Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1) and 2 (MFN2), located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1), in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion. 1. Introduction Mitochondrial fusion and fission are fundamental processes underlying cellular dynamics [1]. They are closely related, and therefore any alterations in their equilibrium may lead to disease. How the impairment of these pathways leads to neurological dysfunction and neurodegeneration is still largely debated. Fusion allows the exchange of contents, DNA, and metabolites between neighboring mitochondria, including damaged or senescent mitochondria, promoting their survival [2, 3]. Fission is necessary for proper mitochondrial transport, which depends on the specific energy demands of subcellular regions. Fission also regulates apoptosis through segregation of the most critically injured mitochondria [1, 4]. Dynamin-related protein 1 (DRP1), a cytosolic dynamin-related GTPase, plays a central role in fission by promoting mitochondrial division through its oligomerization into multimeric spiral structures [5]. To trigger mitochondrial fission, DRP1 must be recruited to the mitochondrial outer membrane, where several molecules of unknown functions colocalize; among them, mitochondrial fission 1 and mitochondrial fission factor have been proposed to be
References
[1]
R. J. Youle and A. M. van der Bliek, “Mitochondrial fission, fusion, and stress,” Science, vol. 337, no. 6098, pp. 1062–1065, 2012.
[2]
M. Yoneda, T. Miyatake, and G. Attardi, “Complementation of mutant and wild-type human mitochondrial DNAs coexisting since the mutation event and lack of complementation of DNAs introduced separately into a cell within distinct organelles,” Molecular and Cellular Biology, vol. 14, no. 4, pp. 2699–2712, 1994.
[3]
K. Nakada, K. Inoue, T. Ono et al., “Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA,” Nature Medicine, vol. 7, no. 8, pp. 934–940, 2001.
[4]
M. Milone and E. E. Benarroch, “Mitochondrial dynamics: general concepts and clinical implications,” Neurology, vol. 78, no. 20, pp. 1612–1619, 2012.
[5]
E. Smirnova, L. Griparic, D. L. Shurland, and A. M. Van der Bliek, “Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells,” Molecular Biology of the Cell, vol. 12, no. 8, pp. 2245–2256, 2001.
[6]
H. Otera, C. Wang, M. M. Cleland et al., “Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells,” Journal of Cell Biology, vol. 191, no. 6, pp. 1141–1158, 2010.
[7]
C. S. Palmer, L. D. Osellame, D. Laine, O. S. Koutsopoulos, A. E. Frazier, and M. T. Ryan, “MiD49 and MiD51, new components of the mitochondrial fission machinery,” EMBO Reports, vol. 12, no. 6, pp. 565–573, 2011.
[8]
O. M. De Brito and L. Scorrano, “Mitofusin 2 tethers endoplasmic reticulum to mitochondria,” Nature, vol. 456, no. 7222, pp. 605–610, 2008.
[9]
M. Darshi, V. L. Mendiola, M. R. Mackey et al., “ChChd3, an inner mitochondrial membrane protein, is essential for maintaining Crista integrity and mitochondrial function,” Journal of Biological Chemistry, vol. 286, no. 4, pp. 2918–2932, 2011.
[10]
S. Cipolat, D. B. Martins, B. Dal Zilio, and L. Scorrano, “OPA1 requires mitofusin 1 to promote mitochondrial fusion,” ,Proceedings of the National Academy of Sciences of the United States of America, vol. 101, pp. 15927–15932, 2004.
[11]
L. Griparic, N. N. Van Der Wel, I. J. Orozco, P. J. Peters, and A. M. Van Der Bliek, “Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria,” Journal of Biological Chemistry, vol. 279, no. 18, pp. 18792–18798, 2004.
[12]
N. Ishihara, Y. Fujita, T. Oka, and K. Mihara, “Regulation of mitochondrial morphology through proteolytic cleavage of OPA1,” EMBO Journal, vol. 25, no. 13, pp. 2966–2977, 2006.
[13]
A. Olichon, L. Baricault, N. Gas et al., “Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis,” Journal of Biological Chemistry, vol. 278, no. 10, pp. 7743–7746, 2003.
[14]
Z. Song, M. Ghochani, J. M. McCaffery, T. G. Frey, and D. C. Chan, “Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion,” Molecular Biology of the Cell, vol. 20, no. 15, pp. 3525–3532, 2009.
