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Mitochondrial Dysfunction in Neurodegenerative Disorders pp 303–328Cite as

Can We Accurately Model Mitochondrial Dysfunction in Neurodegeneration?

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Abstract

Mitochondrial diseases are connected to a plethora of clinical phenotypes, with the majority of them connected to pathologies within the nervous system. Mutations in either mtDNA or nDNA genes coding for mitochondrial proteins are known to lead to catastrophic diseases in humans that are the most common cause of inborn errors of metabolism, with a frequency of about 1 in 5000. Therefore, an understanding of mitochondrial roles in normal physiology and pathological conditions is essential for the development of possible treatments for patients suffering from various forms of mitochondrial disease. Many attempts have been made to model mitochondrial dysfunction, but this has proven to be challenging due to unique features of mitochondrial genetics. Despite this, over the last 20 years, a number of very important transgenic mouse models have been developed that in a lesser or higher degree recapitulated changes detected in human patients. Here we discuss some of the most important mouse models generated to mimic mitochondrial encephalomyopathies and the lessons learned from them.

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References

  1. Wallace DC. Diseases of the mitochondrial DNA. Annu Rev Biochem. 1992;61:1175–212.

    Article  CAS  PubMed  Google Scholar 

  2. Howard MA, Volkov IO, Noh MD, Granner MA, Mirsky R, Garell PC. Chronic microelectrode investigations of normal human brain physiology using a hybrid depth electrode. Stereotact Funct Neurosurg. 1997;68(1–4 Pt 1):236–42.

    CAS  PubMed  Google Scholar 

  3. DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 2008;31:91–123.

    Article  CAS  PubMed  Google Scholar 

  4. Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992;256:628–32.

    Article  CAS  PubMed  Google Scholar 

  5. Marchington DR, Barlow D, Poulton J. Transmitochondrial mice carrying resistance to chloramphenicol on mitochondrial DNA: developing the first mouse model of mitochondrial DNA disease. Nat Med. 1999;5(8):957–60.

    Article  CAS  PubMed  Google Scholar 

  6. Inoue K, Nakada K, Ogura A, Isobe K, Goto Y, Nonaka I, et al. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nat Genet. 2000;26(2):176–81.

    Article  CAS  PubMed  Google Scholar 

  7. Tanaka D, Nakada K, Takao K, Ogasawara E, Kasahara A, Sato A, et al. Normal mitochondrial respiratory function is essential for spatial remote memory in mice. Mol Brain. 2008;1:21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kasahara A, Ishikawa K, Yamaoka M, Ito M, Watanabe N, Akimoto M, et al. Generation of trans-mitochondrial mice carrying homoplasmic mtDNAs with a missense mutation in a structural gene using ES cells. Hum Mol Genet. 2006;15(6):871–81.

    Article  CAS  PubMed  Google Scholar 

  9. Lin CS, Sharpley MS, Fan W, Waymire KG, Sadun AA, Carelli V, et al. Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Proc Natl Acad Sci U S A. 2012;109(49):20065–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shimizu A, Mito T, Hayashi C, Ogasawara E, Koba R, Negishi I, et al. Transmitochondrial mice as models for primary prevention of diseases caused by mutation in the tRNA(Lys) gene. Proc Natl Acad Sci U S A. 2014;111(8):3104–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429:417–23.

    Article  CAS  PubMed  Google Scholar 

  12. Ross JM, Coppotelli G, Hoffer BJ, Olson L. Maternally transmitted mitochondrial DNA mutations can reduce lifespan. Sci Rep. 2014;4:6569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tyynismaa H, Mjosund KP, Wanrooij S, Lappalainen I, Ylikallio E, Jalanko A, et al. Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. Proc Natl Acad Sci U S A. 2005;102(49):17687–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Song L, Shan Y, Lloyd KC, Cortopassi GA. Mutant Twinkle increases dopaminergic neurodegeneration, mtDNA deletions and modulates Parkin expression. Hum Mol Genet. 2012;21(23):5147–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sorensen L, Ekstrand M, Silva JP, Lindqvist E, Xu B, Rustin P, et al. Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J Neurosci. 2001;21(20):8082–90.

    CAS  PubMed  Google Scholar 

  16. Ekstrand MI, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A. 2007;104(4):1325–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhou X, Solaroli N, Bjerke M, Stewart JB, Rozell B, Johansson M, et al. Progressive loss of mitochondrial DNA in thymidine kinase 2-deficient mice. Hum Mol Genet. 2008;17(15):2329–35.

