshouillers JM, Coquet M, Lacombe D, Netter JC, Pedespan JM et al (2000) Statistical analysis of mitochondrial pathologies in childhood: identification of deficiencies using principal component analysis. Lab Invest 7:1019–1030

    Article  Google Scholar 

  23. Leuner K, Hauptmann S, Abdel-Kader R, Scherping I, Keil U, Strosznajder JB, Eckert A, Muller WE (2007) Mitochondrial dysfunction: the first domino in brain aging and Alzheimer’s disease? Antioxid Redox Signal 10:1659–1675

    Article  Google Scholar 

  24. Bai RK, Perng CL, Hsu CH, Wong LJ (2004) Quantitative PCR analysis of mitochondrial DNA content in patients with mitochondrial disease. Ann N Y Acad Sci 304–309

  25. Schneider WC, Hogeboom GH (1951) Cytochemical studies of mammalian tissues; the isolation of cell components by differential centrifugation: a review. Cancer Res 1:1–22

    Google Scholar 

  26. Baloyannis SJ (2006) Mitochondrial alterations in Alzheimer’s disease. J Alzheimers Dis 2:119–126

    Google Scholar 

  27. Bunker JM, Kamath K, Wilson L, Jordan MA, Feinstein SC (2006) FTDP-17 mutations compromise the ability of tau to regulate microtubule dynamics in cells. J Biol Chem 17:11856–11863

    Article  Google Scholar 

  28. Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E (1998) Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J Cell Biol 3:777–794

    Article  Google Scholar 

  29. Roy S, Zhang B, Lee VM, Trojanowski JQ (2005) Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol 1:5–13

    Article  Google Scholar 

  30. Karbowski M, Arnoult D, Chen H, Chan DC, Smith CL, Youle RJ (2004) Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J Cell Biol 4:493–499

    Article  Google Scholar 

  31. Honda S, Hirose S (2003) Stage-specific enhanced expression of mitochondrial fusion and fission factors during spermatogenesis in rat testis. Biochem Biophys Res Commun 2:424–432

    Article  Google Scholar 

  32. Jendrach M, Mai S, Pohl S, Voth M, Bereiter-Hahn J (2008) Short- and long-term alterations of mitochondrial morphology, dynamics and mtDNA after transient oxidative stress. Mitochondrion 4:293–304

    Article  Google Scholar 

  33. Alonso AC, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K (2004) Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem 279:34873–34881

    Google Scholar 

  34. Hasegawa M, Smith MJ, Goedert M (1998) Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett 3:207–210

    Article  Google Scholar 

  35. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A et al (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 5395:1914–1917

    Article  Google Scholar 

  36. Sumpter PQ, Mann DM, Davies CA, Yates PO, Snowden JS, Neary D (1986) An ultrastructural analysis of the effects of accumulation of neurofibrillary tangle in pyramidal neurons of the cerebral cortex in Alzheimer’s disease. Neuropathol Appl Neurobiol 3:305–319

    Article  Google Scholar 

  37. Bonda DJ, Castellani RJ, Zhu X, Nunomura A, Lee HG, Perry G, Smith MA (2011) A novel perspective on tau in Alzheimer’s disease. Curr Alzheimer Res 6:639–642

    Article  Google Scholar 

  38. Su B, Wang X, Lee HG, Tabaton M, Perry G, Smith MA, Zhu X (2010) Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells. Neurosci Lett 3:267–271

    Article  Google Scholar 

  39. Palade GE (1953) An electron microscope study of the mitochondrial structure. J Histochem Cytochem 4:188–211

    Article  Google Scholar 

  40. Demongeot J, Glade N, Hansen O, Moreira A (2007) An open issue: the inner mitochondrial membrane (IMM) as a free boundary problem. Biochimie 9:1049–1057

    Article  Google Scholar 

  41. Hackenbrock CR (1968) Chemical and physical fixation of isolated mitochondria in low-energy and high-energy states. Proc Natl Acad Sci USA 2:598–605

    Article  Google Scholar 

  42. Bereiter-Hahn J, Voeth M. (1983) Metabolic control of shape and structure of mitochondria in situ. Biol Cell 1042:304–309

    Google Scholar 

  43. Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283–292

    Google Scholar 

  44. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 11:5001–5011

    Article  Google Scholar 

  45. Sugioka R, Shimizu S, Tsujimoto Y (2004) Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem 50:52726–52734

    Article  Google Scholar 

  46. Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M, Nunomura A, Szweda LI, Aliev G, Smith MA et al (2007) Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy 6:614–615

    Google Scholar 

  47. Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M, Nunomura A, Szweda LI, Aliev G, Smith MA et al (2007) Autophagocytosis of mitochondria is prominent in Alzheimer disease. J Neuropathol Exp Neurol 6:525–532

    Article  Google Scholar 

  48. Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler DT, Goedert M (2012) Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain Pt 7:2169–2177

