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.
References
[1]
Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11: 872–884. doi: 10.1038/nrm3013
[2]
Chen H, Chan DC (2010) Physiological functions of mitochondrial fusion. Ann N Y Acad Sci 1201: 21–25. doi: 10.1111/j.1749-6632.2010.05615.x
[3]
de Brito OM, Scorrano L (2010) An intimate liaison: spatial organization of the endoplasmic reticulum-mitochondria relationship. The EMBO journal 29: 2715–2723. doi: 10.1038/emboj.2010.177
[4]
Rugarli EI, Langer T (2012) Mitochondrial quality control: A matter of life and death for neurons. EMBO J in press. doi: 10.1038/emboj.2012.38
[5]
Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130: 548–562. doi: 10.1016/j.cell.2007.06.026
[6]
Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO, et al. (2009) Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nature cell biology 11: 958–966. doi: 10.1038/ncb1907
[7]
Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, et al. (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26: 211–215. doi: 10.1038/79944
[8]
Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, et al. (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26: 207–210. doi: 10.1038/79936
[9]
Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, et al. (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36: 449–451. doi: 10.1038/ng1341
[10]
Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, et al. (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nature medicine 17: 377–382. doi: 10.1038/nm.2313
[11]
Su B, Wang X, Zheng L, Perry G, Smith MA, et al. (2010) Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochimica et biophysica acta 1802: 135–142. doi: 10.1016/j.bbadis.2009.09.013
[12]
Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9: 505–518. doi: 10.1038/nrn2417
[13]
Merkwirth C, Dargazanli S, Tatsuta T, Geimer S, Lower B, et al. (2008) Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria. Genes Dev 22: 476–488. doi: 10.1101/gad.460708
[14]
Kasashima K, Sumitani M, Satoh M, Endo H (2008) Human prohibitin 1 maintains the organization and stability of the mitochondrial nucleoids. Exp Cell Res 314: 988–996. doi: 10.1016/j.yexcr.2008.01.005
[15]
Sato S, Murata A, Orihara T, Shirakawa T, Suenaga K, et al. (2011) Marine Natural Product Aurilide Activates the OPA1-Mediated Apoptosis by Binding to Prohibitin. Chem Biol 18: 131–139. doi: 10.1016/j.chembiol.2010.10.017
[16]
Osman C, Merkwirth C, Langer T (2009) Prohibitins and the functional compartmentalization of mitochondrial membranes. J Cell Sci 122: 3823–3830. doi: 10.1242/jcs.037655
[17]
Artal-Sanz M, Tavernarakis N (2010) Opposing function of mitochondrial prohibitin in aging. Aging 2: 1004–1011.
[18]
Tatsuta T, Model K, Langer T (2005) Formation of membrane-bound ring complexes by prohibitins in mitochondria. Mol Biol Cell 16: 248–259. doi: 10.1091/mbc.e04-09-0807
[19]
Osman C, Haag M, Potting C, Rodenfels J, Dip PV, et al. (2009) The genetic interactome of prohibitins: coordinated control of cardiolipin and phosphatidylethanolamine by conserved regulators in mitochondria. J Cell Biol 184: 583–596. doi: 10.1083/jcb.200810189
[20]
Tavernarakis N, Driscoll M, Kyrpides NC (1999) The SPFH domain: implicated in regulating targeted protein turnover in stomatins and other membrane-associated proteins. Trends Biochem Sci 24: 425–427. doi: 10.1016/s0968-0004(99)01467-x
[21]
Browman DT, Hoegg MB, Robbins SM (2007) The SPFH domain-containing proteins: more than lipid raft markers. Trends Cell Biol 17: 394–402. doi: 10.1016/j.tcb.2007.06.005
[22]
Artal-Sanz M, Tsang WY, Willems EM, Grivell LA, Lemire BD, et al. (2003) The mitochondrial prohibitin complex is essential for embryonic viability and germline function in Caenorhabditis elegans. J Biol Chem 278: 32091–32099. doi: 10.1074/jbc.m304877200
[23]
Park SE, Xu J, Frolova A, Liao L, O'Malley BW, et al. (2005) Genetic deletion of the repressor of estrogen receptor activity (REA) enhances the response to estrogen in target tissues in vivo. Mol Cell Biol 25: 1989–1999. doi: 10.1128/mcb.25.5.1989-1999.2005
[24]
Artal-Sanz M, Tavernarakis N (2009) Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans. Nature 461: 793–797. doi: 10.1038/nature08466
[25]
Schleicher M, Shepherd BR, Suarez Y, Fernandez-Hernando C, Yu J, et al. (2008) Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence. J Cell Biol 180: 101–112. doi: 10.1083/jcb.200706072
[26]
Song Z, Chen H, Fiket M, Alexander C, Chan DC (2007) OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol 178: 749–755. doi: 10.1083/jcb.200704110
[27]
Ishihara N, Fujita Y, Oka T, Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J 25: 2966–2977. doi: 10.1038/sj.emboj.7601184
[28]
Griparic L, Kanazawa T, van der Bliek AM (2007) Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol 178: 757–764. doi: 10.1083/jcb.200704112
[29]
Duvezin-Caubet S, Jagasia R, Wagener J, Hofmann S, Trifunovic A, et al. (2006) Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J Biol Chem 281: 37972–37979. doi: 10.1074/jbc.m606059200
[30]
Ehses S, Raschke I, Mancuso G, Bernacchia A, Geimer S, et al. (2009) Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol 187: 1023–1036. doi: 10.1083/jcb.200906084
[31]
Steglich G, Neupert W, Langer T (1999) Prohibitins regulate membrane protein degradation by the m-AAA protease in mitochondria. Mol Cell Biol 19: 3435–3442.
