Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion


The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral1 (OMIM 251880). Known mutant genes, including TK2 (ref. 2), SUCLA2 (ref. 3), DGUOK (ref. 4) and POLG5,6, account for only a fraction of MDDS cases7. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17 (ref. 8). We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product9, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17−/− mice.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Linkage analysis, selection of candidate genes and mutation analysis.
Figure 2: MPV17 transcript, gene organization and protein.
Figure 3: Complementation studies in Saccharomyces cerevisiae.
Figure 4: Mitochondrial localization of MPV17.
Figure 5: Mpv17 versus peroxisomal PMP70 immunostaining.
Figure 6: Characterization of Mpv17−/− mice.


  1. Spinazzola, A. & Zeviani, M. Disorders of nuclear-mitochondrial intergenomic signaling. Gene 354, 162–168 (2005).

    Article  CAS  Google Scholar 

  2. Saada, A. et al. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat. Genet. 29, 342–344 (2001).

    Article  CAS  Google Scholar 

  3. Elpeleg, O. et al. Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am. J. Hum. Genet. 76, 1081–1086 (2005).

    Article  CAS  Google Scholar 

  4. Mandel, H. et al. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat. Genet. 29, 337–341 (2001).

    Article  CAS  Google Scholar 

  5. Nguyen, K.V. et al. POLG mutations in Alpers syndrome. Neurology 65, 1493–1495 (2005).

    Article  CAS  Google Scholar 

  6. Ferrari, G. et al. Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain 128, 723–731 (2005).

    Article  Google Scholar 

  7. Salviati, L. et al. Mitochondrial DNA depletion and dGK gene mutations. Ann. Neurol. 52, 311–317 (2002).

    Article  CAS  Google Scholar 

  8. 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 62, 425–434 (1990).

    Article  CAS  Google Scholar 

  9. Zwacka, R.M. et al. The glomerulosclerosis gene Mpv17 encodes a peroxisomal protein producing reactive oxygen species. EMBO J. 13, 5129–5134 (1994).

    Article  CAS  Google Scholar 

  10. Calvo, S., Jain, M. & Xie, X. et al. Systematic identification of human mitochondrial disease genes through integrative genomics. Nat. Genet., advance online publication 2 April 2006 (doi:10.1038/ng1776).

  11. Trott, A. & Morano, K.A. SYM1 is the stress-induced Saccharomyces cerevisiae ortholog of the mammalian kidney disease gene Mpv17 and is required for ethanol metabolism and tolerance during heat shock. Eukaryot. Cell 3, 620–631 (2004).

    Article  CAS  Google Scholar 

  12. Mounolou, J.C., Jakob, H. & Slonimski, P.P. Mitochondrial DNA from yeast “petite” mutants: specific changes in buoyant density corresponding to different cytoplasmic mutations. Biochem. Biophys. Res. Commun. 24, 218–224 (1966).

    Article  CAS  Google Scholar 

  13. Tiranti, V. et al. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am. J. Hum. Genet. 74, 239–252 (2004).

    Article  CAS  Google Scholar 

  14. Koehler, C.M. New developments in mitochondrial assembly. Annu. Rev. Cell Dev. Biol. 20, 309–335 (2004).

    Article  CAS  Google Scholar 

  15. Wiedemann, N., Frazier, A.E. & Pfanner, N. The protein import machinery of mitochondria. J. Biol. Chem. 279, 14473–14478 (2004).

    Article  CAS  Google Scholar 

  16. Gakh, O., Cavadini, P. & Isaya, G. Mitochondrial processing peptidases. Biochim. Biophys. Acta 1592, 63–77 (2002).

    Article  CAS  Google Scholar 

  17. Rehling, P., Pfanner, N. & Meisinger, C. Insertion of hydrophobic membrane proteins into the inner mitochondrial membrane – a guided tour. J. Mol. Biol. 326, 639–657 (2003).

    Article  CAS  Google Scholar 

  18. Otsuka, M., Mizuno, Y., Yoshida, M., Kagawa, Y. & Ohta, S. Nucleotide sequence of cDNA encoding human cytochrome c oxidase subunit VIc. Nucleic Acids Res. 16, 10916 (1988).

    Article  CAS  Google Scholar 

  19. Hammen, P.K., Gorenstein, D.G. & Weiner, H. Structure of the signal sequences for two mitochondrial matrix proteins that are not proteolytically processed upon import. Biochemistry 33, 8610–8617 (1994).

    Article  CAS  Google Scholar 

  20. 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. 253, 470–474 (1996).

    Article  CAS  Google Scholar 

  21. Fernandez-Vizarra, E., Lopez-Perez, M.J. & Enriquez, J.A. Isolation of biogenetically competent mitochondria from mammalian tissues and cultured cells. Methods 26, 292–297 (2002).

    Article  Google Scholar 

  22. Gallet, P.F. et al. Transbilayer movement and distribution of spin-labelled phospholipids in the inner mitochondrial membrane. Biochim. Biophys. Acta 1418, 61–70 (1999).

    Article  CAS  Google Scholar 

  23. Ohba, M. & Schatz, G. Disruption of the outer membrane restores protein import to trypsin-treated yeast mitochondria. EMBO J. 6, 2117–2122 (1987).

    Article  CAS  Google Scholar 

  24. Tiranti, V. et al. Characterization of SURF-1 expression and Surf-1p function in normal and disease conditions. Hum. Mol. Genet. 8, 2533–2540 (1999).

    Article  CAS  Google Scholar 

  25. Fujiki, Y., Hubbard, A.L., Fowler, S. & Lazarow, P.B. Isolation of intracellular membranes by means of sodium carbonate treatment: application to endoplasmic reticulum. J. Cell. Biol. 93, 97–102 (1982).

    Article  CAS  Google Scholar 

  26. Bugiani, M. et al. Clinical and molecular findings in children with complex I deficiency. Biochim. Biophys. Acta 1659, 136–147 (2004).

    Article  CAS  Google Scholar 

  27. Petruzzella, V. et al. Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain. Genomics 54, 494–504 (1998).

    Article  CAS  Google Scholar 

  28. Ho, S.N., Hunt, H.D., Horton, R.M., Pullen, J.K. & Pease, L.R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77, 51–59 (1989).

    Article  CAS  Google Scholar 

  29. Fontanesi, F. et al. Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations, lead to defective oxidative phosphorylation in Saccharomyces cerevisiae and affect mitochondrial DNA stability. Hum. Mol. Genet. 13, 923–934 (2004).

    Article  CAS  Google Scholar 

  30. Winterthun, S. et al. Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Neurology 64, 1204–1208 (2005).

    Article  CAS  Google Scholar 

Download references


We are indebted to B. Geehan for revising the manuscript, E. Lamantea for technical assistance and L. Palmieri for critical discussion. This work was supported by Fondazione Telethon-Italy (grant GGP030039), Fondazione Pierfranco e Luisa Mariani and MITOCIRCLE and EUMITOCOMBAT network grants from the European Union Framework Program 6.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Massimo Zeviani.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Clinical and molecular characterization of individuals with mutant MPV17. (PDF 101 kb)

Supplementary Fig. 2

Alkali treatment of mitochondrial membranes. (PDF 87 kb)

Supplementary Table 1

Strategy for site-directed mutagenesis. (PDF 40 kb)

Supplementary Table 2

Oligonucleotides used for DNA blot and real-time PCR analyses on mouse genome. (PDF 32 kb)

Supplementary Table 3

Strategy for nucleotide sequencing of the human MPV17 gene. (PDF 31 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E. et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 38, 570–575 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing