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Loss of Prohibitin Membrane Scaffolds Impairs Mitochondrial Architecture and Leads to Tau Hyperphosphorylation and Neurodegeneration
Open accessAbstract
Fusion and fission of mitochondria maintain the functional integrity of mitochondria and protect against neurodegeneration, but how mitochondrial dysfunctions trigger neuronal loss remains ill-defined. Prohibitins form large ring complexes in the inner membrane that are composed of PHB1 and PHB2 subunits and are thought to function as membrane scaffolds. In Caenorhabditis elegans, prohibitin genes affect aging by moderating fat metabolism and energy production. Knockdown experiments in mammalian cells link the function of prohibitins to membrane fusion, as they were found to stabilize the dynamin-like GTPase OPA1 (optic atrophy 1), which mediates mitochondrial inner membrane fusion and cristae morphogenesis. Mutations in OPA1 are associated with dominant optic atrophy characterized by the progressive loss of retinal ganglion cells, highlighting the importance of OPA1 function in neurons. Here, we show that neuron-specific inactivation of Phb2 in the mouse forebrain causes extensive neurodegeneration associated with behavioral impairments and cognitive deficiencies. We observe early onset tau hyperphosphorylation and filament formation in the hippocampus, demonstrating a direct link between mitochondrial defects and tau pathology. Loss of PHB2 impairs the stability of OPA1, affects mitochondrial ultrastructure, and induces the perinuclear clustering of mitochondria in hippocampal neurons. A destabilization of the mitochondrial genome and respiratory deficiencies manifest in aged neurons only, while the appearance of mitochondrial morphology defects correlates with tau hyperphosphorylation in the absence of PHB2. These results establish an essential role of prohibitin complexes for neuronal survival in vivo and demonstrate that OPA1 stability, mitochondrial fusion, and the maintenance of the mitochondrial genome in neurons depend on these scaffolding proteins. Moreover, our findings establish prohibitin-deficient mice as a novel genetic model for tau pathologies caused by a dysfunction of mitochondria and raise the possibility that tau pathologies are associated with other neurodegenerative disorders caused by deficiencies in mitochondrial dynamics.
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“inactivation of PHB-2 in mice brain affects mitochondrial structure and activity resulting in neurodegeneration by hyperphosphorylation of Tau (Merkwirth et al., 2012)”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Merkwirth et al., 2012
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Cites
Generalized lacZ expression with the ROSA26 Cre reporter strain
Soriano, P. (1999) · Nature Genetics · doi:10.1038/5007 · Cited by 5,237
Premature ageing in mice expressing defective mitochondrial DNA polymerase
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., et al. (2004) · Nature · doi:10.1038/nature02517 · Cited by 2,734
Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders
Ballatore, C., Lee, V. M.-Y., & Trojanowski, J. Q. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2194 · Cited by 2,174
Mitochondrial fusion and fission in cell life and death
Westermann, B. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3013 · Cited by 2,002
Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A
Züchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., et al. (2004) · Nature Genetics · doi:10.1038/ng1341 · Cited by 1,572
Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., et al. (2000) · Nature Genetics · doi:10.1038/79936 · Cited by 1,446
Alexander, C., Votruba, M., Pesch, U. E. A., Thiselton, D. L., Mayer, S., Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger, G., et al. (2000) · Nature Genetics · doi:10.1038/79944 · Cited by 1,330
Ishihara, N., Nomura, M., Jofuku, A., Kato, H., Suzuki, S. O., Masuda, K., Otera, H., Nakanishi, Y., Nonaka, I., Goto, Y.-I., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1907 · Cited by 1,066
Mitochondrial fragmentation in neurodegeneration.
