Skip to main content
SpringerLink
Log in

Defects in Mitochondrial Dynamics and Mitochondrial DNA Instability

  • Chapter
  • First Online:
Mitochondrial Disorders Caused by Nuclear Genes

  • 1239 Accesses

Abstract

Mitochondria form a highly interconnected, dynamic, tubular network throughout the cell, with mitochondrial segments budding and fusing continuously in a process partly dictated by local physiological needs. Over the past two decades, key proteins have been identified that regulate the delicate balance between mitochondrial fusion and fission. The main pro-fusion proteins are OPA1, MFN1, and MFN2; and the main pro-fission proteins are DRP1, hFIS1, OPA3, and GDAP1. An important structural similarity shared by a number of these mitochondrial membrane-associated proteins is a highly conserved dynamin-related GTPase domain that is essential for their normal function. Clinically, a number of neurodegenerative phenotypes have been linked to mutations in these nuclear genes. Interestingly, mitochondrial fusion–fission imbalances in OPA1 and MFN2 disorders have also been associated with the accumulation of high levels of somatic mitochondrial DNA (mtDNA) deletions. This recently uncovered link between mitochondrial network disruption and mtDNA instability is mechanistically intriguing, clearly pointing towards shared disease mechanisms in the pathophysiology of these primary mitochondrial dynamic disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

DRP1:

Dynamin-related protein 1

GDAP1:

Ganglioside-induced differentiation-associated protein 1

hFIS1:

Fission 1 homolog

MFN1:

Mitofusin 1

MFN2:

Mitofusin 2

OPA1:

Optic atrophy 1

OPA3:

Optic atrophy 3

References

  1. Holt IJ, Harding AE, Morganhughes JA (1988) Deletions of muscle mitochondrial-DNA in patients with mitochondrial myopathies. Nature 331:717–719

    Article  PubMed  CAS  Google Scholar 

  2. Wallace DC, Singh G, Lott MT et al (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242:1427–1430

    Article  PubMed  CAS  Google Scholar 

  3. DiMauro S, Schon EA (2003) Mechanisms of disease: mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668

    Article  PubMed  CAS  Google Scholar 

  4. Taylor RW, Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6:389–402

    Article  PubMed  CAS  Google Scholar 

  5. McFarland R, Taylor RW, Turnbull DM (2010) A neurological perspective on mitochondrial disease. Lancet Neurol 9:829–840

    Article  PubMed  CAS  Google Scholar 

  6. Van Goethem G, Dermaut B, Lofgren A, Martin JJ, Van Broeckhoven C (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28:211–212

    Article  PubMed  CAS  Google Scholar 

  7. Spelbrink JN, Li FY, Tiranti V et al (2001) Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene LF-like protein localized in mitochondria. Nat Genet 28:223–231

    Article  PubMed  CAS  Google Scholar 

  8. Chinnery PF, Zeviani M (2008) 155th ENMC workshop: polymerase gamma and disorders of mitochondrial DNA synthesis, 21–23 September 2007, Naarden, The Netherlands. Neuromuscul Disord 18:259–267

    Article  PubMed  Google Scholar 

  9. Krishnan KJ, Reeve AK, Samuels DC et al (2008) What causes mitochondrial DNA deletions in human cells? Nat Genet 40:275–279

    Article  PubMed  CAS  Google Scholar 

  10. Khrapko K (2011) The timing of mitochondrial DNA mutations in aging. Nat Genet 43:726–727

    Article  PubMed  CAS  Google Scholar 

  11. Bristow EA, Griffiths PG, Andrews RM, Johnson MA, Turnbull DM (2002) The distribution of mitochondrial activity in relation to optic nerve structure. Arch Ophthalmol 120:791–796

    Article  PubMed  Google Scholar 

  12. Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872–884

    Article  PubMed  CAS  Google Scholar 

  13. Barron MJ, Griffiths P, Turnbull DM, Bates D, Nichols P (2004) The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head. Br J Ophthalmol 88:286–290