[15]
C. S. Palmer, L. D. Osellame, D. Stojanovski, and M. T. Ryan, “The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery,” Cellular Signalling, vol. 23, no. 10, pp. 1534–1545, 2011.
[16]
P. Amati-Bonneau, M. L. Valentino, P. Reynier et al., “OPA1 mutations induce mitochondrial DNA instability and optic atrophy “plus” phenotypes,” Brain, vol. 131, no. 2, pp. 338–351, 2008.
[17]
G. Hudson, P. Amati-Bonneau, E. L. Blakely et al., “Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance,” Brain, vol. 131, no. 2, pp. 329–337, 2008.
[18]
C. Rouzier, S. Bannwarth, A. Chaussenot, et al., “The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy “plus” phenotype,” Brain, vol. 135, no. 1, pp. 23–34, 2012.
[19]
H. Chen, M. Vermulst, Y. E. Wang et al., “Mitochondrial fusion is required for mtdna stability in skeletal muscle and tolerance of mtDNA mutations,” Cell, vol. 141, no. 2, pp. 280–289, 2010.
[20]
A. Hori, M. Yoshida, and F. Ling, “Mitochondrial fusion increases the mitochondrial DNA copy number in budding yeast,” Genes to Cells, vol. 16, no. 5, pp. 527–544, 2011.
[21]
D. Bach, S. Pich, F. X. Soriano, et al., “Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity,” Journal of Biological Chemistry, vol. 278, pp. 17190–17197, 2003.
[22]
K. H. Chen, X. Guo, D. Ma, et al., “Dysregulation of HSG triggers vascular proliferative disorders,” Nature Cell Biology, vol. 6, pp. 872–883, 2006.
[23]
A. Zorzano, M. Liesa, D. . Sebastián, et al., “Mitochondrial fusion proteins: dual regulators of morphology and metabolism,” Seminars in Cell & Developmental Biology, vol. 21, no. 6, pp. 566–574, 2010.
[24]
K. N. Papanicolaou, R. J. Khairallah, G. A. Ngoh et al., “Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes,” Molecular and Cellular Biology, vol. 31, no. 6, pp. 1309–1328, 2011.
[25]
Y. Chen, Y. Liu, and G. W. Dorn II, “Mitochondrial fusion is essential for organelle function and cardiac homeostasis,” Circulation Research, vol. 109, pp. 1327–1331, 2011.
[26]
L. Chen, T. Liu, A. Tran, et al., “OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability,” Journal of the American Heart Association, vol. 1, no. 5, Article ID e003012, 2012.
[27]
P. Reynier, P. Amati-Bonneau, C. Verny et al., “OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract,” Journal of Medical Genetics, vol. 41, no. 9, p. e110, 2004.
[28]
Y. Anikster, R. Kleta, A. Shaag, W. A. Gahl, and O. Elpeleg, “Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews,” American Journal of Human Genetics, vol. 69, no. 6, pp. 1218–1224, 2001.
[29]
M. Huizing, H. Dorward, L. Ly et al., “OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria,” Molecular Genetics and Metabolism, vol. 100, no. 2, pp. 149–154, 2010.
[30]
D. Y. Thomas and D. Wilkie, “Recombination of mitochondrial drug-resistance factors in Saccharomyces, cerevisiae,” Biochemical and Biophysical Research Communications, vol. 30, no. 4, pp. 368–372, 1968.
[31]
J. Nunnari, W. F. Marshall, A. Straight, A. Murray, J. W. Sedat, and P. Walter, “Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA,” Molecular Biology of the Cell, vol. 8, no. 7, pp. 1233–1242, 1997.
[32]
J. Bereiter-Hahn and M. Voth, “Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria,” Microscopy Research and Technique, vol. 27, no. 3, pp. 198–219, 1994.
[33]
J. D. Cortese, L. A. Voglino, and C. R. Hackenbrock, “Novel fluorescence membrane fusion assays reveal GTP-dependent fusogenic properties of outer mitochondrial membrane-derived proteins,” Biochimica et Biophysica Acta, vol. 1371, no. 2, pp. 185–198, 1998.
[34]
K. G. Hales and M. T. Fuller, “Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase,” Cell, vol. 90, no. 1, pp. 121–129, 1997.
