Skip to main content
Springer Nature Link
Log in

Diseases of the Human Mitochondrial Oxidative Phosphorylation System

  • Chapter
  • First Online:
Inherited Neuromuscular Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 652))

Abstract

Mitochondrial diseases, or diseases of the oxidative phosphorylation system, consist of a group of disorders originated by a deficient synthesis of ATP. This system is composed of proteins codified in the two genetic systems of the cell, the nuclear and the mitochondrial genomes, and, therefore, the mode of inheritance could be either mendelian or maternal. The diseases can also appear sporadically. Due to the central role that mitochondria play in cellular physiology, these diseases are a social and health problem of great importance. They are considered rare diseases; however, together they constitute a large variety of genetic disorders.

It is also believed that mitochondria are involved, directly or indirectly, in many other human diseases, mainly in age-related diseases. This review will focus mainly on describing the special characteristics of the mitochondrial genetic system and the diseases caused by mitochondrial DNA mutations. We will also note the difficulties in studying these pathologies, and the possible involvement of the genetic variability of the mitochondrial genome in the development of these diseases.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Anderson, S., Bankier, A. T., Barrell, B. G., de-Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, H. P., Smith, A. J. H., Stader, R. and Young, I. G. Sequence and organization of the human mitochondrial genome. Nature (1981) 290: 427–465.

    Google Scholar 

  2. Andrews, R. M., Kubacka, I., Chinnery, P. F., Lightowlers, R. N., Turnbull, D. M. and Howell, N. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet (1999) 23: 147.

    Article  CAS  PubMed  Google Scholar 

  3. Barel, O., Shorer, Z., Flusser, H., Ofir, R., Narkis, G., Finer, G., Shalev, H., Nasasra, A., Saada, A. and Birk, O. S. Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. Am J Hum Genet (2008) 82: 1211–1216.

    Article  CAS  PubMed  Google Scholar 

  4. Bindoff, L. A., Howell, N., Poulton, J., Mccullough, D. A., Morten, K. J., Lightowlers, R. N., Turnbull, D. M. and Weber, K. Abnormal RNA processing associated with a novel transfer RNA mutation in mitochondrial DNA - a potential disease mechanism. J Biol Chem (1993) 268: 19559–19564.

    CAS  PubMed  Google Scholar 

  5. Bourgerom, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A. and Rotig, A. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet (1995) 11: 144–149.

    Article  Google Scholar 

  6. Bowmaker, M., Yang, M. Y., Yasukawa, T., Reyes, A., Jacobs, H. T., Huberman, J. A. and Holt, I. J. Mammalian mitochondrial DNA replicates bidirectionally from an initiation zone. J Biol Chem (2003) 278: 50961–50969.

    Article  CAS  PubMed  Google Scholar 

  7. Brown, M. D., Allen, J. C., Van Stavern, G. P., Newman, N. J. and Wallace, D. C. Clinical, genetic, and biochemical characterization of a Leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations. Am J Med Genet (2001) 104: 331–338.

    CAS  PubMed  Google Scholar 

  8. Bykhovskaya, Y., Mengesha, E., Wang, D., Yang, H., Estivill, X., Shohat, M. and Fischel-Ghodsian, N. Human mitochondrial transcription factor B1 as a modifier gene for hearing loss associated with the mitochondrial A1555G mutation. Mol Genet Metab (2004) 82: 27–32.

    Article  CAS  PubMed  Google Scholar 

  9. Chomyn, A., Mariottini, P., Cleeter, M. W. J., Ragan, C. I., Doolittle, R. F., Matsuno-Yagi, A., Hatefi, Y. and Attardi, G. Functional assignment of the products of the unidentified reading frames o human mitochondrial DNA. In: Achievements and Perspectives of Mitochondrial Research (Quagliarello, E., Slater, E. C., Plamieri, F., Saccone, C. and Kroon, A. M. Amsterdam, eds). Volume II Elsevier Sciences. 1985, 259–275.