    Article  PubMed  CAS  Google Scholar 

  14. Chan DC (2006) Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 22:79–99

    Article  PubMed  CAS  Google Scholar 

  15. Campello S, Scorrano L (2010) Mitochondrial shape changes: orchestrating cell pathophysiology. EMBO Rep 11:678–684

    Article  PubMed  CAS  Google Scholar 

  16. Praefcke GJK, McMahon HT (2004) The dynamin superfamily: universal membrane tubulation and fission molecules? Nat Rev Mol Cell Biol 5:133–147

    Article  PubMed  CAS  Google Scholar 

  17. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505–518

    Article  PubMed  CAS  Google Scholar 

  18. Chen H, Chan DC (2009) Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases. Hum Mol Genet 18:R169–R176

    Article  PubMed  CAS  Google Scholar 

  19. Yu-Wai-Man P, Griffiths PG, Chinnery PF (2011) Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies. Prog Retin Eye Res 30(2):81–114

    Article  PubMed  CAS  Google Scholar 

  20. Huizing M, Brooks BP, Anikster Y (2005) Optic atrophies in metabolic disorders. Mol Genet Metab 86:51–60

    Article  PubMed  CAS  Google Scholar 

  21. Yu-Wai-Man P, Griffiths PG, Burke A et al (2010) The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmol 117:1538–1546

    Article  Google Scholar 

  22. Cohn AC, Toomes C, Potter C et al (2007) Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations. Amer J Ophthalmol 143:656–662

    Article  Google Scholar 

  23. Cohn AC, Toomes C, Hewitt AW et al (2008) The natural history of OPA1-related autosomal dominant optic atrophy. Br J Ophthalmol 24:24

    Google Scholar 

  24. Votruba M, Fitzke FW, Holder GE, Carter A, Bhattacharya SS, Moore AT (1998) Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy. Arch Ophthalmol 116:351–358

    PubMed  CAS  Google Scholar 

  25. Yu-Wai-Man P, Griffiths PG, Hudson G, Chinnery PF (2009) Inherited mitochondrial optic neuropathies. J Med Genet 46:145–158

    Article  PubMed  CAS  Google Scholar 

  26. La Morgia C, Ross-Cisneros FN, Sadun AA et al (2010) Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies. Brain 133:2426–2438

    Article  PubMed  Google Scholar 

  27. Davies V, Votruba M (2006) Focus on molecules: the OPA1 protein. Exp Eye Res 83:1003–1004

    Article  PubMed  CAS  Google Scholar 

  28. Olichon A, Elachouri G, Baricault L, Delettre C, Belenguer P, Lenaers G (2007) OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis. Cell Death Diff 14:682–692

    Article  CAS  Google Scholar 

  29. Akepati VR (2008) Characterization of OPA1 isoforms isolated from mouse tissues. J Neurochem 106:372–383

    Article  PubMed  CAS  Google Scholar 

  30. Lenaers G, Reynier P, Elachouri G et al (2009) OPA1 functions in mitochondria and dysfunctions in optic nerve. Int J Biochem Cell Biol 41:1866–1874

    Article  PubMed  CAS  Google Scholar 

  31. Alexander C, Votruba M, Pesch UEA 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

    Article  PubMed  CAS  Google Scholar 

  32. Delettre C, Lenaers G, Griffoin JM et al (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26:207–210

    Article  PubMed  CAS  Google Scholar 

  33. Ferre M, Amati-Bonneau P, Tourmen Y, Malthiery Y, Reynier P (2005) eOPA1: an online database for OPA1 mutations. Hum Mutat 25:423–428

    Article  PubMed  CAS  Google Scholar 

  34. Ferre M, Bonneau D, Milea D et al (2009) Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novel OPA1 mutations. Hum Mutat 30:E692–705

    Article  PubMed  Google Scholar 

  35. Fuhrmann N, Alavi MV, Bitoun P et al (2009) Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy. J Med Genet 46:136–144

    Article  PubMed  CAS  Google Scholar 

  36. Almind GJ, Gronskov K, Milea D, Larsen M, Brondum-Nielsen K, Ek J (2011) Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy. BMC Med Genet 12:49

    Article  PubMed  CAS  Google Scholar 

  37. Schimpf S, Fuhrmann N, Schaich S, Wissinger B (2008) Comprehensive cDNA study and quantitative transcript analysis of mutant OPA1 transcripts containing premature termination codons. Hum Mutat 29:106–112

    Article  PubMed  CAS  Google Scholar 

  38. Amati-Bonneau P, Odent S, Derrien C et al (2003) The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 gene. Am J Ophthalmol 136:1170–1171

    Article  PubMed  CAS  Google Scholar 

  39. Amati-Bonneau P, Guichet A, Olichon A et al (2005) OPA1 R445H mutation in optic atrophy associated with sensorineural deafness. Ann Neurol 58:958–963

    Article  PubMed  CAS  Google Scholar 

  40. Li CM, Kosmorsky G, Zhang K, Katz BJ, Ge J, Traboulsi EI (2005) Optic atrophy and sensorineural hearing loss in a family caused by an R445H OPA1 mutation. Am J Med Genet Part A 138A:208–211

    Article  PubMed  Google Scholar 

  41. Payne M, Yang ZL, Katz BJ et al (2004) Dominant optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia: a syndrome caused by a missense mutation in OPA1. Am J Ophthalmol 138:749–755

    Article  PubMed  CAS  Google Scholar 

  42. Hudson G, Amati-Bonneau P, Blakely EL et al (2008) Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain 131:329–337

    Article  PubMed  Google Scholar 

  43. Amati-Bonneau P, Valentino ML, Reynier P et al (2008) OPA1 mutations induce mitochondrial DNA instability and optic atrophy plus phenotypes. Brain 131:338–351

    Article  PubMed  Google Scholar 

  44. Spinazzi M, Cazzola S, Bortolozzi M et al (2008) A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function. Hum Mol Genet 17:3291–3302

    Article  PubMed  CAS  Google Scholar 

  45. Yu-Wai-Man P, Griffiths PG, Gorman GS et al (2010) Multi-system neurological disease is common in patients with OPA1 mutations. Brain 133:771–786

    Article  PubMed  CAS  Google Scholar 

  46. Marchbank NJ, Craig JE, Leek JP et al (2002) Deletion of the OPA1 gene in a dominant optic atrophy family: evidence that haploinsufficiency is the cause of disease. J Med Genet 39:e47

    Google Scholar 

  47. Aijaz S, Erskine L, Jeffery G, Bhattacharya SS, Votruba M (2004) Developmental expression profile of the optic atrophy gene product: OPA1 is not localized exclusively in the mammalian retinal ganglion cell layer. Invest Ophthalmol Visual Sci 45:1667–1673

    Article  Google Scholar 

  48. Bette S, Schlaszus H, Wissinger B, Meyermann R, Mittelbronn M (2005) OPA1, associated with autosomal dominant optic atrophy, is widely expressed in the human brain. Acta Neuropathol 109:393–399

    Article  PubMed  CAS  Google Scholar 

  49. Wang AG, Fann MJ, Yu HY, Yen MY (2006) OPA1 expression in the human retina and optic nerve. Exp Eye Res 83:1171–1178

    Article  PubMed  CAS  Google Scholar 

  50. Pellegrini L, Scorrano L (2007) A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis. Cell Death Diff 14:1275–1284

    Article  CAS  Google Scholar 

  51. Martinelli P, Rugarli EI (2010) Emerging roles of mitochondrial proteases in neurodegeneration. Biochim Biophys Acta 1797

    Google Scholar 

  52. Rugarli EI, Langer T (2006) Translating m-AAA protease function in mitochondria to hereditary spastic paraplegia. Trends Mol Med 12:262–269

    Article  PubMed  CAS  Google Scholar 

  53. Casari G, De Fusco M, Ciarmatori S et al (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93:973–983

    Article  PubMed  CAS  Google Scholar 

  54. Chevrollier A (2008) Hereditary optic neuropathies share a common mitochondrial coupling defect. Ann Neurol 63:794–798

