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Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice

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Viscomi, Carlo, Spinazzola, Antonella, Maggioni, Marco, Fernandez-Vizarra, Erika, Massa, Valeria, Pagano, Claudio, Vettor, Roberto, Mora, Marina +1 more·2009·Human Molecular Genetics
DOI 10.1093/hmg/ddn309PMC PMC2644642
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Abstract

In humans, MPV17 mutations are responsible for severe mitochondrial depletion syndrome, mainly affecting the liver and the nervous system. To gain insight into physiopathology of MPV17-related disease, we investigated an available Mpv17 knockout animal model. We found severe mtDNA depletion in liver and, albeit to a lesser extent, in skeletal muscle, whereas hardly any depletion was detected in brain and kidney, up to 1 year after birth. Mouse embryonic fibroblasts did show mtDNA depletion, but only after several culturing passages, or in a serumless culturing medium. In spite of severe mtDNA depletion, only moderate decrease in respiratory chain enzymatic activities, and mild cytoarchitectural alterations, were observed in the Mpv17(-/-) livers, but neither cirrhosis nor failure ever occurred in this organ at any age. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensate the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf1, a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear and kidney. The coat of the Mpv17(-/-) mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter lifespan. Coincidental with the onset of FSGS, there was hardly any mtDNA left in the glomerular tufts. These results demonstrate that Mpv17 controls mtDNA copy number by a highly tissue- and possibly cytotype-specific mechanism.