    Article  Google Scholar 

  49. Brandt R, Leger J, Lee G (1995) Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J Cell Biol 5:1327–1340

    Article  Google Scholar 

  50. Magnani E, Fan J, Gasparini L, Golding M, Williams M, Schiavo G, Goedert M, Amos LA, Spillantini MG (2007) Interaction of tau protein with the dynactin complex. EMBO J 21:4546–4554

    Article  Google Scholar 

  51. Liot G, Bossy B, Lubitz S, Kushnareva Y, Sejbuk N, Bossy-Wetzel E (2009) Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an. Cell Death Differ 16:899–909

    Google Scholar 

  52. Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 3:548–562

    Article  CAS  Google Scholar 

  53. Hansen MB, Nielsen SE, Berg K (1989) Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods 2:203–210

    Article  Google Scholar 

  54. Crouch SP, Kozlowski R, Slater KJ, Fletcher J (1993) The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity. J Immunol Methods 1:81–88

    Article  Google Scholar 

  55. Baracca A, Sgarbi G, Solaini G, Lenaz G (2003) Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F(0) during ATP synthesis. Biochim Biophys Acta 1–3:137–146

    Google Scholar 

  56. Djafarzadeh R, Kerscher S, Zwicker K, Radermacher M, Lindahl M, Schagger H, Brandt U (2000) Biophysical and structural characterization of proton-translocating NADH–dehydrogenase (complex I) from the strictly aerobic yeast Yarrowia lipolytica. Biochim Biophys Acta 1:230–238

    Google Scholar 

  57. Aleardi AM, Benard G, Augereau O, Malgat M, Talbot JC, Mazat JP, Letellier T, Dachary-Prigent J, Solaini GC, Rossignol R (2005) Gradual alteration of mitochondrial structure and function by beta-amyloids: importance of membrane viscosity changes, energy deprivation, reactive oxygen species production, and cytochrome c release. J Bioenerg Biomembr 4:207–225

    Article  Google Scholar 

  58. Krahenbuhl S, Chang M, Brass EP, Hoppel CL (1991) Decreased activities of ubiquinol:ferricytochrome c oxidoreductase (complex III) and ferrocytochrome c:oxygen oxidoreductase (complex IV) in liver mitochondria from rats with hydroxycobalamin[c-lactam]-induced methylmalonic aciduria. J Biol Chem 31:20998–21003

    Google Scholar 

  59. Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: a functional characterization. Mol Cell Biochem 1–2:37–44

    Article  Google Scholar 

  60. Patterson GH, Lippincott-Schwartz J (2002) A photoactivatable GFP for selective photolabeling of proteins and cells. Science 5588:1873–1877

    Article  Google Scholar 

  61. Bai RK, Perng CL, Hsu CH, Wong LJ (2004) Quantitative PCR analysis of mitochondrial DNA content in patients with mitochondrial disease. Ann N Y Acad Sci

  62. Cote HC, Brumme ZL, Craib KJ, Alexander CS, Wynhoven B, Ting L, Wong H, Harris M, Harrigan PR, O’Shaughnessy MV et al (2002) Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 11:811–820

    Article  Google Scholar 

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Acknowledgements

The authors thank M. Vöth for support with the mitochondrial movement data analysis, F. Haas for experimental support with the real-time PCR and F. Meier with regard to Western blotting. This work was supported in part by grants from the Swiss National Research Foundation (SNF # 31000_122572) and Synapsis Foundation to AE, by the DFG grant REI1575-1/1 (AR), he Cluster of Excellence Frankfurt Macromolecular Complexes at the University of Frankfurt DFG project EXC 115 (AR), and the BMBF, Germany, GerontoMitoSys project (AR).

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Authors and Affiliations

  1. Department of Pharmacology, ZAFES, Biocenter, University of Frankfurt, 60438, Frankfurt, Germany

    Kathrin L. Schulz, Walter E. Müller & Kristina Leuner

  2. Neurobiology Laboratory for Brain Aging and Mental Health, Associated Research Group Department of Biomedicine, Psychiatric University Clinics, University of Basel, 4025, Basel, Switzerland

    Anne Eckert & Virginie Rhein

  3. Kinematic Cell Research Group, Institute for Cell Biology and Neuroscience, Center of Excellence Frankfurt, Macromolecular Complexes, University of Frankfurt, 60438, Frankfurt, Germany

    Sören Mai & Marina Jendrach

  4. Department of Structural Biology, Max Planck Institute of Biophysics, 60438, Frankfurt, Germany

    Winfried Haase

  5. Mitochondrial Biology, Buchmann Institute of Molecular Life Science, Goethe University Frankfurt am Main, Fachbereich Medizin, Max-von-Laue-Strasse 15, 60438, Frankfurt, Germany

    Andreas S. Reichert

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  1. Kathrin L. Schulz
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Schulz, K.L., Eckert, A., Rhein, V. et al. A New Link to Mitochondrial Impairment in Tauopathies. Mol Neurobiol 46, 205–216 (2012). https://doi.org/10.1007/s12035-012-8308-3

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