Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue

Acta Neuropathologica

Volumn 132, Issue 3, 2016, Pages 453-473

  Winter, Lilli ^a   Wittig, Ilka ^b,c   Peeva, Viktoriya ^d   Eggers, Britta ^e   Heidler, Juliana ^b   Chevessier, Frederic ^a   Kley, Rudolf A ^f   Barkovits, Katalin ^e   Strecker, Valentina ^b   Berwanger, Carolin ^g   Herrmann, Harald ^a   Marcus, Katrin ^e   Kornblum, Cornelia ^d   Kunz, Wolfram S ^d   Schröder, Rolf ^a   Clemen, Christoph S ^g  

^a UNIVERSITY HOSPITAL ERLANGEN   (Germany)

^b GOETHE UNIVERSITY   (Germany)

^c DZHK GERMAN CENTRE FOR CARDIOVASCULAR RESEARCH   (Germany)

^d UNIVERSITY HOSPITAL BONN   (Germany)

^e RUHR UNIVERSITY BOCHUM   (Germany)

^f RUHR UNIVERSITY BOCHUM   (Germany)

^g UNIVERSITY OF COLOGNE   (Germany)

Author keywords

Desmin knock out; Desminopathy; Intermediate filament; Mitochondria; mtDNA; Myofibrillar myopathy; Protein aggregate myopathy; Proteome; R349P desmin knock in; R350P desmin

Indexed keywords

CELL NUCLEUS DNA; DESMIN; MITOCHONDRIAL DNA; MITOCHONDRIAL PROTEIN;

ANIMAL MODEL; ARTICLE; CASE REPORT; CELL COUNT; CELL FUNCTION; CELL SHAPE; CELL STRUCTURE; CELLULAR DISTRIBUTION; CONTROLLED STUDY; CYTOSKELETON; DESMINOPATHY; DISORDERS OF MITOCHONDRIAL FUNCTIONS; GENE EXPRESSION; GENE MUTATION; HETEROZYGOSITY; HISTOPATHOLOGY; HOMOZYGOSITY; HUMAN; HUMAN CELL; HUMAN TISSUE; MITOCHONDRION; MOUSE; MULTILEVEL ANALYSIS; MUSCLE BIOPSY; MUSCLE TISSUE; MYOPATHY; NONHUMAN; PRIORITY JOURNAL; PROTEIN AGGREGATION; RESPIRATORY CHAIN; SKELETAL MUSCLE; VASTUS LATERALIS MUSCLE; ANIMAL; GENETICS; INTERMEDIATE FILAMENT; METABOLISM; MUSCLE DISEASE; MUTATION; PATHOLOGY; TRANSGENIC MOUSE;

ANIMALS; CYTOSKELETON; DESMIN; HUMANS; INTERMEDIATE FILAMENTS; MICE, TRANSGENIC; MITOCHONDRIA; MUSCLE, SKELETAL; MUSCULAR DISEASES; MUTATION;

EID: 84978035687     PISSN: 00016322     EISSN: 14320533     Source Type: Journal    
DOI: 10.1007/s00401-016-1592-7     Document Type: Article

References (83)

