Abstract
Mitochondrial dysfunction plays a relevant role in the pathogenesis of neurological and neuromuscular diseases. Mitochondria may be involved as a primary defect of either the mtDNA or nuclear genome encoded subunits of the respiratory chain. These organelles have also been directly involved in the pathogenesis of Mendelian neurodegenerative disorders caused by mutations in nuclear-encoded proteins targeted to mitochondria, such as Friedreich ataxia, hereditary spastic paraplegia, or some monogenic forms of Parkinson disease. In addition, mitochondria also participate in the pathogenic mechanisms affecting neurodegenerative disorders such Huntington disease or amyotrophic lateral sclerosis. Cell death in neurodegeneration associated with neurological diseases usually occurs by apoptosis being the most common route the intrinsic mitochondria pathway. Along with regulation of apoptosis, mitochondria also modulate cell pathogenesis by means of energy production, reactive oxygen species (ROS) generation, and calcium buffering. Mitochondria form dynamic tubular networks that continually change their shape and move throughout the cell. Here we review the critical role of mitochondria in monogenic neuromuscular disorders, especially inherited peripheral neuropathies caused by abnormal mitochondrial network dynamics. In yeast, at least three proteins are required for mitochondrial fusion, Fzo1, Ugo1 and Mgm1. The human counterparts of Fzo1p and Mgm1p, MFN1/MFN2 and OPA1 respectively, are related to human disease. Mutations in the MFN2 gene cause the most frequent form of autosomal dominant axonal Charcot-Marie-Tooth disease, CMT2A. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA). For the opposite process of mitochondrial fission, four proteins are at least involved in yeast. Very recently a mutation in the DRP1 gene (the human homologue of yeast Dnm1) has been reported in an infant with a syndrome with encephalopathy, optic atrophy and lactic acidosis. GDAP1 has been recently related to the mitochondrial fission in mammalian cells and, interestingly, mutations in the GDAP1 gene are the cause of the most common form of autosomal recessive CMT, either axonal or demyelinating. These and other disorders are the most recent instances of disease related with mitochondrial abnormal motility, fusion and fission. We propose that the pathomechanisms underlying these disorders also include a complex relationship between mitochondrial dynamics and transport across the axon.
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Combarros O, Calleja J, Polo JM, et al. Prevalence of hereditary motor and sensory neuropathy in Cantabria. Acta Neurol Scand 1987;75(1):9–12.
Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet 1974;6(2):98–118.
DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci 2008;31:91–123.
Knott AB, Perkins G, Schwarzenbacher R, et al. Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 2008;9(7):505–518.
Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006;443(7113):787–795.
Deng H, Dodson MW, Huang H, et al. The Parkinson’s disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci U S A 2008;105(38):14503–14508.
Yang Y, Ouyang Y, Yang L, et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci U S A 2008;105(19):7070–7075.
Cerveny KL, Tamura Y, Zhang Z, et al. Regulation of mitochondrial fusion and division. Trends Cell Biol 2007;17(11):563–569.
Chan DC. Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 2006;22:79–99.
Detmer SA, Chan DC. Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 2007;8(11):870–879.
Lawson VH, Graham BV, Flanigan KM. Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 2005;65(2):197–204.
Zuchner S, Mersiyanova IV, Muglia M, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 2004;36(5):449–451.
Alexander C, Votruba M, Pesch UE, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 2000;26(2):211–115.
Delettre C, Lenaers G, Griffoin JM, et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 2000;26(2):207–210.
Chen H, Detmer SA, Ewald AJ, et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 2003;160(2):189–200.
Koshiba T, Detmer SA, Kaiser JT, et al. Structural basis of mitochondrial tethering by mitofusin complexes. Science 2004;305(5685):858–862.
de Brito OM, Scorrano L. Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion. Antioxid Redox Signal 2008;10(3):621–633.
de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 2008;456(7222):605–610.
Olichon A, Emorine LJ, Descoins E, et al. The human dynamin-related protein OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space. FEBS Lett 2002;523(1–3):171–176.
Cipolat S, Martins de Brito O, Dal Zilio B, et al. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A 2004;101(45):15927–15932.