    Article  PubMed  Google Scholar 

  55. Zanna C, Ghelli A, Porcelli AM et al (2008) OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain 131:352–367

    Article  PubMed  Google Scholar 

  56. Song ZY, 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

    Article  PubMed  CAS  Google Scholar 

  57. Cipolat S, Rudka T, Hartmann D et al (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126:163–175

    Article  PubMed  CAS  Google Scholar 

  58. Frezza C, Cipolat S, de Brito OM et al (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126:177–189

    Article  PubMed  CAS  Google Scholar 

  59. Suen DF, Norris KL, Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes Dev 22:1577–1590

    Article  PubMed  CAS  Google Scholar 

  60. Lodi R, Tonon C, Valentino ML et al (2004) Deficit of in vivo mitochondrial ATP production in OPA1-related dominant optic atrophy. Ann Neurol 56:719–723

    Article  PubMed  CAS  Google Scholar 

  61. Yu-Wai-Man P, Trenell MI, Hollingsworth KG, Griffiths PG, Chinnery PF (2011) OPA1 mutations impair mitochondrial function in both pure and complicated dominant optic atrophy. Brain 134:e164

    Google Scholar 

  62. Lodi R, Tonon C, Valentino ML et al (2011) Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations. Arch Neurol 68:67–73

    Article  PubMed  Google Scholar 

  63. Yu-Wai-Man P, Sitarz KS, Samuels DC et al (2010) OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules. Hum Mol Genet 19:3043–3052

    Article  PubMed  CAS  Google Scholar 

  64. Capps GJ, Samuels DC, Chinnery PF (2003) A model of the nuclear control of mitochondrial DNA replication. J Theor Biol 221:565–583

    Article  PubMed  CAS  Google Scholar 

  65. Chinnery PF, Samuels DC (1999) Relaxed replication of mtDNA: a model with implications for the expression of disease. Am J Hum Genet 64:1158–1165

    Article  PubMed  CAS  Google Scholar 

  66. Durham SE, Samuels DC, Cree LM, Chinnery PF (2007) Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A→G. Am J Hum Genet 81:189–195

    Article  PubMed  CAS  Google Scholar 

  67. Davies VJ, Hollins AJ, Piechota MJ et al (2007) Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum Mol Genet 16:1307–1318

    Article  PubMed  CAS  Google Scholar 

  68. Alavi MV, Bette S, Schimpf S et al (2007) A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain 130:1029–1042

    Article  PubMed  Google Scholar 

  69. Williams PA, Morgan JE, Votruba M (2011) Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell dendropathy. Brain 133:2942–2951

    Article  Google Scholar 

  70. Yu-Wai-Man P, Davies VJ, Piechota MJ, Cree LM, Votruba M, Chinnery PF (2009) Secondary mtDNA defects do not cause optic nerve dysfunction in a mouse model of dominant optic atrophy. Invest Ophthalmol Vis Sci 50:4561–4566

    Article  PubMed  Google Scholar 

  71. Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O (2001) 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. Am J Hum Genet 69:1218–1224

    Article  PubMed  CAS  Google Scholar 

  72. Reynier P, Amati-Bonneau P, Verny C et al (2004) OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet 41(9):e110

    Google Scholar 

  73. Da Cruz S, Xenarios I, Langridge J, Vilbois F, Parone PA, Martinou JC (2003) Proteomic analysis of the mouse liver mitochondrial inner membrane. J Biol Chem 278:41566–41571

    Article  PubMed  CAS  Google Scholar 

  74. Huizing M, Dorward H, Ly L et al (2010) OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria. Mol Genet Metab 100:149–154

    Article  PubMed  CAS  Google Scholar 

  75. Ryu SW, Jeong HJ, Choi M, Karbowski M, Choi C (2010) Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation. Cell Mol Life Sci 67:2839–2850

    Article  PubMed  CAS  Google Scholar 

  76. Pei WH, Kratz LE, Bernardini I et al (2010) A model of Costeff syndrome reveals metabolic and protective functions of mitochondrial OPA3. Dev 137:2587–2596

    Article  CAS  Google Scholar 

  77. Davies VJ, Powell KA, White KE et al (2008) A missense mutation in the murine Opa3 gene models human Costeff syndrome. Brain 131:368–380