Knott, A. B., Perkins, G., Schwarzenbacher, R., & Bossy-Wetzel, E. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2417 · Cited by 1,002
Tau phosphorylation: the therapeutic challenge for neurodegenerative disease
Hanger, D. P., Anderton, B. H., & Noble, W. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.01.003 · Cited by 965
Mitochondrial fusion protects against neurodegeneration in the cerebellum
Chen, H., McCaffery, J. M., & Chan, D. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.026 · Cited by 924
Regulation of mitochondrial morphology through proteolytic cleavage of OPA1
Ishihara, N., Fujita, Y., Oka, T., & Mihara, K. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601184 · Cited by 899
Biochemistry and Cell Biology of Tau Protein in Neurofibrillary DegenerationPreprint
Mandelkow, E., & Mandelkow, E. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006247 · Cited by 897
Casari, G., Fusco, M. D., Ciarmatori, S., Zeviani, M., Mora, M., Fernández‐Silva, P., Michele, G. D., Filla, A., Cocozza, S., Marconi, R., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81203-9 · Cited by 826
Song, Z., Chen, H., Fiket, M., Alexander, C., & Chan, D. C. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200704110 · Cited by 818
Essential Role for TrkB Receptors in Hippocampus-Mediated Learning
Minichiello, L., Korte, M., Wolfer, D., Kühn, R., Unsicker, K., Cestari, V., Rossi-Arnaud, C., Lipp, H.-P., Bonhoeffer, T., & Klein, R. (1999) · Neuron · doi:10.1016/s0896-6273(00)80853-3 · Cited by 799
Köpke, E., Tung, Y. C., Shaikh, S., Alonso, A. C., Iqbal, K., & Grundke-Iqbal, I. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80536-5 · Cited by 779
Regulation of OPA1 processing and mitochondrial fusion by m -AAA protease isoenzymes and OMA1
Ehses, S., Lauria, I., Mancuso, G., Bernacchia, A., Geimer, S., Tondera, D., Martinou, J., Westermann, B., Rugarli, E. I., & Langer, T. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200906084 · Cited by 596
Self-citationSong, W., Chen, J., Petrilli, A. M., Liot, G., Klinglmayr, E., Zhou, Y., Poquiz, P., Tjong, J., Pouladi, M. A., Hayden, M. R., et al. (2011) · Nature Medicine · doi:10.1038/nm.2313 · Cited by 575
Mitochondria: The Next (Neurode)Generation
Schon, E. A., & Przedborski, S. (2011) · Neuron · doi:10.1016/j.neuron.2011.06.003 · Cited by 568
Merkwirth, C., Dargazanli, S., Tatsuta, T., Geimer, S., Löwer, B., Wunderlich, F. T., von Kleist-Retzow, J., Waisman, A., Westermann, B., & Langer, T. (2008) · Genes & Development · doi:10.1101/gad.460708 · Cited by 535
Self-citationRegulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage
Griparić, L., Kanazawa, T., & van der Bliek, A. M. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200704112 · Cited by 486
Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases
Mazanetz, M. P., & Fischer, P. M. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2111 · Cited by 459
Zhu, X.-W., Raina, A., Rottkamp, C., Aliev, G., Perry, G., Boux, H., & Smith, M. A. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00046.x · Cited by 440
Duvezin‐Caubet, S., Jagasia, R., Wagener, J., Hofmann, S., Trifunović, A., Hansson, A., Chomyn, A., Bauer, M. F., Attardi, G. M., Larsson, N., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606059200 · Cited by 431
The Layered Structure of Human Mitochondrial DNA Nucleoids
Bogenhagen, D. F., Rousseau, D. L., & Burke, S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m708444200 · Cited by 426
Mitochondrial quality control: a matter of life and death for neurons
Rugarli, E. I., & Langer, T. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.38 · Cited by 423
Self-citationThe SPFH domain-containing proteins: more than lipid raft markers
Browman, D., Hoegg-Beiler, M. B., & Robbins, S. M. (2007) · Trends in Cell Biology · doi:10.1016/j.tcb.2007.06.005 · Cited by 390
Prohibitins Regulate Membrane Protein Degradation by the m -AAA Protease in Mitochondria
Steglich, G., Neupert, W., & Langer, T. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.5.3435 · Cited by 362
Self-citationFormation of Membrane-bound Ring Complexes by Prohibitins in Mitochondria
Tatsuta, T., Model, K., & Langer, T. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-09-0807 · Cited by 350
Self-citationProhibitins and the functional compartmentalization of mitochondrial membranes
Osman, C., Merkwirth, C., & Langer, T. (2009) · Journal of Cell Science · doi:10.1242/jcs.037655 · Cited by 316
Self-citationReddy, P. H. (2011) · Brain Research · doi:10.1016/j.brainres.2011.07.052 · Cited by 311
An intimate liaison: spatial organization of the endoplasmic reticulum–mitochondria relationship
de Brito, O. M., & Scorrano, L. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.177 · Cited by 310
Abnormal mitochondrial dynamics and neurodegenerative diseases
Su, B., Wang, X., Zheng, L., Perry, G. L., Smith, M. A., & Zhu, X. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.09.013 · Cited by 301
Osman, C., Haag, M., Potting, C., Rodenfels, J., Dip, P. V., Wieland, F., Brügger, B., Westermann, B., & Langer, T. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200810189 · Cited by 301
Self-citationTiveron, M.-C., Hirsch, M., & Brunet, J. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-23-07649.1996 · Cited by 295
Prohibitin and mitochondrial biology
Artal‐Sanz, M., & Tavernarakis, N. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.04.004 · Cited by 295
Microtubule-Associated Protein Tau
Yen, S.-H. C., Nacharaju, P., Ko, L., Kenessey, Á., & Liu, W.-K. (1998) · Elsevier eBooks · doi:10.1016/b978-012734610-6/50012-9 · Cited by 284