    Article  CAS  PubMed  Google Scholar 

  18. Akman HO, Dorado B, Lopez LC, Garcia-Cazorla A, Vila MR, Tanabe LM, et al. Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance. Hum Mol Genet. 2008;17(16):2433–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science. 1999;283(5402):689–92.

    Article  CAS  PubMed  Google Scholar 

  20. Lopez LC, Akman HO, Garcia-Cazorla A, Dorado B, Marti R, Nishino I, et al. Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice. Hum Mol Genet. 2009;18(4):714–22.

    Article  CAS  PubMed  Google Scholar 

  21. Haraguchi M, Tsujimoto H, Fukushima M, Higuchi I, Kuribayashi H, Utsumi H, et al. Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice. Mol Cell Biol. 2002;22(14):5212–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab. 2008;7(4):312–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Quintana A, Kruse SE, Kapur RP, Sanz E, Palmiter RD. Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome. Proc Natl Acad Sci U S A. 2010;107(24):10996–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sterky FH, Hoffman AF, Milenkovic D, Bao B, Paganelli A, Edgar D, et al. Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons. Hum Mol Genet. 2012;21(5):1078–89.

    Article  CAS  PubMed  Google Scholar 

  25. Peralta S, Torraco A, Wenz T, Garcia S, Diaz F, Moraes CT. Partial complex I deficiency due to the CNS conditional ablation of Ndufa5 results in a mild chronic encephalopathy but no increase in oxidative damage. Hum Mol Genet. 2014;23(6):1399–412.

    Article  CAS  PubMed  Google Scholar 

  26. Garcia-Corzo L, Luna-Sanchez M, Doerrier C, Garcia JA, Guaras A, Acin-Perez R, et al. Dysfunctional Coq9 protein causes predominant encephalomyopathy associated with CoQ deficiency. Hum Mol Genet. 2013;22(6):1233–48.

    Article  CAS  PubMed  Google Scholar 

  27. Diaz F, Garcia S, Padgett KR, Moraes CT. A defect in the mitochondrial complex III, but not complex IV, triggers early ROS-dependent damage in defined brain regions. Hum Mol Genet. 2012;21(23):5066–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dell’agnello C, Leo S, Agostino A, Szabadkai G, Tiveron C, Zulian A, et al. Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. Hum Mol Genet. 2007;16(4):431–44.

    Article  PubMed  Google Scholar 

  29. Funfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature. 2012;485(7399):517–21.

    PubMed  PubMed Central  Google Scholar 

  30. Tiranti V, Viscomi C, Hildebrandt T, Di Meo I, Mineri R, Tiveron C, et al. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med. 2009;15(2):200–5.

    Article  CAS  PubMed  Google Scholar 

  31. Tuppen HA, Blakely EL, Turnbull DM, Taylor RW. Mitochondrial DNA mutations and human disease. Biochim Biophys Acta. 2010;1797(2):113–28.

    Article  CAS  PubMed  Google Scholar 

  32. Nakada K, Sato A, Hayashi J. Reverse genetic studies of mitochondrial DNA-based diseases using a mouse model. Proc Jpn Acad Ser B Phys Biol Sci. 2008;84(5):155–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Seibel P, Trappe J, Villani G, Klopstock T, Papa S, Reichmann H. Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases. Nucleic Acids Res. 1995;23(1):10–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vestweber D, Schatz G. DNA-protein conjugates can enter mitochondria via the protein import pathway. Nature. 1989;338:170–2.

    Article  CAS  PubMed  Google Scholar 

  35. Moraes CT, Bacman SR, Williams SL. Manipulating mitochondrial genomes in the clinic: playing by different rules. Trends Cell Biol. 2014;24(4):209–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Moraes CT. A magic bullet to specifically eliminate mutated mitochondrial genomes from patients’ cells. EMBO Mol Med. 2014;6(4):434–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pinto M, Moraes CT. Mitochondrial genome changes and neurodegenerative diseases. Biochim Biophys Acta. 2014;1842(8):1198–207.

    Article  CAS  PubMed  Google Scholar 

  38. Sligh JE, Levy SE, Waymire KG, Allard P, Dillehay DL, Nusinowitz S, et al. Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice. Proc Natl Acad Sci U S A. 2000;97(26):14461–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P, Lewandoski M, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet. 1998;18(3):231–6.