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  1. [1]Spinazzola A. Zeviani M. Disorders of nuclear-mitochondrial intergenomic communication Biosci. Rep. 2007 27 39 51 17510790
  2. [2]Sarzi E. Bourbon A. Chrétien D. Zarhrate M. Colcos J. Slama A. Cormier-Daire V. de Lonlay P. Munnich A. Rötig A. Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood J. Pediatr. 2007 150 531 534 17452231
  3. [3]Saada A. Shaag A. Mandel H. Nevo Y. Eriksson S. Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy Nat. Genet. 2001 29 342 344 11687801
  4. [4]Mandel H. Szargel R. Labay V. Elpeleg O. Saada A. Shalata A. Anbinder Y. Berkowitz D. Hartman C. Barak M. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA Nat. Genet. 2001 29 337 341 11687800
  5. [5]Bourdon A. Minai L. Serre V. Jais J.P. Sarzi E. Aubert S. Chrétien D. de Lonlay P. Paquis-Flucklinger V. Arakawa H. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion Nat. Genet. 2007 39 776 780 17486094
  6. [6]Nishino I. Spinazzola A. Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder Science 1999 283 689 692 9924029
  7. [7]Naviaux R.K. Nguyen K.V. POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion Ann. Neurol. 2004 55 706 712 15122711
  8. [8]Ferrari G. Lamantea E. Donati A. Filosto M. Briem E. Carrara F. Parini R. Limonati A. Santer R. Zeviani M. Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA Brain 2005 128 723 731 15689359
  9. [9]Hakonen A.H. Isohanni P. Paetau A. Herva R. Suomalainen A. Lonnqvist T. Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion Brain 2007 130 3032 3040 17921179
  10. [10]Sarzi E. Goffart S. Serre V. Chretien D. Slama A. Munnich A. Spelbrink J.N. Rotig A. Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion Ann. Neurol. 2007 62 579 587 17722119
  11. [11]Elpeleg O. Miller C. Hershkovitz E. Bitner-Glindzicz M. Bondi-Rubinstein G. Rahman S. Pagnamenta A. Eshhar S. Saada A. Deficiency of the ADP-forming succinyl–CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion Am. J. Hum. Genet. 2005 76 1081 1086 15877282 PMC1196446
  12. [12]Ostergaard E. Christensen E. Kristensen E. Mogensen B. Duno M. Shoubridge E.A. Wibrand F. Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion Am. J. Hum. Genet. 2007 81 383 387 17668387 PMC1950792
  13. [13]Spinazzola A. Viscomi C. Fernandez-Vizarra E. Carrara F. D’Adamo P. Calvo S. Marsano R.M. Donnini C. Weiher H. Strisciuglio P. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion Nat. Genet. 2006 38 570 575 16582910
  14. [14]Wong L.J. Brunetti-Pierri N. Zhang Q. Yazigi N. Bove K.E. Dahms B.B. Puchowicz M.A. Gonzalez-Gomez I. Schmitt E.S. Truong C.K. Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy Hepatology 2007 46 1218 1227 17694548
  15. [15]Navarro-Sastre A. Martín-Hernández E. Campos Y. Quintana E. Medina E. de Las Heras R.S. Lluch M. Muñoz A. del Hoyo P. Martín R. Lethal hepatopathy and leukodystrophy caused by a novel mutation in MPV17 gene: description of an alternative MPV17 spliced form Mol. Genet. Metab. 2008 94 234 239 18329934
  16. [16]Spinazzola A. Santer R. Akman O.H. Tsiakas K. Schaefer H. Ding X. Karadimas C.L. Shanske S. Ganesh J. Di Mauro S. Hepatocerebral form of mitochondrial DNA depletion syndrome Arch. Neurol. 2008 65 1 6 18695062
  17. [17]Karadimas C.L. Vu T.H. Holve S.A. Chronopoulou P. Quinzii C. Johnsen S.D. Kurth J. Eggers E. Palenzuela L. Tanji K. Navajo neurohepatopathy is caused by a mutation in the MPV17 gene Am. J. Hum. Genet. 2006 79 544 548 16909392 PMC1559552
  18. [18]Appenzeller O. Kornfeld M. Snyder R. Acromutilating, paralyzing neuropathy with corneal ulceration in Navajo children Arch. Neurol. 1976 33 733 738 185990
  19. [19]Spinazzola A. Massa V. Hirano M. Zeviani M. Lack of founder effect for an identical mtDNA depletion syndrome (MDS)-associated MPV17 mutation shared by Navajos and Italians Neuromuscul. Disord. 2008 18 315 318 18261905
  20. [20]Weiher H. Noda T. Gray D.A. Sharpe A.H. Jaenisch R. Transgenic mouse model of kidney disease: insertional inactivation of ubiquitously expressed gene leads to nephrotic syndrome Cell 1990 62 425 434 1696177
  21. [21]O’Bryan T. Weiher H. Rennke H.G. Kren S. Hostetter T.H. Course of renal injury in the Mpv17-deficient transgenic mouse J. Am. Soc. Nephrol. 2000 11 1067 1074 10820170
  22. [22]Clozel M. Hess P. Fischli W. Löffler B.M. Zwacka R.M. Reuter A. Weiher H. Age-dependent hypertension in Mpv17-deficient mice, a transgenic model of glomerulosclerosis and inner ear disease Exp. Gerontol. 1999 34 1007 1015 10673153
  23. [23]Meyer zum Gottesberge A.M. Reuter A. Weiher H. Inner ear defect similar to Alport’s syndrome in the glomerulosclerosis mouse model Mpv17 Eur. Arch. Otorhinolaryngol. 1996 253 470 474 9044568
  24. [24]Meyer zum Gottesberge A.M. Felix H. Abnormal basement membrane in the inner ear and the kidney of the Mpv17−/− mouse strain: ultrastructural and immunohistochemical investigations Histochem. Cell. Biol. 2005 124 507 516 16041630
  25. [25]Zwacka R.M. Reuter A. Pfaff E. Moll J. Gorgas K. Karasawa M. Weiher H. The glomerulosclerosis gene Mpv17 encodes a peroxisomal protein producing reactive oxygen species EMBO J. 1994 13 5129 5134 7957077 PMC395460
  26. [29]Zhou X. Solaroli N. Bjerke M. Stewart J.B. Rozell B. Johansson M. Karlsson A. Progressive loss of mitochondrial DNA in thymidine kinase 2-deficient mice Hum. Mol. Genet. 2008 17 2329 2335 18434326
  27. [30]Akman H.O. Dorado B. López L.C. García-Cazorla A. Vilà M.R. Tanabe L.M. Dauer W.T. Bonilla E. Tanji K. Hirano M. Thymidine kinase 2 (H126 N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance Hum. Mol. Genet. 2008 17 2433 2440 18467430 PMC3115590