    Article  PubMed  Google Scholar 

  78. Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK (2011) ER tubules mark sites of mitochondrial division. Science 334:358–362

    Article  PubMed  CAS  Google Scholar 

  79. Waterham HR, Koster J, van Roermund CWT, Mooyer PAW, Wanders RJA, Leonard JV (2007) A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 356:1736–1741

    Article  PubMed  CAS  Google Scholar 

  80. Chang CR, Manlandro CM, Arnoult D et al (2010) A lethal de novo mutation in the middle domain of the dynamin-related GTPase Drp1 impairs higher order assembly and mitochondrial division. J Biol Chem 285:32494–32503

    Article  PubMed  CAS  Google Scholar 

  81. Pareyson D, Marchesi C (2009) Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 8:654–667

    Article  PubMed  CAS  Google Scholar 

  82. Zuchner S, Vance JM (2006) Mechanisms of disease: a molecular genetic update on hereditary axonal neuropathies. Nat Clin Pract Neurol 2:45–53

    Article  PubMed  CAS  Google Scholar 

  83. Amati-Bonneau P, Milea D, Bonneau D et al (2009) OPA1-associated disorders: phenotypes and pathophysiology. Int J Biochem Cell Biol 41:1855–1865

    Article  PubMed  CAS  Google Scholar 

  84. Zuchner S, Mersiyanova IV, Muglia M et al (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449–451

    Article  PubMed  CAS  Google Scholar 

  85. Zuchner S, De Jonghe P, Jordanova A et al (2006) Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 59:276–281

    Article  PubMed  CAS  Google Scholar 

  86. Cartoni R, Martinou JC (2009) Role of mitofusin 2 mutations in the physiopathology of Charcot-Marie-Tooth disease type 2A. Exp Neurol 218:268–273

    Article  PubMed  CAS  Google Scholar 

  87. Chen HC, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200

    Article  PubMed  CAS  Google Scholar 

  88. Detmer SA, Velde CV, Cleveland DW, Chan DC (2008) Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A. Hum Mol Genet 17:367–375

    Article  PubMed  CAS  Google Scholar 

  89. Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130:548–562

    Article  PubMed  CAS  Google Scholar 

  90. Guillet V, Gueguen N, Cartoni R et al (2011) Bioenergetic defect associated with mKATP channel opening in a mouse model carrying a mitofusin 2 mutation. Faseb J 25:1618–1627

    Article  PubMed  CAS  Google Scholar 

  91. Detmer SA, Chan DC (2007) Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol 176:405–414

    Article  PubMed  CAS  Google Scholar 

  92. Loiseau D, Chevrollier A, Verny C et al (2007) Mitochondrial coupling defect in Charcot-Marie-Tooth type 2A disease. Ann Neurol 61:315–323

    Article  PubMed  CAS  Google Scholar 

  93. Del Bo R, Moggio M, Rango M et al (2008) Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction. Neurology 71:1959–1966

    Article  PubMed  CAS  Google Scholar 

  94. Pich S, Bach D, Briones P et al (2005) The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet 14:1405–1415

    Article  PubMed  CAS  Google Scholar 

  95. Chen HC, Vermulst M, Wang YE et al (2010) Mitochondrial fusion is Rrquired for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141:280–289

    Article  PubMed  CAS  Google Scholar 

  96. Rouzier C, Bannwarth S, Chaussenot A et al (2012) The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy ‘plus’ phenotype. Brain 135:23–34

    Article  PubMed  Google Scholar 

  97. Yu-Wai-Man P, Chinnery PF (2012) Dysfunctional mitochondrial maintenance: what breaks the circle of life? Brain 135:9–11

    Article  PubMed  Google Scholar 

  98. Sitarz KS, Yu-Wai-Man P, Pyle A, Stewart JD, Rautenstrauss B, Seeman P, Reilly MM, Horvath R, Chinnery PF (2012) MFN2 mutations cause compensatory mitochondrial DNA proliferation. Brain. Epub ahead of print. PMID:22492563