Sesaki H, Jensen RE. Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J Cell Biol 1999;147(4):699–706.
Smirnova E, Griparic L, Shurland DL, et al. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 2001;12(8):2245–2256.
Koch A, Thiemann M, Grabenbauer M, et al. Dynamin-like protein 1 is involved in peroxisomal fission. J Biol Chem 2003;278(10):8597–8605.
Koch A, Yoon Y, Bonekamp NA, et al. A role for Fis1 in both mitochondrial and peroxisomal fission in mammalian cells. Mol Biol Cell 2005;16(11):5077–5086.
Waterham HR, Koster J, van Roermund CW, et al. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 2007;356(17):1736–1741.
Niemann A, Ruegg M, La Padula V, et al. Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J Cell Biol 2005;170(7):1067–1078.
Pedrola L, Espert A, Wu X, et al. GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. Hum Mol Genet 2005;14(8):1087–1094.
Baxter RV, Ben Othmane K, Rochelle JM, et al. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 2002;30(1):21–22.
Cuesta A, Pedrola L, Sevilla T, et al. The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 2002; 30(1):22–25.
Zhao C, Takita J, Tanaka Y, et al. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 2001;105(5):587–597.
Zuchner S, De Jonghe P, Jordanova A, et al. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 2006;59(2):276–281.
Chung KW, Kim SB, Park KD, et al. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 2006;129(Pt 8):2103–2118.
Pich S, Bach D, Briones P, et al. The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet 2005;14(11):1405–1415.
Baloh RH, Schmidt RE, Pestronk A, et al. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci 2007;27(2):422–430.
Sevilla T, Cuesta A, Chumillas MJ, et al. Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene. Brain 2003;126(Pt 9):2023–2033.
Nelis E, Erdem S, Van Den Bergh PY, et al. Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. Neurology 2002;59(12):1865–1872.
Ammar N, Nelis E, Merlini L, et al. Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease. Neuromuscul Disord 2003;13(9):720–728.
Boerkoel CF, Takashima H, Nakagawa M, et al. CMT4A: identification of a Hispanic GDAP1 founder mutation. Ann Neurol 2003;53(3):400–405.
Sevilla T, Jaijo T, Nauffal D, et al. Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy. Brain 2008;131(11):3051–3061.
De Sandre-Giovannoli A, Chaouch M, Boccaccio I, et al. Phenotypic and genetic exploration of severe demyelinating and secondary axonal neuropathies resulting from GDAP1 nonsense and splicing mutations. J Med Genet 2003;40(7):e87.
Senderek J, Bergmann C, Ramaekers VT, et al. Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain 2003;126(Pt 3):642–649.
Pedrola L, Espert A, Valdes-Sanchez T, et al. Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease. J Cell Mol Med 2008;12(2):679–689.
Claramunt R, Pedrola L, Sevilla T, et al. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet 2005;42(4):358–365.
Chung KW, Kim SM, Sunwoo IN, Cho SY, Hwang SJ, Kim J, Kang SH, Park KD, Choi KG, Choi IS, Choi BO. A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease. J Hum Genet 2008;53(4):360–364.
Di Maria E, Gulli R, Balestra P, et al. A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect. J Neurol Neurosurg Psychiatry 2004;75(10):1495–1498.
Tatsuta T, Langer T. Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J 2008;27(2):306–314.
Baloh RH. Mitochondrial dynamics and peripheral neuropathy. Neuroscientist 2008;14(1):12–18.
Acknowledgements
This work is supported by the Spanish Ministry of Science and Innovation and the Fondo de Investigación Sanitaria. The CIBER de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III.
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Palau, F., Estela, A., Pla-Martín, D., Sánchez-Piris, M. (2009). The Role of Mitochondrial Network Dynamics in the Pathogenesis of Charcot-Marie-Tooth Disease. In: Espinós, C., Felipo, V., Palau, F. (eds) Inherited Neuromuscular Diseases. Advances in Experimental Medicine and Biology, vol 652. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2813-6_9
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DOI: https://doi.org/10.1007/978-90-481-2813-6_9
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