    Article  CAS  PubMed  Google Scholar 

  40. Nakada K, Sato A, Sone H, Kasahara A, Ikeda K, Kagawa Y, et al. Accumulation of pathogenic DeltamtDNA induced deafness but not diabetic phenotypes in mito-mice. Biochem Biophys Res Commun. 2004;323(1):175–84.

    Article  CAS  PubMed  Google Scholar 

  41. Irwin MH, Johnson LW, Pinkert CA. Isolation and microinjection of somatic cell-derived mitochondria and germline heteroplasmy in transmitochondrial mice. Transgenic Res. 1999;8(2):119–23.

    Article  CAS  PubMed  Google Scholar 

  42. Nakada K, Inoue K, Ono T, Isobe K, Ogura A, Goto YI, et al. Inter-mitochondrial complementation: mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med. 2001;7(8):934–9.

    Article  CAS  PubMed  Google Scholar 

  43. Nakada K, Sato A, Yoshida K, Morita T, Tanaka H, Inoue S, et al. Mitochondria-related male infertility. Proc Natl Acad Sci U S A. 2006;103(41):15148–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jackson DC. Surviving extreme lactic acidosis: the role of calcium lactate formation in the anoxic turtle. Respir Physiol Neurobiol. 2004;144(2–3):173–8.

    Article  CAS  PubMed  Google Scholar 

  45. Grady JP, Campbell G, Ratnaike T, Blakely EL, Falkous G, Nesbitt V, et al. Disease progression in patients with single, large-scale mitochondrial DNA deletions. Brain. 2014;137(Pt 2):323–34.

    Article  PubMed  Google Scholar 

  46. Berio A, Piazzi A. Multiple endocrinopathies (growth hormone deficiency, autoimmune hypothyroidism and diabetes mellitus) in Kearns-Sayre syndrome. Pediatr Med Chir. 2013;35(3):137–40.

    Article  CAS  PubMed  Google Scholar 

  47. Varlamov DA, Kudin AP, Vielhaber S, Schroder R, Sassen R, Becker A, et al. Metabolic consequences of a novel missense mutation of the mtDNA CO I gene. Hum Mol Genet. 2002;11(16):1797–805.

    Article  CAS  PubMed  Google Scholar 

  48. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AMS, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science. 1988;242:1427–30.

    Article  CAS  PubMed  Google Scholar 

  49. Sadun AA, La Morgia C, Carelli V. Leber’s hereditary optic neuropathy. Curr Treat Options Neurol. 2011;13(1):109–17.

    Article  PubMed  Google Scholar 

  50. Yokota M, Shitara H, Hashizume O, Ishikawa K, Nakada K, Ishii R, et al. Generation of trans-mitochondrial mito-mice by the introduction of a pathogenic G13997A mtDNA from highly metastatic lung carcinoma cells. FEBS Lett. 2010;584(18):3943–8.

    Article  CAS  PubMed  Google Scholar 

  51. Hashizume O, Shimizu A, Yokota M, Sugiyama A, Nakada K, Miyoshi H, et al. Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development. Proc Natl Acad Sci U S A. 2012;109(26):10528–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Korhonen JA, Pham XH, Pellegrini M, Falkenberg M. Reconstitution of a minimal mtDNA replisome in vitro. EMBO J. 2004;23(12):2423–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Edgar D, Trifunovic A. The mtDNA mutator mouse: dissecting mitochondrial involvement in aging. Aging (Albany NY). 2009;1(12):1028–32.

    Article  CAS  Google Scholar 

  54. Ross JM, Oberg J, Brene S, Coppotelli G, Terzioglu M, Pernold K, et al. High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. Proc Natl Acad Sci U S A. 2010;107(46):20087–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ahlqvist KJ, Hamalainen RH, Yatsuga S, Uutela M, Terzioglu M, Gotz A, et al. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 2012;15(1):100–9.

    Article  CAS  PubMed  Google Scholar 

  56. Suomalainen A, Kaukonen J. Diseases caused by nuclear genes affecting mtDNA stability. Am J Med Genet. 2001;106(1):53–61.

    Article  CAS  PubMed  Google Scholar 

  57. Van Goethem G, Dermaut B, Lofgren A, Martin JJ, Van Broeckhoven C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001;28(3):211–2.

    Article  PubMed  Google Scholar 

  58. Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei S, et al. Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. Ann Neurol. 2002;52(2):211–9.