    Google Scholar 

  99. Baxter RV, Ben Othmane K, Rochelle JM et al (2002) Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 30:21–22

    Article  PubMed  CAS  Google Scholar 

  100. Claramunt R, Pedrola L, Sevilla T et al (2005) Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet 42:358–365

    Article  PubMed  CAS  Google Scholar 

  101. Zimon M, Baets J, Fabrizi GM et al (2011) Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology 77:540–548

    Article  PubMed  CAS  Google Scholar 

  102. Niemann A, Wagner KM, Ruegg M, Suter U (2009) GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance. Neurobiol Dis 36:509–520

    Article  PubMed  CAS  Google Scholar 

  103. Pedrola L, Espert A, Wu X, Claramunt R, Shy ME, Palau F (2005) GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. Hum Mol Genet 14:1087–1094

    Article  PubMed  CAS  Google Scholar 

  104. Niemann A, Ruegg M, La Padula V, Schenone A, Suter U (2005) Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J Cell Biol 170:1067–1078

    Article  PubMed  CAS  Google Scholar 

  105. Cassereau J, Chevrollier A, Gueguen N et al (2009) Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K). Neurogenetics 10:145–150

    Article  PubMed  CAS  Google Scholar 

  106. Payne BA, Wilson IJ, Hateley CA et al (2011) Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat Genet 43:806–810

    Article  PubMed  CAS  Google Scholar 

  107. Cao LQ, Shitara H, Horii T et al (2007) The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nat Genet 39:386–390

    Article  PubMed  CAS  Google Scholar 

  108. Cree LM, Samuels DC, Lopes S et al (2008) A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet 40:249–254

    Article  PubMed  CAS  Google Scholar 

  109. Khrapko K (2008) Two ways to make an mtDNA bottleneck. Nat Genet 40:134–135

    Article  PubMed  CAS  Google Scholar 

  110. Elachouri G, Vidoni S, Zanna C et al (2011) OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res 21:12–20

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

PYWM is a Medical Research Council (MRC, UK) Clinician Scientist. GL is supported by INSERM, Université de Montpellier I et II, and the patient associations Retina France and Ouvrir Les Yeux. PFC is a Wellcome Trust Senior Fellow in Clinical Science and a UK National Institute of Health Senior Investigator who also receives funding from the MRC (UK), Parkinson’s UK, the Association Francaise contre les Myopathies, and the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust.

Author information

Authors and Affiliations

  1. Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, NE1 3BZ, Newcastle Upon Tyne, UK

    Dr. Patrick Yu-Wai-Man BMedSci MBBS PhD FRCOphth & Patrick F. Chinnery BMedSci MBBS PhD FRCPath FRCP FMedSci

  2. Neuropathies Optiques Héréditaires, Institut des Neurosciences de Montpellier, Université Montpellier I et II, INSERM U1051, Montpellier, France

    Guy Lenaers PhD

  3. Department of Neurology, Royal Victoria Infirmary, NE1 4LP, Newcastle Upon Tyne, UK

    Patrick F. Chinnery BMedSci MBBS PhD FRCPath FRCP FMedSci

  4. Department of Ophthalmology, Neuro-Ophthalmology Division, Royal Victoria Infirmar, NE1 4LP, Newcastle Upon Tyne, UK

    Dr. Patrick Yu-Wai-Man BMedSci MBBS PhD FRCOphth

Authors
  1. Dr. Patrick Yu-Wai-Man BMedSci MBBS PhD FRCOphth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guy Lenaers PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick F. Chinnery BMedSci MBBS PhD FRCPath FRCP FMedSci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Yu-Wai-Man BMedSci MBBS PhD FRCOphth .

Editor information

Editors and Affiliations

  1. , Dept. of Molecular and Human Genetics, Baylor College of Medicine, Baylor Plaza ONE, Houston, 77030, Texas, USA

    Lee-Jun C. Wong

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Yu-Wai-Man, P., Lenaers, G., Chinnery, P. (2013). Defects in Mitochondrial Dynamics and Mitochondrial DNA Instability. In: Wong, LJ. (eds) Mitochondrial Disorders Caused by Nuclear Genes. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3722-2_9

Download citation

Publish with us

Policies and ethics

Search

Navigation