Tavernarakis, N., Driscoll, M., & Kyrpides, N. C. (1999) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(99)01467-x · Cited by 260
Physiological functions of mitochondrial fusion
Chen, H., & Chan, D. C. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05615.x · Cited by 231
Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia
Ittner, L. M., Fath, T., Ke, Y. D., Bi, M., van Eersel, J., Li, K. M., Gunning, P. W., & Götz, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808084105 · Cited by 230
Pierson, T. M., Adams, D. R., Bonn, F., Martinelli, P., Cherukuri, P. F., Teer, J. K., Hansen, N. F., Cruz, P., Mullikin, J. C., Blakesley, R. W., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002325 · Cited by 226
Self-citationArtal‐Sanz, M., Tsang, W. Y., Willems, E., Grivell, L. A., Lemire, B. D., van der Spek, H., & Nijtmans, L. G. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304877200 · Cited by 220
Kasashima, K., Ohta, E., Kagawa, Y., & Endo, H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605260200 · Cited by 208
Schleicher, M., Shepherd, B. R., Suárez, Y., Fernandez-Hernando, C. F., Yu, J. Q., Pan, Y., Acevedo, L. M., Shadel, G. S., & Sessa, W. C. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200706072 · Cited by 207
Shahpasand, K., Uemura, I., Saito, T., Asano, T., Hata, K., Shibata, K., Toyoshima, Y., Hasegawa, M., & Hisanaga, S.-I. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5927-11.2012 · Cited by 206
Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans
Artal-Sanz, M., & Tavernarakis, N. (2009) · Nature · doi:10.1038/nature08466 · Cited by 196
Ferreira, A., Lu, Q., Orecchio, L., & Kosik, K. S. (1997) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.1997.0615 · Cited by 178
Human prohibitin 1 maintains the organization and stability of the mitochondrial nucleoids
Kasashima, K., Sumitani, M., Satoh, M., & Endo, H. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2008.01.005 · Cited by 141
Marine Natural Product Aurilide Activates the OPA1-Mediated Apoptosis by Binding to Prohibitin
Sato, S., Murata, A., Orihara, T., Shirakawa, T., Suenaga, K., Kigoshi, H., & Uesugi, M. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.10.017 · Cited by 127
Characterization of OPA1 isoforms isolated from mouse tissues
Akepati, V. R., Müller, E., Otto, A., Strauss, H. M., Portwich, M., & Alexander, C. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05401.x · Cited by 114
Park, S.-E., Xu, J., Frolova, A. I., Liao, L., O’Malley, B. W., & Katzenellenbogen, B. S. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.5.1989-1999.2005 · Cited by 99
Birner‐Gruenberger, R., Nebauer, R., Schneiter, R., & Daum, G. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-05-0263 · Cited by 96
Zhou, P., Qian, L., D’Aurelio, M., Cho, S., Wang, G., Manfredi, G., Pickel, V. M., & Iadecola, C. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.2849-11.2012 · Cited by 82
Piechota, J., Kołodziejczak, M., Juszczak, I., Sakamoto, W., & Jańska, H. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.063644 · Cited by 72
George, S. K., Jiao, Y., Bishop, C. E., & Lu, B. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00686.x · Cited by 66
Martinelli, P., Mattina, V. L., Bernacchia, A., Magnoni, R., Cerri, F., Cox, G. A., Quattrini, A., Casari, G., & Rugarli, E. I. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp124 · Cited by 65
Self-citationOpposing function of mitochondrial prohibitin in aging
Artal‐Sanz, M., & Tavernarakis, N. (2010) · Aging · doi:10.18632/aging.100246 · Cited by 25
Atypical tauopathy with massive involvement of the white matter
Giaccone, G., Marcon, G., Mangieri, M., Morbin, M., Rossi, G., Fetoni, V., Patriarca, C., Catania, M., Fede, G. D., & Tagliavini, F. (2008) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2007.00927.x · Cited by 24
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- D DiBella, 2008, AFG3L2 mutations cause autosomal dominant ataxia SCA28 and reveal an essential role of the m-AAA AFG3L2 homocomplex in the cerebellum, Annual meeting of the American Society of Human Genetics
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Metadata
- Authors
- Merkwirth, C., Martinelli, P., Korwitz, A., Morbin, M., Brönneke, H. S., Jordan, S. D., Rugarli, E. I., & Langer, T.
- Affiliations
- University of Cologne (DE)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Corresponding author
- Langer, Thomas
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-11-08
- Volume
- 8
- Issue
- 11
- Pages
- e1003021
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3493444
- OpenAlex
- W2005255392
- Cited by
- 162
- References
- 59
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 13 · 2022: 20 · 2021: 16 · 2020: 18 · 2019: 15 · 2018: 11 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 9 · 2013: 8
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (SFB635, C4, 233078, SFB 635)
- FP7 Ideas: European Research Council (233078)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- prohibitin, PHB2, prohibitin 1, OPA1, mitochondrial fusion, mitochondrial fission, mitochondrial dynamics, tau hyperphosphorylation, neurodegeneration, hippocampal neurons, mitochondrial ultrastructure, mitochondrial genome stability, respiratory deficiency, neuronal aging, cognitive impairment, autosomal dominant optic atrophy
- MeSH terms
- Prohibitins, Animals, Membrane Fusion, Mitochondria, Morphogenesis, Neurons, Phosphorylation, Repressor Proteins, tau Proteins, Apoptosis, Neurodegenerative Diseases, Optic Atrophy, Autosomal Dominant, Caenorhabditis elegans Proteins, Mitochondrial Membranes, Mice, Genome, Mitochondrial
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