  28. [31]Masuyama M. Iida R. Takatsuka H. Yasuda T. Matsuki T. Quantitative change in mitochondrial DNA content in various mouse tissues during aging Biochim. Biophys. Acta 2005 1723 302 308 15820144
  29. [32]Mandel H. Hartman C. Berkowitz D. Elpeleg O.N. Manov I. Iancu T.C. The hepatic mitochondrial DNA depletion syndrome: ultrastructural changes in liver biopsies Hepatology 2001 34 776 784 11584375
  30. [33]Larsson N.G. Wang J. Wilhelmsson H. Oldfors A. Rustin P. Lewandoski M. Barsh G.S. Clayton D.A. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice Nat. Genet. 1998 18 231 236 9500544
  31. [34]Barthelemy C. Ogier de Baulny H. Diaz J. Cheval M.A. Frachon P. Romero N. Goutieres F. Fardeau M. Lombes A. Late-onset mitochondrial DNA depletion: DNA copy number, multiple deletions, and compensation Ann. Neurol. 2001 49 607 617 11357951
  32. [35]Martin M. Cho J. Cesare A.J. Griffith J.D. Attardi G. Termination factor-mediated DNA loop between termination and initiation sites drives mitochondrial rRNA synthesis Cell 2005 123 1227 1240 16377564
  33. [36]Montoya J. Christianson T. Levens D. Rabinowitz M. Attardi G. Identification of initiation sites for heavy-strand and light-strand transcription in human mitochondrial DNA Proc. Natl Acad. Sci. 1982 79 7195 7199 6185947 PMC347305
  34. [37]Montoya J. Gaines G.L. Attardi G. The pattern of transcription of the human mitochondrial rRNA genes reveals two overlapping transcription units Cell 1983 42 151 159 6883508
  35. [38]Park C.B. Asin-Cayuela J. Cámara Y. Shi Y. Pellegrini M. Gaspari M. Wibom R. Hultenby K. Erdjument-Bromage H. Tempst P. MTERF3 is a negative regulator of mammalian mtDNA transcription Cell 2007 130 273 285 17662942
  36. [40]Mak S.S. Moriyama M. Nishioka E. Osawa M. Nishikawa S. Indispensable role of Bcl2 in the development of the melanocyte stem cell Develop. Biol. 2006 291 144 153 16427619
  37. [41]Tobin D.J. Paus R. Graying: gerontobiology of the hair follicle pigmentary unit Exp. Gerontol. 2001 36 29 54 11162910
  38. [42]Binder C.J. Weiher H. Exner M. Kerjaschki D. Glomerular overproduction of oxygen radicals in Mpv17 gene-inactivated mice causes podocyte foot process flattening and proteinuria: a model of steroid-resistant nephrosis sensitive to radical scavenger therapy Am. J. Pathol. 1999 154 1067 1075 10233845 PMC1866567
  39. [43]Hagiwara M. Yamagata K. Capaldi R.A. Koyama A. Mitochondrial dysfunction in focal segmental glomerulosclerosis of puromycin aminonucleoside nephrosis Kidney Int. 2006 69 1146 1152 16609681
  40. [44]Rötig A. Renal disease and mitochondrial genetics J. Nephrol. 2003 16 286 292 12768079
  41. [45]Inoue K. Nakada K. Ogura A. Isobe K. Goto Y. Nonaka I. Hayashi J.I. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes Nat. Genet. 2000 26 176 181 11017072
  42. [46]Kimura T. Takeda S. Sagiya Y. Gotoh M. Nakamura Y. Arakawa H. Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools Nat. Genet. 2003 34 440 445 12858174
  43. [47]Gubler M.C. Inherited diseases of the glomerular basement membrane Nat. Clin. Pract. Nephrol. 2008 4 24 37 18094725
  44. [48]Reuter A. Nestl A. Zwacka R.M. Tuckermann J. Waldherr R. Wagner E.M. Höyhtyä M. Meyer zum Gottesberge A.M. Angel P. Weiher H. Expression of the recessive glomerulosclerosis gene Mpv17 regulates MMP-2 expression in fibroblasts, the kidney, and the inner ear of mice Mol. Biol. Cell 1998 9 1675 1682 9658163 PMC25405
  45. [49]Irwin W.A. Bergamin N. Sabatelli P. Reggiani C. Megighian A. Merlini L. Braghetta P. Columbaro M. Volpin D. Bressan G.M. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency Nat. Genet. 2003 35 367 371 14625552
  46. [50]Angelin A. Tiepolo T. Sabatelli P. Grumati P. Bergamin N. Golfieri C. Mattioli E. Gualandi F. Ferlini A. Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins Proc. Natl. Acad. Sci. 2007 104 991 996 17215366 PMC1783427
  47. [51]Merlini L. Angelin A. Tiepolo T. Braghetta P. Sabatelli P. Zamparelli A. Ferlini A. Maraldi N.M. Bonaldo P. Bernardi P. Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies Proc. Natl. Acad. Sci. 2008 105 5225 5229 18362356 PMC2278179
  48. [52]Heath K.E. Campos-Barros A. Toren A. Rozenfeld-Granot G. Carlsson L.E. Savige J. Denison J.C. Gregory M.C. White J.G. Barker D.F. Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes Am. J. Hum. Genet. 2001 69 1033 1045 11590545 PMC1274350
  49. [53]Lalwani A.K. Atkin G. Li Y. Lee J.Y. Hillman D.E. Mhatre A.N. Localization in stereocilia, plasma membrane, and mitochondria suggests diverse roles for NMHC-IIa within cochlear hair cells Brain. Res. 2008 1197 13 22 18241845 PMC2757014
  50. [54]Sciacco M. Bonilla E. Cytochemistry and immunocytochemistry of mitochondria in tissue sections Meth. Enzymol. 1996 264 509 521 8965723
  51. [55]Cree L.M. Patel S.K. Pyle A. Lynn S. Turnbull D.M. Chinnery P.F. Walker M. Age-related decline in mitochondrial DNA copy number in isolated human pancreatic islets Diabetologia 2008 51 1440 1443 18528676
  52. [56]Fernández-Vizarra E. López-Pérez M.J. Enriquez J.A. Isolation of biogenetically competent mitochondria from mammalian tissues and cultured cells Methods 2002 26 292 297 12054919
  53. [57]Fernández-Vizarra E. Enriquez J.A. Pérez-Martos A. Montoya J. Fernández-Silva P. Mitochondrial gene expression is regulated at multiple levels and differentially in the heart and liver by thyroid hormones Curr. Genet. 2008 54 13 22 18481068
  54. [58]Bugiani M. Tiranti V. Farina L. Uziel G. Zeviani M. Novel mutations in COX15 in long surviving Leigh syndrome patient with cytochrome c oxidase deficiency J. Med. Genet. 2005 42 e28 15863660 PMC1736058