[35]
M. P. Yaffe, “The machinery of mitochondrial inheritance and behavior,” Science, vol. 283, pp. 1493–1497, 1999.
[36]
W. Bleazard, J. M. McCaffery, E. J. King et al., “The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast,” Nature Cell Biology, vol. 1, no. 5, pp. 298–304, 1999.
[37]
A. M. Labrousse, M. D. Zappaterra, D. A. Rube, and A. M. Van der Bliek, “C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane,” Molecular Cell, vol. 4, no. 5, pp. 815–826, 1999.
[38]
H. W. Shin, C. Shinotsuka, S. Torii, K. Murakami, and K. Nakayama, “Identification and subcellular localization of a novel mammalian dynamin-related protein homologous to yeast Vps1p and Dnm1p,” Journal of Biochemistry, vol. 122, no. 3, pp. 525–530, 1997.
[39]
M. Imoto, I. Tachibana, and R. Urrutia, “Identification and functional characterization of a novel human protein highly related to the yeast dynamin-like GTPase Vps1p,” Journal of Cell Science, vol. 111, no. 10, pp. 1341–1349, 1998.
[40]
S. Meeusen, J. M. McCaffery, and J. Nunnari, “Mitochondrial fusion intermediates revealed in vitro,” Science, vol. 305, no. 5691, pp. 1747–1752, 2004.
[41]
S. L. Meeusen and J. Nunnari, “Mitochondrial fusion in vitro,” Methods in Molecular Biology, vol. 372, pp. 461–466, 2007.
[42]
S. Züchner, I. V. Mersiyanova, M. Muglia, et al., “Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A,” Nature Genetics, vol. 36, no. 5, pp. 449–451, 2004.
[43]
D. Zhu, M. L. Kennerson, G. Walizada, S. Züchner, J. M. Vance, and G. A. Nicholson, “Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations,” Neurology, vol. 65, no. 3, pp. 496–497, 2005.
[44]
S. Züchner, P. De Jonghe, A. Jordanova, et al., “Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2,” Annals of Neurology, vol. 59, no. 2, pp. 276–281, 2006.
[45]
C. Verny, D. Loiseau, C. Scherer et al., “Multiple sclerosis-like disorder in OPA1-related autosomal dominant optic atrophy,” Neurology, vol. 70, no. 13, part 2, pp. 1152–1153, 2008.
[46]
P. Yu-Wai-Man, P. G. Griffiths, G. S. Gorman, et al., “Multi-system neurological disease is common in patients with OPA1 mutations,” Brain, vol. 133, part 3, pp. 771–786, 2010.
[47]
S. Vielhaber, G. Debska-Vielhaber, V. Peeva, et al., “Mitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion,” Acta Neuropathologica, vol. 125, no. 2, pp. 245–256, 2013.
[48]
S. Lee, F. H. Sterky, A. Mourier, et al., “Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons,” Human Molecular Genetics, vol. 21, no. 22, pp. 4827–4835, 2012.
[49]
N. Ishihara, H. Otera, T. Oka, and K. Mihara, “Regulation and physiologic functions of GTPases in mitochondrial fusion and fission in mammals,” Antioxidants & Redox Signaling. In press.
[50]
F. Anton, J. M. Fres, A. Schauss et al., “Ugo1 and Mdm30 act sequentially during Fzo1-mediated mitochondrial outer membrane fusion,” Journal of Cell Science, vol. 124, no. 7, pp. 1126–1135, 2011.
[51]
M. M. Cohen, E. A. Amiott, A. R. Day et al., “Sequential requirements for the GTPase domain of the mitofusin Fzo1 and the ubiquitin ligase SCFMdm30 in mitochondrial outer membrane fusion,” Journal of Cell Science, vol. 124, no. 9, pp. 1403–1410, 2011.
[52]
A. Tanaka, M. M. Cleland, S. Xu et al., “Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin,” Journal of Cell Biology, vol. 191, no. 7, pp. 1367–1380, 2010.
[53]
T. Koshiba, S. A. Detmer, J. T. Kaiser, H. Chen, J. M. McCaffery, and D. C. Chan, “Structural basis of mitochondrial tethering by mitofusin complexes,” Science, vol. 305, no. 5685, pp. 858–862, 2004.