1. Acin-Perez R, Bayona-Bafaluy MP, Fernandez-Silva P, Moreno-Loshuertos R, Perez-Martos A, Bruno C, Moraes CT, Enriquez JA (2004) Respiratory complex III is required to maintain complex I in mammalian mitochondria. Mol Cell 13:805–815
2. Arbustini E, Morbini P, Grasso M, Fasani R, Verga L, Bellini O, Dal Bello B, Campana C, Piccolo G, Febo O, Opasich C, Gavazzi A, Ferrans VJ (1998) Restrictive cardiomyopathy, atrioventricular block and mild to subclinical myopathy in patients with desmin-immunoreactive material deposits. J Am Coll Cardiol 31:645–653
3. Bär H, Fischer D, Goudeau B, Kley RA, Clemen CS, Vicart P, Herrmann H, Vorgerd M, Schröder R (2005) Pathogenic effects of a novel heterozygous R350P desmin mutation on the assembly of desmin intermediate filaments in vivo and in vitro. Hum Mol Genet 14:1251–1260
4. Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA, Ganie SA (2015) Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother 74:101–110
5. Burte F, Carelli V, Chinnery PF, Yu-Wai-Man P (2015) Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol 11:11–24
6. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55:611–622
7. Carmignac V, Sharma S, Arbogast S, Fischer D, Serreri C, Serria M, Stoltenburg G, Maurage CA, Herrmann H, Cuisset JM, Bär H, Ferreiro A (2009) A homozygous desmin deletion causes an Emery-Dreifuss like recessive myopathy with desmin depletion. Neuromuscul Disord 19:600
8. Carrozzo R, Wittig I, Santorelli FM, Bertini E, Hofmann S, Brandt U, Schagger H (2006) Subcomplexes of human ATP synthase mark mitochondrial biosynthesis disorders. Ann Neurol 59:265–275
9. Cetin N, Balci-Hayta B, Gundesli H, Korkusuz P, Purali N, Talim B, Tan E, Selcen D, Erdem-Ozdamar S, Dincer P (2013) A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathies. J Med Genet 50:437–443
10. Chaban Y, Boekema EJ, Dudkina NV (2014) Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation. Biochim Biophys Acta 1837:418–426
11. Chen J, Shinde S, Koch MH, Eisenacher M, Galozzi S, Lerari T, Barkovits K, Subedi P, Kruger R, Kuhlmann K, Sellergren B, Helling S, Marcus K (2015) Low-bias phosphopeptide enrichment from scarce samples using plastic antibodies. Sci Rep 5:11438
12. Chevessier F, Schuld J, Orfanos Z, Plank AC, Wolf L, Maerkens A, Unger A, Schlotzer-Schrehardt U, Kley RA, Von Horsten S, Marcus K, Linke WA, Vorgerd M, van der Ven PF, Furst DO, Schroder R (2015) Myofibrillar instability exacerbated by acute exercise in filaminopathy. Hum Mol Genet 24:7207–7220
13. Chopard A, Pons F, Charpiot P, Marini JF (2000) Quantitative analysis of relative protein contents by Western blotting: comparison of three members of the dystrophin–glycoprotein complex in slow and fast rat skeletal muscle. Electrophoresis 21:517–522
14. Clemen CS, Fischer D, Reimann J, Eichinger L, Muller CR, Muller HD, Goebel HH, Schröder R (2009) How much mutant protein is needed to cause a protein aggregate myopathy in vivo? Lessons from an exceptional desminopathy. Hum Mutat 30:E490–E499
15. Clemen CS, Herrmann H, Strelkov SV, Schröder R (2013) Desminopathies: pathology and mechanisms. Acta Neuropathol 125:47–75
16. Clemen CS, Stöckigt F, Strucksberg KH, Chevessier F, Winter L, Schütz J, Bauer R, Thorweihe JM, Wenzel D, Schlötzer-Schrehardt U, Rasche V, Krsmanovic P, Katus HA, Rottbauer W, Just S, Müller OJ, Friedrich O, Meyer R, Herrmann H, Schrickel JW, Schröder R (2015) The toxic effect of R350P mutant desmin in striated muscle of man and mouse. Acta Neuropathol 129:297–315