    Google Scholar 

  10. Chomyn, A., Martinuzzi, A., Yoneda, M., Daga, A., Hurko, O., Johns, D., Lai, S. T., Nonaka, I., Angelini, C. and Attardi, G. MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcritps. Proc Natl Acad Sci U S A (1992) 89: 4221–4225.

    Article  CAS  PubMed  Google Scholar 

  11. Chomyn, A., Meola, G., Bresolin, N., Lai, S. T., Scarlato, G. and Attardi, G. In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathty-patient mitochodria. Mol Cell Biol (1991) 11: 2236–2244.

    CAS  PubMed  Google Scholar 

  12. Clayton, D. A. Replication of animal mitochondrial DNA. Cell (1982) 28: 693–705.

    Article  CAS  PubMed  Google Scholar 

  13. DiMauro, S. and Bonilla, E. Mitochondrial encephalomyopathies. In: The molecular and Genetic Basis of neurological diseases (Rosenberg, R. N., Prusiner, S. B., DiMauro, S. and Barchi, R. L., eds). Boston, Butterworth-Heinemann: 1998, 201–235.

    Google Scholar 

  14. Dimauro, S. and Hirano, M. Mitochondrial encephalomyopathies: an update. Neuromuscul Disord (2005) 15: 276–286.

    Article  PubMed  Google Scholar 

  15. DiMauro, S., Hirano, M. and Schon, E. A., Eds.. Mitochondrial Medicine. Abingdon, Informa Health Care: 2006.

    Google Scholar 

  16. Dimauro, S. and Schon, E. A. Mitochondrial disorders in the nervous system. Annu Rev Neurosci (2008) 31: 91–123.

    Article  CAS  PubMed  Google Scholar 

  17. Evans, M. and Rees, A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Safety (2002) 25: 649–663.

    Article  CAS  PubMed  Google Scholar 

  18. Guan, M. X., Enriquez, J. A., Fischel-Ghodsian, N., Puranam, R. S., Lin, C. P., Maw, M. A. and Attardi, G. The deafness-associated mitochondrial DNA mutation at position 7445, which affects tRNASer(UCN) precursor processing, has long-range effects on NADH dehydrogenase subunit ND6 gene expression. Mol Cell Biol (1998) 18: 5868–5879.

    CAS  PubMed  Google Scholar 

  19. Hao, H. L. and Moraes, C. T. Functional and molecular mitochondrial abnormalities associated with a C->T transition at position 3256 of the human mitochondrial genome – the effects of a pathogenic mitochondrial tRNA point mutation in organelle translation and RNA processing. J Biol Chem (1996) 271: 2347–2352.

    Article  CAS  PubMed  Google Scholar 

  20. Herrero-Martin, M. D., Pineda, M., Briones, P., Lopez-Gallardo, E., Carreras, M., Benac, M., Angel Idoate, M., Vilaseca, M. A., Artuch, R., Lopez-Perez, M. J., Ruiz-Pesini, E. and Montoya, J. A new pathologic mitochondrial DNA mutation in the cytochrome oxidase subunit I (MT-CO1). Hum Mutat (2008) 29: E103–E111.

    Article  Google Scholar 

  21. Hess, J. F., Parisi, M. A., Bennett, J. L. and Clayton, D. A. Impairment of mitochondrial transcription termination by a point mutation associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature (1991) 351: 236–239.

    Article  CAS  PubMed  Google Scholar 

  22. Holt, I. J., Harding, A. E. and Morgan-Hughes, J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature (1988) 331: 717–719.

    Article  CAS  PubMed  Google Scholar 

  23. Kasamatsu, H., Robberson, D. L. and Vinograd, J. A novel closed-circular mitochondrial DNA with properties of a replicating intermediate. Proc Natl Acad Sci U S A (1971) 68: 2252–2257.

    Article  CAS  PubMed  Google Scholar 

  24. King, M. P. and Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science (1989) 246: 500–503.

    Article  CAS  PubMed  Google Scholar 

  25. King, M. P., Koga, Y., Davidson, M. and Schon, E. A. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the transfer RNA(Leu)(UUR) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Mol Cell Biol (1992) 12: 480–490.