[54]
P. Huang, C. A. Galloway, and Y. Yoon, “Control of mitochondrial morphology through differential interactions of mitochondrial fusion and fission proteins,” PLoS ONE, vol. 6, no. 5, Article ID e20655, 2011.
[55]
S. Duvezin-Caubet, M. Koppen, J. Wagener et al., “OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria,” Molecular Biology of the Cell, vol. 18, no. 9, pp. 3582–3590, 2007.
[56]
L. Pellegrini, B. J. Passer, M. Canelles et al., “PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2,” Journal of Alzheimer's Disease, vol. 3, no. 2, pp. 181–190, 2001.
[57]
Z. Song, H. Chen, M. Fiket, C. Alexander, and D. C. Chan, “OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L,” Journal of Cell Biology, vol. 178, no. 5, pp. 749–755, 2007.
[58]
R. Kar, N. Mishra, P. K. Singha, M. A. Venkatachalam, and P. Saikumar, “Mitochondrial remodeling following fission inhibition by 15d-PGJ2 involves molecular changes in mitochondrial fusion protein OPA1,” Biochemical and Biophysical Research Communications, vol. 399, no. 4, pp. 548–554, 2010.
[59]
A. Makino, J. Suarez, T. Gawlowski et al., “Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes,” American Journal of Physiology, vol. 300, no. 6, pp. 1296–1302, 2011.
[60]
N. Ishihara, A. Jofuku, Y. Eura, and K. Mihara, “Regulation of mitochondrial morphology by membrane potential, and DRP1-dependent division and FZO1-dependent fusion reaction in mammalian cells,” Biochemical and Biophysical Research Communications, vol. 301, no. 4, pp. 891–898, 2003.
[61]
F. Legros, A. Lombès, P. Frachon, and M. Rojo, “Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins,” Molecular Biology of the Cell, vol. 13, no. 12, pp. 4343–4354, 2002.
[62]
S. W. Ryu, H. J. Jeong, M. Choi, M. Karbowski, and C. Choi, “Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation,” Cellular and Molecular Life Sciences, vol. 67, no. 16, pp. 2839–2850, 2010.
[63]
J. M. Vance, “The many faces of Charcot-Marie-Tooth disease,” Archives of Neurology, vol. 57, no. 5, pp. 638–640, 2000.
[64]
A. E. Harding and P. K. Thomas, “The clinical features of hereditary motor and sensory neuropathy types I and II,” Brain, vol. 103, no. 2, pp. 259–280, 1980.
[65]
J. M. Polke, M. Laurá, D. Pareyson, et al., “Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations,” Neurology, vol. 77, no. 2, pp. 168–173, 2011.
[66]
K. Kijima, C. Numakura, H. Izumino et al., “Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A,” Human Genetics, vol. 116, no. 1-2, pp. 23–27, 2005.
[67]
K. W. Chung, S. B. Kim, K. D. Park et al., “Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations,” Brain, vol. 129, no. 8, pp. 2103–2118, 2006.
[68]
K. Verhoeven, K. G. Claeys, S. Züchner, et al., “MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2,” Brain, vol. 129, no. 8, pp. 2093–2102, 2006.
[69]
J. Calvo, B. Funalot, R. A. Ouvrier et al., “Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations,” Archives of Neurology, vol. 66, no. 12, pp. 1511–1516, 2009.
[70]
E. A. Amiott, P. Lott, J. Soto et al., “Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations,” Experimental Neurology, vol. 211, no. 1, pp. 115–127, 2008.
[71]
S. A. Detmer and D. C. Chan, “Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations,” Journal of Cell Biology, vol. 176, no. 4, pp. 405–414, 2007.
[72]
P. J. Dyck, P. Chance, R. Lebo, and J. A. Carney, “Hereditary motor and sensory neuropathy,” in Peripheral Neuropathy, P. J. Dyck and P. K. Thomas, Eds., vol. 2, pp. 1094–1136, WB Sauders, Philadelphia, Pa, USA, 3rd edition, 1993.
[73]
R. M. Chalmers, A. C. Bird, and A. E. Harding, “Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy,” Journal of Neurology Neurosurgery and Psychiatry, vol. 60, no. 2, pp. 195–196, 1996.
[74]
K. Huoponen, “Leber hereditary optic neuropathy: clinical and molecular genetic findings,” Neurogenetics, vol. 3, no. 3, pp. 119–125, 2001.
[75]
C. Alexander, M. Votruba, U. E. A. Pesch et al., “OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28,” Nature Genetics, vol. 26, no. 2, pp. 211–215, 2000.
[76]
I. Voo, B. E. Allf, N. Udar, R. Silva-Garcia, J. Vance, and K. W. Small, “Hereditary motor and sensory neuropathy type VI with optic atrophy,” American Journal of Ophthalmology, vol. 136, no. 4, pp. 670–677, 2003.
[77]
P. Kjer, “Infantile optic atrophy with dominant mode of inheritance: a clinical and genetic study of 19 Danish families,” Acta Ophthalmologica, vol. 164, supplement 54, pp. 1–147, 1959.
[78]
M. Ferré, P. Amati-Bonneau, Y. Tourmen, Y. Malthièry, and P. Reynier, “eOPA1: an online database for OPA1 mutations,” Human Mutation, vol. 25, no. 5, pp. 423–428, 2005.
[79]
R. Garcin, P. Raverdy, S. Delthil, et al., “On a heredo-familial disease combining cataract, optic atrophy, extrapyramidal symptoms and certain defects of Friedreich's disease. (Its nosological position in relation to the Behr's syndrome, the Marinesco-Sjogren syndrome and Friedreich's disease with ocular symptoms,” Revue Neurologique, vol. 104, pp. 373–379, 1961.
[80]
A. Nystuen, H. Costeff, O. N. Elpeleg et al., “Iraqi-Jewish kindreds with optic atrophy plus (3-methylglutaconic aciduria type 3) demonstrate linkage disequilibrium with the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene,” Human Molecular Genetics, vol. 6, no. 4, pp. 563–569, 1997.
[81]
R. Kleta, F. Skovby, E. Christensen, T. Rosenberg, W. A. Gahl, and Y. Anikster, “3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings,” Molecular Genetics and Metabolism, vol. 76, no. 3, pp. 201–206, 2002.
[82]
G. Hudson and P. F. Chinnery, “Mitochondrial DNA polymerase-γ and human disease,” Human Molecular Genetics, vol. 15, no. 2, pp. R244–R252, 2006.
[83]
C. Kornblum, T. J. Nicholls, T. B. Haack, et al., “Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease,” Nature Genetics, vol. 45, no. 2, pp. 214–219, 2013.
[84]
D. Ronchi, A. Di Fonzo, W. Lin, et al., “Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability,” American Journal of Human Genetics, vol. 92, no. 2, pp. 293–300, 2013.
[85]
D. Ronchi, C. Garone, A. Bordoni, et al., “Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions,” Brain, vol. 135, pp. 3404–3415, 2012.
[86]
H. Tyynismaa, R. Sun, S. Ahola-Erkkil？, et al., “Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions,” Human Molecular Genetics, vol. 21, no. 1, pp. 66–75, 2012.
[87]
H. Tyynismaa, E. Ylikallio, M. Patel, M. J. Molnar, R. G. Haller, and A. Suomalainen, “A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions,” American Journal of Human Genetics, vol. 85, no. 2, pp. 290–295, 2009.
[88]
P. Amati-Bonneau, D. Milea, D. Bonneau, et al., “OPA1-associated disorders: phenotypes and pathophysiology,” International Journal of Biochemistry & Cell Biology, vol. 41, no. 10, pp. 1855–1865, 2009.
[89]
R. Lodi, C. Tonon, M. L. Valentino et al., “Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations,” Archives of Neurology, vol. 68, no. 1, pp. 67–73, 2011.
[90]
P. Yu-Wai-Man, M. I. Trenell, K. G. Hollingsworth, P. G. Griffiths, and P. F. Chinnery, “OPA1 mutations impair mitochondrial function in both pure and complicated dominant optic atrophy,” Brain, vol. 134, no. 4, p. e164, 2011.
[91]
K. S. Sitarz, P. Yu-Wai-Man, A. Pyle, et al., “MFN2 mutations cause compensatory mitochondrial DNA proliferation,” Brain, vol. 135, part 8, article e219, pp. 1–3, 2012.
[92]
E. Ricci, C. T. Moraes, S. Servidei, P. Tonali, E. Bonilla, and S. DiMauro, “Disorders associated with depletion of mitochondrial DNA,” Brain Pathology, vol. 2, no. 2, pp. 141–147, 1992.