17. Corona JC, Duchen MR (2015) Impaired mitochondrial homeostasis and neurodegeneration: towards new therapeutic targets? J Bioenerg Biomembr 47:89–99
18. Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M (2014) Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteomics 13:2513–2526
19. Cox J, Mann M (2008) MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26:1367–1372
20. Dahl R, Larsen S, Dohlmann TL, Qvortrup K, Helge JW, Dela F, Prats C (2015) Three-dimensional reconstruction of the human skeletal muscle mitochondrial network as a tool to assess mitochondrial content and structural organization. Acta Physiol (Oxf) 213:145–155
21. Diaz F, Fukui H, Garcia S, Moraes CT (2006) Cytochrome c oxidase is required for the assembly/stability of respiratory complex I in mouse fibroblasts. Mol Cell Biol 26:4872–4881
22. Dubowitz V, Sewry C, Oldfors A (2013) Muscle biopsy: a practical approach. Saunders/Elsevier Ltd., Oxford. ISBN 9780702043406
23. Durmuş H, Ayhan Ö, Çırak S, Deymeer F, Parman Y, Franke A, Eiber N, Chevessier F, Schlötzer-Schrehardt U, Clemen CS, Hashemolhosseini S, Schröder R, Hemmrich-Stanisak G, Tolun A, Serdaroğlu-Oflazer P (2016) Neuromuscular endplate pathology in recessive desminopathies: lessons from man and mice. Neurology (in press)
24. Fidzianska A, Kotowicz J, Sadowska M, Goudeau B, Walczak E, Vicart P, Hausmanowa-Petrusewicz I (2005) A novel desmin R355P mutation causes cardiac and skeletal myopathy. Neuromuscul Disord 15:525–531
25. Fountoulakis M, Soumaka E, Rapti K, Mavroidis M, Tsangaris G, Maris A, Weisleder N, Capetanaki Y (2005) Alterations in the heart mitochondrial proteome in a desmin null heart failure model. J Mol Cell Cardiol 38:461–474
26. Francis BM, Yang J, Song BJ, Gupta S, Maj M, Bazinet RP, Robinson B, Mount HT (2014) Reduced levels of mitochondrial complex I subunit NDUFB8 and linked complex I + III oxidoreductase activity in the TgCRND8 mouse model of Alzheimer’s disease. J Alzheimers Dis 39:347–355
27. Genova ML, Lenaz G (2014) Functional role of mitochondrial respiratory supercomplexes. Biochim Biophys Acta 1837:427–443
28. Glancy B, Hartnell LM, Malide D, Yu ZX, Combs CA, Connelly PS, Subramaniam S, Balaban RS (2015) Mitochondrial reticulum for cellular energy distribution in muscle. Nature 523:617–620
29. Goldfarb LG, Park KY, Cervenakova L, Gorokhova S, Lee HS, Vasconcelos O, Nagle JW, Semino-Mora C, Sivakumar K, Dalakas MC (1998) Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nat Genet 19:402–403
30. Heidler J, Strecker V, Csintalan F, Bleier L, Wittig I (2013) Quantification of protein complexes by blue native electrophoresis. Methods Mol Biol 1033:363–379
31. Henderson M, De Waele L, Hudson J, Eagle M, Sewry C, Marsh J, Charlton R, He L, Blakely EL, Horrocks I, Stewart W, Taylor RW, Longman C, Bushby K, Barresi R (2013) Recessive desmin-null muscular dystrophy with central nuclei and mitochondrial abnormalities. Acta Neuropathol 125:917–919
32. Hong D, Wang Z, Zhang W, Xi J, Lu J, Luan X, Yuan Y (2011) A series of Chinese patients with desminopathy associated with six novel and one reported mutations in the desmin gene. Neuropathol Appl Neurobiol 37:257–270