    CAS  PubMed  Google Scholar 

  26. Koga, Y., Davidson, M., Schon, E. A. and King, M. P. Fine mapping of mitochondrial RNAs derived from the mtDNA region containing a point mutation associated with MELAS. Nucleic Acids Res (1993) 21: 657–662.

    Article  CAS  PubMed  Google Scholar 

  27. Kruse, B., Narasimhan, N. and Attardi, G. Termination of transcription in human mitochondria: identification and purification of a DNA binding protein factor that promotes termination. Cell (1989) 58: 391–397.

    Article  CAS  PubMed  Google Scholar 

  28. Langston, J. W., Ballard, P., Tetrud, J. W. and Irwin, I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science (1983) 219: 979–980.

    Article  CAS  PubMed  Google Scholar 

  29. Lannuzel, A., Michel, P. P., Hoglinger, G. U., Champy, P., Jousset, A., Medja, F., Lombes, A., Darios, F., Gleye, C., Laurens, A., Hocquemiller, R., Hirsch, E. C. and Ruberg, M. The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism. Neuroscience (2003) 121: 287–296.

    Article  CAS  PubMed  Google Scholar 

  30. Loeffen, J. L. C. M., Smeitink, J. A. M., Trijbels, J. M. F., Janssen, A. J. M., Triepels, R. H., Sengers, R. C. A. and van den Heuvel, L. P. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat (2000) 15: 123–134.

    Article  CAS  PubMed  Google Scholar 

  31. Martin, M., Cho, J., Cesare, A. J., Griffith, J. D. and Attardi, G. Termination factor-mediated DNA loop between termination and initiation sites drives mitochondrial rRNA synthesis. Cell (2005) 123: 1227–1240.

    Article  CAS  PubMed  Google Scholar 

  32. Massa, V., Fernandez-Vizarra, E., Alshahwan, S., Bakhsh, E., Goffrini, P., Ferrero, I., Mereghetti, P., D'Adamo, P., Gasparini, P. and Zeviani, M. Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome C oxidase. Am J Hum Genet (2008) 82: 1281–1289.

    Article  CAS  PubMed  Google Scholar 

  33. McCulloch, V., Seidel-Rogol, B. L. and Shadel, G. S. A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds s-adenosylmethionine. Mol Cell Biol (2002) 22: 1116–1125.

    Article  CAS  PubMed  Google Scholar 

  34. Michikawa, Y., Mazzucchelli, F., Bresolin, N., Scarlato, G. and Attardi, G. Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science (1999) 286: 774–779.

    Article  CAS  PubMed  Google Scholar 

  35. Miller, C., Saada, A., Shaul, N., Shabtai, N., Ben-Shalom, E., Shaag, A., Hershkovitz, E. and Elpeleg, O. Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation. Ann Neurol (2004) 56: 734–738.

    Article  CAS  PubMed  Google Scholar 

  36. Montoya, J., Christianson, T., Levens, D., Rabinowitz, M. and Attardi, G. Identification of initiation sites for heavy strand and light strand transcription in human mitochondrial DNA. Proc Natl Acad Sci U S A (1982) 79: 7195–7199.

    Article  CAS  PubMed  Google Scholar 

  37. Montoya, J., Gaines, G. L. and Attardi, G. The pattern of transcription of the human mitochondrial rRNA genes reveals two overlapping transcription units. Cell (1983) 34: 151–159.

    Article  CAS  PubMed  Google Scholar 

  38. Montoya, J., Lopez-Gallardo, E., Diez-Sanchez, C., Lopez-Perez, M. J. and Ruiz-Pesini, E. 20 years of human mtDNA pathologic point mutations: Carefully reading the pathogenicity criteria. Bba Bioenergetics (2009) 1787: 476–483.

    Google Scholar 

  39. Montoya, J., Lopez-Perez, M. J. and Ruiz-Pesini, E. Mitochondrial DNA transcription and diseases: past, present and future. Biochim Biophys Acta (2006) 1757: 1179–1189.

    Article  CAS  PubMed  Google Scholar 

  40. Montoya, J., Ojala, D. and Attardi, G. Distinctive features of the 5`-terminal sequences of the human mitochondrial mRNAs. Nature (1981) 290: 465–470.