    Article  CAS  PubMed  Google Scholar 

  59. Agostino A, Valletta L, Chinnery PF, Ferrari G, Carrara F, Taylor RW, et al. Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology. 2003;60(8):1354–6.

    Article  CAS  PubMed  Google Scholar 

  60. Van Goethem G, Schwartz M, Lofgren A, Dermaut B, Van Broeckhoven C, Vissing J. Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet. 2003;11(7):547–9.

    Article  PubMed  Google Scholar 

  61. Naviaux RK, Nguyen KV. POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann Neurol. 2004;55(5):706–12.

    Article  CAS  PubMed  Google Scholar 

  62. Ferrari G, Lamantea E, Donati A, Filosto M, Briem E, Carrara F, et al. Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-{gamma}A. Brain. 2005;128(Pt 4):723–31. Epub 2005 Feb 2.

    Article  PubMed  Google Scholar 

  63. Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet. 2004;364(9437):875–82.

    Article  CAS  PubMed  Google Scholar 

  64. Suomalainen A. Mitochondrial DNA, and disease. Ann Med. 1997;29(3):235–46.

    Article  CAS  PubMed  Google Scholar 

  65. Gellhaar S, Marcellino D, Abrams MB, Galter D. Chronic L-DOPA induces hyperactivity, normalization of gait and dyskinetic behavior in MitoPark mice. Genes Brain Behav. 2015;14(3):260–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Grauer SM, Hodgson R, Hyde LA. MitoPark mice, an animal model of Parkinson’s disease, show enhanced prepulse inhibition of acoustic startle and no loss of gating in response to the adenosine A(2A) antagonist SCH 412348. Psychopharmacology (Berl). 2014;231(7):1325–37.

    Article  CAS  Google Scholar 

  67. Li X, Redus L, Chen C, Martinez PA, Strong R, Li S, et al. Cognitive dysfunction precedes the onset of motor symptoms in the MitoPark mouse model of Parkinson’s disease. PLoS One. 2013;8(8):e71341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ferraro P, Pontarin G, Crocco L, Fabris S, Reichard P, Bianchi V. Mitochondrial deoxynucleotide pools in quiescent fibroblasts: a possible model for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). J Biol Chem. 2005;280(26):24472–80.

    Article  CAS  PubMed  Google Scholar 

  69. Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet. 2001;29(3):342–4.

    Article  CAS  PubMed  Google Scholar 

  70. Oskoui M, Davidzon G, Pascual J, Erazo R, Gurgel-Giannetti J, Krishna S, et al. Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene. Arch Neurol. 2006;63(8):1122–6.

    Article  PubMed  Google Scholar 

  71. Hirano M, Lagier-Tourenne C, Valentino ML, Marti R, Nishigaki Y. Thymidine phosphorylase mutations cause instability of mitochondrial DNA. Gene. 2005;354:152–6.

    Article  CAS  PubMed  Google Scholar 

  72. Joza N, Oudit GY, Brown D, Benit P, Kassiri Z, Vahsen N, et al. Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy. Mol Cell Biol. 2005;25(23):10261–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hirst J, Carroll J, Fearnley IM, Shannon RJ, Walker JE. The nuclear encoded subunits of complex I from bovine heart mitochondria. Biochim Biophys Acta. 2003;1604(3):135–50.

    Article  CAS  PubMed  Google Scholar 

  74. Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, et al. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat. 2000;15(2):123–34.

    Article  CAS  PubMed  Google Scholar 

  75. Morris AAM, Leonard IV, Brown GK, Bidouki SK, Bindoff LA, Woodward CE, et al. Deficiency of respiratory chain complex I is a common cause of Leigh disease. Ann Neurol. 1996;40(1):25–30.

    Article  CAS  PubMed  Google Scholar 

  76. Anderson SL, Chung WK, Frezzo J, Papp JC, Ekstein J, DiMauro S, et al. A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family. J Inherit Metab Dis. 2008;31 Suppl 2:S461–7.

    Article  PubMed  Google Scholar 

  77. Betts J, Lightowlers RN, Turnbull DM. Neuropathological aspects of mitochondrial DNA disease. Neurochem Res. 2004;29(3):505–11.