33. Jackson S, Schaefer J, Meinhardt M, Reichmann H (2015) Mitochondrial abnormalities in the myofibrillar myopathies. Eur J Neurol 22:1429–1435
34. Joshi PR, Hauburger A, Kley R, Claeys KG, Schneider I, Kress W, Stoltenburg G, Weis J, Vorgerd M, Deschauer M, Hanisch F (2014) Mitochondrial abnormalities in myofibrillar myopathies. Clin Neuropathol 33:134–142
35. Katsetos CD, Koutzaki S, Melvin JJ (2013) Mitochondrial dysfunction in neuromuscular disorders. Semin Pediatr Neurol 20:202–215
36. Keogh MJ, Chinnery PF (2015) Mitochondrial DNA mutations in neurodegeneration. Biochim Biophys Acta 1847:1401–1411
37. Kley RA, Hellenbroich Y, van der Ven PF, Furst DO, Huebner A, Bruchertseifer V, Peters SA, Heyer CM, Kirschner J, Schroder R, Fischer D, Muller K, Tolksdorf K, Eger K, Germing A, Brodherr T, Reum C, Walter MC, Lochmuller H, Ketelsen UP, Vorgerd M (2007) Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients. Brain 130:3250–3264
38. Kostareva A, Sjoberg G, Bruton J, Zhang SJ, Balogh J, Gudkova A, Hedberg B, Edstrom L, Westerblad H, Sejersen T (2008) Mice expressing L345P mutant desmin exhibit morphological and functional changes of skeletal and cardiac mitochondria. J Muscle Res Cell Motil 29:25–36
39. Kunz WS, Kuznetsov AV, Schulze W, Eichhorn K, Schild L, Striggow F, Bohnensack R, Neuhof S, Grasshoff H, Neumann HW, Gellerich FN (1993) Functional characterization of mitochondrial oxidative phosphorylation in saponin-skinned human muscle fibers. Biochim Biophys Acta 1144:46–53
40. Li Z, Colucci-Guyon E, Pincon-Raymond M, Mericskay M, Pournin S, Paulin D, Babinet C (1996) Cardiovascular lesions and skeletal myopathy in mice lacking desmin. Dev Biol 175:362–366
41. Li Z, Mericskay M, Agbulut O, Butler-Browne G, Carlsson L, Thornell LE, Babinet C, Paulin D (1997) Desmin is essential for the tensile strength and integrity of myofibrils but not for myogenic commitment, differentiation, and fusion of skeletal muscle. J Cell Biol 139:129–144
42. Li ZL, Lilienbaum A, Butler-Browne G, Paulin D (1989) Human desmin-coding gene: complete nucleotide sequence, characterization and regulation of expression during myogenesis and development. Gene 78:243–254
43. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795
44. Linden M, Li Z, Paulin D, Gotow T, Leterrier JF (2001) Effects of desmin gene knockout on mice heart mitochondria. J Bioenerg Biomembr 33:333–341
45. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
46. Luan X, Hong D, Zhang W, Wang Z, Yuan Y (2010) A novel heterozygous deletion-insertion mutation (2695-2712 del/GTTTGT ins) in exon 18 of the filamin C gene causes filaminopathy in a large Chinese family. Neuromuscul Disord 20:390–396
47. Maerkens A, Olive M, Schreiner A, Feldkirchner S, Schessl J, Uszkoreit J, Barkovits K, Guttsches AK, Theis V, Eisenacher M, Tegenthoff M, Goldfarb LG, Schroder R, Schoser B, van der Ven PF, Furst DO, Vorgerd M, Marcus K, Kley RA (2016) New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses. Acta Neuropathol Commun 4:8
48. Malfatti E, Olive M, Taratuto AL, Richard P, Brochier G, Bitoun M, Gueneau L, Laforet P, Stojkovic T, Maisonobe T, Monges S, Lubieniecki F, Vasquez G, Streichenberger N, Lacene E, Saccoliti M, Prudhon B, Alexianu M, Figarella-Branger D, Schessl J, Bonnemann C, Eymard B, Fardeau M, Bonne G, Romero NB (2013) Skeletal muscle biopsy analysis in reducing body myopathy and other FHL1-related disorders. J Neuropathol Exp Neurol 72:833–845