    Article  CAS  PubMed  Google Scholar 

  41. Nam, S. C. and Kang, C. DNA light-strand preferential recognition of human mitochondria transcription termination factor mTERF. J Biochem Mol Biol (2005) 38: 690–694.

    CAS  PubMed  Google Scholar 

  42. Ojala, D., Merkel, C., Gelfand, R. and Attardi, G. The tRNA genes punctuate the reading of genetic information in human mitochondrial DNA. Cell (1980) 22: 393–403.

    Article  CAS  PubMed  Google Scholar 

  43. Ojala, D., Montoya, J. and Attardi, G. The putative mRNA per subunit II of human cytochrome c starts directly at the translation initiation codon. Nature (1980) 287: 79–82.

    Article  CAS  PubMed  Google Scholar 

  44. Ojala, D., Montoya, J. and Attardi, G. tRNA punctuation model of RNA processing in human mitochondria. Nature (1981) 290: 470–474.

    Article  CAS  PubMed  Google Scholar 

  45. Rife, J. P. and Moore, P. B. The structure of a methylated tetraloop in 16S ribosomal RNA. Structure (1998) 6: 747–756.

    Article  CAS  PubMed  Google Scholar 

  46. Robberson, D. L., Kasamatsu, H. and Vinograd, J. Replication of mitochondrial DNA. Circular replicative intermediates in mouse L cells. Proc Natl Acad Sci U S A (1972) 69: 713–741.

    Google Scholar 

  47. Ruiz-Pesini, E., Lopez-Gallardo, E., Dahmani, Y., Herrero, M. D., Solano, A., Diez-Sanchez, C., Lopez-Perez, M. and Montoya, J. Diseases of the human mitochondrial oxidative phosphorylation system. Rev Neurol (2006) 43: 416–424.

    CAS  PubMed  Google Scholar 

  48. SeidelRogol, B. L., McCulloch, V. and Shadel, G. S. Human mitochondrial transcription factor B1 methylates ribosomal RNA at a conserved stem-loop. Nat Genet (2003) 33: 23–24.

    Article  CAS  Google Scholar 

  49. Skladal, D., Halliday, J. and R., T. D. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain: J Neurol (2003) 126: 1905–1912.

    Google Scholar 

  50. Smeitink, J. A., Elpeleg, O., Antonicka, H., Diepstra, H., Saada, A., Smits, P., Sasarman, F., Vriend, G., Jacob-Hirsch, J., Shaag, A., Rechavi, G., Welling, B., Horst, J., Rodenburg, R. J., van den Heuvel, B. and Shoubridge, E. A. Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am J Hum Genet (2006) 79: 869–877.

    Article  CAS  PubMed  Google Scholar 

  51. Sutovsky, P., Neuber, E. and Schatten, G. Ubiquitin-dependent sperm quality control mechanism recognizes spermatozoa with DNA defects as revealed by dual ubiquitin-TUNEL assay. Mol Reprod Dev (2002) 61: 406–413.

    Article  CAS  PubMed  Google Scholar 

  52. Takaku, H., Minagawa, A., Takagi, M. and Nashimoto, M. A candidate prostate cancer susceptibility gene encodes tRNA 3' processing endoribonuclease. Nucleic Acids Res (2003) 31: 2272–2278.

    Article  CAS  PubMed  Google Scholar 

  53. Temperley, R. J., Seneca, S. H., Tonska, K., Bartnik, E., Bindoff, L. A., Lightowlers, R. N. and Chrzanowska-Lightowlers, Z. M. Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria. Hum Mol Genet (2003) 12: 2341–2348.

    Article  CAS  PubMed  Google Scholar 

  54. Tiranti, V., Savoia, A., Forti, F., DApolito, M. F., Centra, M., Racchi, M. and Zeviani, M. Identification of the gene encoding the human mitochondrial RNA polymerase (h-mtRPOL) by cyberscreening of the expressed sequence tags database. Hum Mol Genet (1997) 6: 615–625.