Cited by

Sorted by citations

Authors
Viscomi, C., Spinazzola, A., Maggioni, M., Fernandez-Vizarra, E., Massa, V., Pagano, C., Vettor, R., Mora, M., & Zeviani, M.
Affiliations
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • Ospedale San Paolo (IT)
  • University of Padua (IT)
Corresponding author
Zeviani, Massimo
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2008-09-24
Volume
18
Issue
1
Pages
12-26
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddn309
PMC
PMC2644642
OpenAlex
W2165573674
Cited by
102
References
4
Citations by year
2026: 1 · 2025: 6 · 2024: 7 · 2022: 4 · 2021: 8 · 2020: 4 · 2019: 7 · 2018: 2 · 2017: 7 · 2016: 6 · 2015: 7 · 2014: 3 · 2013: 7 · 2012: 10
FWCI
3.15
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc)
  • UCL Discovery (University College London) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • European Commission
  • Ministero della Salute
  • Fondazione Pierfranco e Luisa Mariani (RF2006)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
MPV17, mitochondrial DNA depletion syndrome, focal segmental glomerulosclerosis, proteinuria, mtDNA transcription, mitochondrial respiratory chain, inner ear degeneration
MeSH terms
Animals, Cells, Cultured, Disease Models, Animal, DNA, Mitochondrial, Fibroblasts, Glomerulosclerosis, Focal Segmental, Humans, Liver, Membrane Proteins, Organ Specificity, Proteinuria, Transcription Factors, Transcription, Genetic, Age of Onset, Mice, Knockout, Mitochondrial Proteins, Mice

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