49. Maranzana E, Barbero G, Falasca AI, Lenaz G, Genova ML (2013) Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. Antioxid Redox Signal 19:1469–1480
50. McCormick EM, Kenyon L, Falk MJ (2015) Desmin common mutation is associated with multi-systemic disease manifestations and depletion of mitochondria and mitochondrial DNA. Front Genet 6:199
51. McLaughlin HM, Kelly MA, Hawley PP, Darras BT, Funke B, Picker J (2013) Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy. BMC Med Genet 14:68
52. Mena NP, Urrutia PJ, Lourido F, Carrasco CM, Nunez MT (2015) Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders. Mitochondrion 21:92–105
53. Meng F, Yao D, Shi Y, Kabakoff J, Wu W, Reicher J, Ma Y, Moosmann B, Masliah E, Lipton SA, Gu Z (2011) Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation. Mol Neurodegener 6:34
54. Milner DJ, Mavroidis M, Weisleder N, Capetanaki Y (2000) Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function. J Cell Biol 150:1283–1298
55. Milner DJ, Weitzer G, Tran D, Bradley A, Capetanaki Y (1996) Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J Cell Biol 134:1255–1270
56. Munoz-Marmol AM, Strasser G, Isamat M, Coulombe PA, Yang Y, Roca X, Vela E, Mate JL, Coll J, Fernandez-Figueras MT, Navas-Palacios JJ, Ariza A, Fuchs E (1998) A dysfunctional desmin mutation in a patient with severe generalized myopathy. Proc Natl Acad Sci USA 95:11312–11317
57. Nardin RA, Johns DR (2001) Mitochondrial dysfunction and neuromuscular disease. Muscle Nerve 24:170–191
58. Nubel E, Wittig I, Kerscher S, Brandt U, Schagger H (2009) Two-dimensional native electrophoretic analysis of respiratory supercomplexes from Yarrowia lipolytica. Proteomics 9:2408–2418
59. Olive M, Goldfarb LG, Shatunov A, Fischer D, Ferrer I (2005) Myotilinopathy: refining the clinical and myopathological phenotype. Brain 128:2315–2326
60. Pinol-Ripoll G, Shatunov A, Cabello A, Larrode P, de la Puerta I, Pelegrin J, Ramos FJ, Olive M, Goldfarb LG (2009) Severe infantile-onset cardiomyopathy associated with a homozygous deletion in desmin. Neuromuscul Disord 19:418–422
61. Pinto M, Moraes CT (2014) Mitochondrial genome changes and neurodegenerative diseases. Biochim Biophys Acta 1842:1198–1207
62. Prior KK, Wittig I, Leisegang MS, Groenendyk J, Weissmann N, Michalak M, Jansen-Durr P, Shah AM, Brandes RP (2016) The endoplasmic reticulum chaperone calnexin is a NADPH oxidase NOX4 interacting protein. J Biol Chem 291:7045–7059
63. Reipert S, Steinbock F, Fischer I, Bittner RE, Zeold A, Wiche G (1999) Association of mitochondria with plectin and desmin intermediate filaments in striated muscle. Exp Cell Res 252:479–491
64. Rezniczek GA, Konieczny P, Nikolic B, Reipert S, Schneller D, Abrahamsberg C, Davies KE, Winder SJ, Wiche G (2007) Plectin 1f scaffolding at the sarcolemma of dystrophic (mdx) muscle fibers through multiple interactions with beta-dystroglycan. J Cell Biol 176:965–977
65. Schagger H, Pfeiffer K (2000) Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J 19:1777–1783
66. Schröder R (2013) Protein aggregate myopathies: the many faces of an expanding disease group. Acta Neuropathol 125:1–2
67. Schröder R, Goudeau B, Simon MC, Fischer D, Eggermann T, Clemen CS, Li Z, Reimann J, Xue Z, Rudnik-Schoneborn S, Zerres K, van der Ven PF, Fürst DO, Kunz WS, Vicart P (2007) Erratum for: “On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria”. Hum Mol Genet 16:2989–2990