    Article  CAS  PubMed  Google Scholar 

  55. Toompuu, M., Levinger, L. L., Nadal, A., Gomez, J. and Jacobs, H. T. The 7472insC mtDNA mutation impairs 5' and 3' processing of tRNA(Ser(UCN)). Biochem Biophys Res Commun (2004) 322: 803–813.

    Article  CAS  PubMed  Google Scholar 

  56. Valente, L., Tiranti, V., Marsano, R. M., Malfatti, E., Fernandez-Vizarra, E., Donnini, C., Mereghetti, P., De Gioia, L., Burlina, A., Castellan, C., Comi, G. P., Savasta, S., Ferrero, I. and Zeviani, M. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. Am J Hum Genet (2007) 80: 44–58.

    Article  CAS  PubMed  Google Scholar 

  57. Wallace, D. C., Ruiz-Pesini, E. and Mishmar, D. mtDNA variation, climatic adaptation, degenerative diseases, and longevity. Cold Spring Harb Symp Quant Biol (2003) 68: 479–486.

    Article  CAS  PubMed  Google Scholar 

  58. Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M. S., II, L. J. E. and Nikoskelainen, E. K. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science (1988) 242: 1427–1430.

    Google Scholar 

  59. Yan, H., Zareen, N. and Levinger, L. Naturally occurring mutations in human mitochondrial pre-tRNASer(UCN) can affect the tRNase Z cleavage site, processing kinetics and substrate secondary structure. J Biol Chem (2006) 281: 3926–3935.

    Article  CAS  PubMed  Google Scholar 

  60. Yasukawa, T., Yang, M. Y., Jacobs, H. T. and Holt, I. J. A bidirectional origin of replication maps to the major noncoding region of human mitochondrial DNA. Mol Cell (2005) 18: 651–662.

    Article  CAS  PubMed  Google Scholar 

  61. Zeviani, M., Moraes, C. T., DiMauro, S., Nakase, H., Bonilla, E., Schon, E. and Rowland, L. P. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology (1988) 38: 1339–1346.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This project was supported by grants from the Instituto de Salud Carlos III-FIS (PI07-0045 and PI05-0647) and the Diputación General de Aragón (Grupos Consolidados B33 and PM063-2007). CIBER de Enfermedades Raras (CIBERER) is an initiative of the ISCIII.

Author information

Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain

    Julio Montoya

  2. Services of Neurology, Clinical Neurophysiology and Radiology, University Hospital “Marqués de Valdecilla”, University of Cantabria, CIBERNED and IFIMAV, Santander, Spain

    Ester López-Gallardo

  3. CIBER de Enfermedades Raras (CIBERER), ISCIII and Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain

    María Dolores Herrero-Martín, Íñigo Martínez-Romero, Aurora Gómez-Durán, David Pacheu, Magdalena Carreras, Carmen Díez-Sánchez, Manuel J. López-Pérez & Eduardo Ruiz-Pesini

Authors
  1. Julio Montoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ester López-Gallardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. María Dolores Herrero-Martín
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Íñigo Martínez-Romero
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aurora Gómez-Durán
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Pacheu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Magdalena Carreras
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carmen Díez-Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Manuel J. López-Pérez
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eduardo Ruiz-Pesini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julio Montoya .

Editor information

Editors and Affiliations

  1. CIBERER-BIOBANK, Avda. Campanar 21, Valencia, 46009, Spain

    Carmen Espinós

  2. Lab. Neurobiología, Centro de Investigación Príncipe Felipe, Av. Autopista del Saler 16, Valencia, 46012, Spain

    Vicente Felipo

  3. Inst. Biomedicina, CSIC Valencia, C/ Jaime Roig 11, Valencia, 46010, Spain

    Francesc Palau

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Montoya, J. et al. (2009). Diseases of the Human Mitochondrial Oxidative Phosphorylation System. In: Espinós, C., Felipo, V., Palau, F. (eds) Inherited Neuromuscular Diseases. Advances in Experimental Medicine and Biology, vol 652. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2813-6_5

Download citation

Publish with us

Policies and ethics