    Article  CAS  PubMed  Google Scholar 

  78. Leong DW, Komen JC, Hewitt CA, Arnaud E, McKenzie M, Phipson B, et al. Proteomic and metabolomic analyses of mitochondrial complex I-deficient mouse model generated by spontaneous B2 short interspersed nuclear element (SINE) insertion into NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene. J Biol Chem. 2012;287(24):20652–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ingraham CA, Burwell LS, Skalska J, Brookes PS, Howell RL, Sheu SS, et al. NDUFS4: creation of a mouse model mimicking a Complex I disorder. Mitochondrion. 2009;9(3):204–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Guzman M, Blazquez C. Ketone body synthesis in the brain: possible neuroprotective effects. Prostaglandins Leukot Essent Fatty Acids. 2004;70(3):287–92.

    Article  CAS  PubMed  Google Scholar 

  81. Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004;1660(1–2):171–99.

    Article  CAS  PubMed  Google Scholar 

  82. Luna-Sanchez M, Diaz-Casado E, Barca E, Tejada MA, Montilla-Garcia A, Cobos EJ, et al. The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene. EMBO Mol Med. 2015;7(5):670–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Emmanuele V, Lopez LC, Berardo A, Naini A, Tadesse S, Wen B, et al. Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol. 2012;69(8):978–83.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Duncan AJ, Bitner-Glindzicz M, Meunier B, Costello H, Hargreaves IP, Lopez LC, et al. A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. Am J Hum Genet. 2009;84(5):558–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Benit P, Lebon S, Rustin P. Respiratory-chain diseases related to complex III deficiency. Biochim Biophys Acta. 2009;1793(1):181–5.

    Article  CAS  PubMed  Google Scholar 

  86. Arnold S. Cytochrome c oxidase and its role in neurodegeneration and neuroprotection. Adv Exp Med Biol. 2012;748:305–39.

    Article  CAS  PubMed  Google Scholar 

  87. Shoubridge EA. Cytochrome c oxidase deficiency. Am J Med Genet. 2001;106(1):46–52.

    Article  CAS  PubMed  Google Scholar 

  88. Sacconi S, Salviati L, Sue CM, Shanske S, Davidson MM, Bonilla E, et al. Mutation screening in patients with isolated cytochrome c oxidase deficiency. Pediatr Res. 2003;53(2):224–30.

    Article  CAS  PubMed  Google Scholar 

  89. Pulliam DA, Deepa SS, Liu Y, Hill S, Lin AL, Bhattacharya A, et al. Complex IV-deficient Surf1(–/–) mice initiate mitochondrial stress responses. Biochem J. 2014;462(2):359–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Deepa SS, Pulliam D, Hill S, Shi Y, Walsh ME, Salmon A, et al. Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity. FASEB J. 2013;27(4):1371–80.

    Article  CAS  PubMed  Google Scholar 

  91. Valnot I, von Kleist-Retzow JC, Barrientos A, Gorbatyuk M, Taanman JW, Mehaye B, et al. A mutation in the human heme a: farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency. Hum Mol Genet. 2000;9(8):1245–9 [In Process Citation].

    Article  CAS  PubMed  Google Scholar 

  92. Tiranti V, D’Adamo P, Briem E, Ferrari G, Mineri R, Lamantea E, et al. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am J Hum Genet. 2004;74(2):239–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, Institute for Mitochondrial Diseases and Aging, University of Cologne, Cologne, Germany

    Marijana Aradjanski MSc

  2. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, Institute for Mitochondrial Diseases and Aging, Cologne University Clinic, University of Cologne, Cologne, Germany

    Aleksandra Trifunovic PhD

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  1. Marijana Aradjanski MSc
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Correspondence to Aleksandra Trifunovic PhD .

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Editors and Affiliations

  1. Newcastle University Medical School, Well. Trust Ctr. for Mitochondrial Res., Newcastle upon Tyne, United Kingdom

    Amy K. Reeve

  2. Newcastle University Medical School, Well. Trust Ctr. for Mitochondrial Res., Newcastle upon Tyne, United Kingdom

    Eve M. Simcox

  3. Cell and Developmental Biology, University College London, London, United Kingdom

    Michael R. Duchen

  4. Newcastle University Medical School, Well. Trust Ctr. for Mitochondrial Res., Newcastle upon Tyne, United Kingdom

    Doug M. Turnbull

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Aradjanski, M., Trifunovic, A. (2016). Can We Accurately Model Mitochondrial Dysfunction in Neurodegeneration?. In: Reeve, A., Simcox, E., Duchen, M., Turnbull, D. (eds) Mitochondrial Dysfunction in Neurodegenerative Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-28637-2_13

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