[32]
Piechota J, Kolodziejczak M, Juszczak I, Sakamoto W, Janska H (2010) Identification and characterization of high molecular weight complexes formed by matrix AAA proteases and prohibitins in mitochondria of Arabidopsis thaliana. The Journal of biological chemistry 285: 12512–12521. doi: 10.1074/jbc.m109.063644
[33]
Casari G, De-Fusco M, Ciarmatori S, Zeviani M, Mora M, et al. (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93: 973–983. doi: 10.1016/s0092-8674(00)81203-9
[34]
DiBella D, Lazzaro F, Brusco A, Battaglia G, A P, et al. (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 Philadelphia, Pennsylvania.
[35]
Pierson TM, Adams D, Bonn F, Martinelli P, Cherukuri PF, et al. (2011) Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet 7: e1002325 doi:10.1371/journal.pgen.1002325.
[36]
Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, et al. (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24: 401–414. doi: 10.1016/s0896-6273(00)80853-3
[37]
Soriano P (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21: 70–71.
[38]
Akepati VR, Muller EC, Otto A, Strauss HM, Portwich M, et al. (2008) Characterization of OPA1 isoforms isolated from mouse tissues. Journal of neurochemistry 106: 372–383. doi: 10.1111/j.1471-4159.2008.05401.x
[39]
Giaccone G, Marcon G, Mangieri M, Morbin M, Rossi G, et al. (2008) Atypical tauopathy with massive involvement of the white matter. Neuropathology and applied neurobiology 34: 468–472. doi: 10.1111/j.1365-2990.2007.00927.x
[40]
Hanger DP, Anderton BH, Noble W (2009) Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends in molecular medicine 15: 112–119. doi: 10.1016/j.molmed.2009.01.003
[41]
Mazanetz MP, Fischer PM (2007) Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nature reviews Drug discovery 6: 464–479. doi: 10.1038/nrd2111
[42]
Schon EA, Przedborski S (2011) Mitochondria: the next (neurode)generation. Neuron 70: 1033–1053. doi: 10.1016/j.neuron.2011.06.003
[43]
Reddy PH (2011) Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer's disease. Brain research 1415: 136–148. doi: 10.1016/j.brainres.2011.07.052
[44]
Kasashima K, Ohta E, Kagawa Y, Endo H (2006) Mitochondrial functions and estrogen receptor-dependent nuclear translocation of pleiotropic human prohibitin 2. J Biol Chem 281: 36401–36410. doi: 10.1074/jbc.m605260200
[45]
Zhou P, Qian L, D'Aurelio M, Cho S, Wang G, et al. (2012) Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities. The Journal of neuroscience: the official journal of the Society for Neuroscience 32: 583–592. doi: 10.1523/jneurosci.2849-11.2012
[46]
George SK, Jiao Y, Bishop CE, Lu B (2011) Mitochondrial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewal. Aging cell 10: 584–594. doi: 10.1111/j.1474-9726.2011.00686.x
[47]
Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, et al. (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423. doi: 10.1038/nature02517
[48]
Artal-Sanz M, Tavernarakis N (2009) Prohibitin and mitochondrial biology. Trends in endocrinology and metabolism: TEM 20: 394–401. doi: 10.1016/j.tem.2009.04.004
[49]
Bogenhagen DF, Rousseau D, Burke S (2008) The layered structure of human mitochondrial DNA nucleoids. J Biol Chem 283: 3665–3675. doi: 10.1074/jbc.m708444200
[50]
Birner R, Nebauer R, Schneiter R, Daum G (2003) Synthetic lethal interaction of the mitochondrial phosphatidylethanolamine biosynthetic machinery with the prohibitin complex of Saccharomyces cerevisiae. Mol Biol Cell 14: 370–383. doi: 10.1091/mbc.e02-05-0263
[51]
Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nature reviews Neuroscience 8: 663–672. doi: 10.1038/nrn2194
[52]
Ittner LM, Fath T, Ke YD, Bi M, van Eersel J, et al. (2008) Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proceedings of the National Academy of Sciences of the United States of America 105: 15997–16002. doi: 10.1073/pnas.0808084105
[53]
Shahpasand K, Uemura I, Saito T, Asnao T, Hata K, et al. (2012) Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease. J Neurosci 32: 2430–2441. doi: 10.1523/jneurosci.5927-11.2012
[54]
Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, et al. (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. The Journal of biological chemistry 268: 24374–24384.
[55]
Ferreira A, Lu Q, Orecchio L, Kosik KS (1997) Selective phosphorylation of adult tau isoforms in mature hippocampal neurons exposed to fibrillar A beta. Molecular and cellular neurosciences 9: 220–234. doi: 10.1006/mcne.1997.0615
[56]
Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, et al. (2001) Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. Journal of neurochemistry 76: 435–441. doi: 10.1046/j.1471-4159.2001.00046.x
[57]
Mandelkow EM, Mandelkow E (2012) Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harbor perspectives in medicine 2: a006247. doi: 10.1101/cshperspect.a006247
[58]
Martinelli P, La Mattina V, Bernacchia A, Magnoni R, Cerri F, et al. (2009) Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration. Hum Mol Genet 18: 2001–2013. doi: 10.1093/hmg/ddp124
[59]
Tiveron MC, Hirsch MR, Brunet JF (1996) The expression pattern of the transcription factor Phox2 delineates synaptic pathways of the autonomic nervous system. The Journal of neuroscience: the official journal of the Society for Neuroscience 16: 7649–7660.