68. Schröder R, Goudeau B, Simon MC, Fischer D, Eggermann T, Clemen CS, Li Z, Reimann J, Xue Z, Rudnik-Schoneborn S, Zerres K, van der Ven PF, Fürst DO, Kunz WS, Vicart P (2003) On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria. Hum Mol Genet 12:657–669
69. Schröder R, Kunz WS, Rouan F, Pfendner E, Tolksdorf K, Kappes-Horn K, Altenschmidt-Mehring M, Knoblich R, van der Ven PF, Reimann J, Furst DO, Blümcke I, Vielhaber S, Zillikens D, Eming S, Klockgether T, Uitto J, Wiche G, Rolfs A (2002) Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy. J Neuropathol Exp Neurol 61:520–530
70. Stockburger C, Gold VA, Pallas T, Kolesova N, Miano D, Leuner K, Muller WE (2014) A cell model for the initial phase of sporadic Alzheimer’s disease. J Alzheimers Dis 42:395–411
71. Strecker V, Wumaier Z, Wittig I, Schagger H (2010) Large pore gels to separate mega protein complexes larger than 10 MDa by blue native electrophoresis: isolation of putative respiratory strings or patches. Proteomics 10:3379–3387
72. Su B, Wang X, Zheng L, Perry G, Smith MA, Zhu X (2010) Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochim Biophys Acta 1802:135–142
73. Thornell L, Carlsson L, Li Z, Mericskay M, Paulin D (1997) Null mutation in the desmin gene gives rise to a cardiomyopathy. J Mol Cell Cardiol 29:2107–2124
74. Uszkoreit J, Maerkens A, Perez-Riverol Y, Meyer HE, Marcus K, Stephan C, Kohlbacher O, Eisenacher M (2015) PIA: an intuitive protein inference engine with a web-based user interface. J Proteome Res 14:2988–2997
75. Vernengo L, Chourbagi O, Panuncio A, Lilienbaum A, Batonnet-Pichon S, Bruston F, Rodrigues-Lima F, Mesa R, Pizzarossa C, Demay L, Richard P, Vicart P, Rodriguez MM (2010) Desmin myopathy with severe cardiomyopathy in a Uruguayan family due to a codon deletion in a new location within the desmin 1A rod domain. Neuromuscul Disord 20:178–187
76. Winter L, Kuznetsov AV, Grimm M, Zeold A, Fischer I, Wiche G (2015) Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle. Hum Mol Genet 24:4530–4544
77. Winter L, Turk M, Harter PN, Mittelbronn M, Kornblum C, Norwood F, Jungbluth H, Thiel CT, Schlotzer-Schrehardt U, Schroder R (2016) Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy. Acta Neuropathol Commun 4:44
78. Wittig I, Braun HP, Schagger H (2006) Blue native PAGE. Nat Protoc 1:418–428
79. Wittig I, Carrozzo R, Santorelli FM, Schagger H (2006) Supercomplexes and subcomplexes of mitochondrial oxidative phosphorylation. Biochim Biophys Acta 1757:1066–1072
80. Wittig I, Karas M, Schagger H (2007) High resolution clear native electrophoresis for in-gel functional assays and fluorescence studies of membrane protein complexes. Mol Cell Proteomics 6:1215–1225
81. Zerbetto E, Vergani L, Dabbeni-Sala F (1997) Quantification of muscle mitochondrial oxidative phosphorylation enzymes via histochemical staining of blue native polyacrylamide gels. Electrophoresis 18:2059–2064
82. Zhao S, Fernald RD (2005) Comprehensive algorithm for quantitative real-time polymerase chain reaction. J Comput Biol 12:1047–1064
83. Zsurka G, Baron M, Stewart JD, Kornblum C, Bos M, Sassen R, Taylor RW, Elger CE, Chinnery PF, Kunz WS (2008) Clonally expanded mitochondrial DNA mutations in epileptic individuals with mutated DNA polymerase gamma. J Neuropathol Exp Neurol 67:857–866