[93]
D. Santos and S. M. Cardoso, “Mitochondrial dynamics and neuronal fate in Parkinson's disease,” Mitochondrion, vol. 12, no. 4, pp. 428–437, 2012.
[94]
D. H. Cho, T. Nakamura, and S. A. Lipton, “Mitochondrial dynamics in cell death and neurodegeneration,” Cellular and Molecular Life Sciences, vol. 67, no. 20, pp. 3435–3447, 2010.
[95]
J. Kim, J. P. Moody, C. K. Edgerly et al., “Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease,” Human Molecular Genetics, vol. 19, no. 20, Article ID ddq306, pp. 3919–3935, 2010.
[96]
P. H. Reddy and U. P. Shirendeb, “Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease,” Biochimica et Biophysica Acta, vol. 1822, no. 2, pp. 101–110, 2012.
[97]
N. G. Larsson, “Somatic mitochondrial DNA mutations in mammalian aging,” Annual Review of Biochemistry, vol. 79, pp. 683–706, 2010.
[98]
D. C. Wallace, “Mitochondrial DNA mutations in disease and aging,” Environmental and Molecular Mutagenesis, vol. 51, no. 5, pp. 440–450, 2010.
[99]
X. Wang, B. Su, H. G. Lee et al., “Impaired balance of mitochondrial fission and fusion in Alzheimer's disease,” Journal of Neuroscience, vol. 29, no. 28, pp. 9090–9103, 2009.
[100]
M. Manczak and P. H. Reddy, “Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage,” Human Molecular Genetics, vol. 21, no. 11, pp. 2538–2547, 2012.
[101]
M. Manczak, M. J. Calkins, and P. H. Reddy, “Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage,” Human Molecular Genetics, vol. 20, no. 13, Article ID ddr139, pp. 2495–2509, 2011.
[102]
R. J. Youle and D. P. Narendra, “Mechanisms of mitophagy,” Nature Reviews Molecular Cell Biology, vol. 12, no. 1, pp. 9–14, 2011.
[103]
T. Kitada, S. Asakawa, N. Hattori et al., “Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism,” Nature, vol. 392, no. 6676, pp. 605–608, 1998.
[104]
M. E. Gegg, J. M. Cooper, K. Y. Chau, M. Rojo, A. H. V. Schapira, and J. W. Taanman, “Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy,” Human Molecular Genetics, vol. 19, no. 24, pp. 4861–4870, 2010.
[105]
A. L. Misko, Y. Sasaki, E. Tuck, et al., “Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration,” Journal of Neuroscience, vol. 32, no. 12, pp. 4145–4155, 2012.
[106]
A. H. Pham, S. Meng, Q. N. Chu, and D. C. Chan, “Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit,” Human Molecular Genetics, vol. 21, no. 22, pp. 4817–4826, 2012.
[107]
H. Manev, M. Favaron, A. Guidotti, and E. Costa, “Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death,” Molecular Pharmacology, vol. 36, no. 1, pp. 106–112, 1989.
[108]
R. D. Randall and S. A. Thayer, “Glutamate-induced calcium transient triggers delayed calcium overload and neurotoxicity in rat hippocampal neurons,” Journal of Neuroscience, vol. 12, no. 5, pp. 1882–1895, 1992.
[109]
S. L. Budd and D. G. Nicholls, “Mitochondria, calcium regulation, and acute glutamate excitotoxicity in cultured cerebellar granule cells,” Journal of Neurochemistry, vol. 676, pp. 2282–2291, 1996.
[110]
Y. E. Kushnareva, A. A. Gerencser, B. Bossy, et al., “Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity,” Cell Death & Differentiation, vol. 20, no. 2, pp. 353–365, 2013.
[111]
A. Jahani-Asl, K. Pilon-Larose, W. Xu et al., “The mitochondrial inner membrane GTPase, optic atrophy 1 (Opa1), restores mitochondrial morphology and promotes neuronal survival following excitotoxicity,” Journal of Biological Chemistry, vol. 286, no. 6, pp. 4772–4782, 2011.
[112]
D. Nguyen, M. V. Alavi, K. Y. Kim T, et al., “A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics,” Cell Death and Disease, vol. 2, p. e240, 2011.
