Skip to main content

Thank you for visiting nature.com. 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.

  • Review Article
  • Published:

Mitochondrial disorders as windows into an ancient organelle

Nature volume 491, pages 374–383 (2012)Cite this article

Subjects

Abstract

Much of our current knowledge about mitochondria has come from studying patients who have respiratory chain disorders. These disorders comprise a large collection of individually rare syndromes, each presenting in a unique and often devastating way. In recent years, there has been great progress in defining their genetic basis, but we still know little about the cascade of events that gives rise to such diverse pathology. Here, we review these disorders and explore them in the context of a contemporary understanding of mitochondrial evolution, biochemistry and genetics. Fully deciphering their pathogenesis is a challenging next step that will inspire the development of drug treatments for rare and common diseases.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phenotypic spectrum of mitochondrial disorders.
Figure 2: Mitochondrial evolution and the respiratory chain.
Figure 3: Mitochondrial tissue heterogeneity and robustness.
Figure 4: Genetic pathways underlying mitochondrial respiratory chain disorders.

Similar content being viewed by others

References

  1. Ernster, L., Ikkos, D. & Luft, R. Enzymic activities of human skeletal muscle mitochondria: a tool in clinical metabolic research. Nature 184, 1851–1854 (1959). This paper reports a fascinating case of euthyroid hypermetabolism, which is now regarded as the first case of a biochemically proven mitochondrial disease.

    Article  ADS  CAS  PubMed  Google Scholar 

  2. DiMauro, S. et al. Luft's disease. Further biochemical and ultrastructural studies of skeletal muscle in the second case. J. Neurol. Sci. 27, 217–232 (1976).

    Article  CAS  PubMed  Google Scholar 

  3. Skladal, D., Halliday, J. & Thorburn, D. R. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126, 1905–1912 (2003).

    Article  PubMed  Google Scholar 

  4. Munnich, A., Rotig, A., Cormier-Daire, V. & Rustin, P. in Scriver's Online Metabolic and Molecular Basis of Inherited Disease (eds Valle, D. et al.) Ch. 99 http://dx.doi.org/10.1036/ommbid.127 (McGraw-Hill, 2006)

    Google Scholar 

  5. Shoffner, J. in Scriver's Online Metabolic and Molecular Basis of Inherited Disease (eds Valle, D. et al.) Ch. 104 http://dx.doi.org/10.1036/ommbid.127 (McGraw-Hill, 2006).

    Google Scholar 

  6. McKenzie, R. et al. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N. Engl. J. Med. 333, 1099–1105 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008). This paper reports an accurate inventory of the mammalian mitochondrial proteome, called MitoCarta, consisting of about 1,100 proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Andersson, S. G. et al. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 396, 133–140 (1998). This paper reports the complete genome sequence of Rickettsia prowazekii , providing support for an α-proteobacterial ancestor of human mitochondria.

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Szklarczyk, R. & Huynen, M. A. Mosaic origin of the mitochondrial proteome. Proteomics 10, 4012–4024 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Sharma, M. R. et al. Structure of the mammalian mitochondrial ribosome reveals an expanded functional role for its component proteins. Cell 115, 97–108 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Shutt, T. E. & Gray, M. W. Bacteriophage origins of mitochondrial replication and transcription proteins. Trends Genet. 22, 90–95 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Bourdon, A. et al. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nature Genet. 39, 776–780 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Tibbetts, A. S. & Appling, D. R. Compartmentalization of mammalian folate-mediated one-carbon metabolism. Annu. Rev. Nutr. 30, 57–81 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hackenbrock, C. R., Chazotte, B. & Gupte, S. S. The random collision model and a critical assessment of diffusion and collision in mitochondrial electron transport. J. Bioenerg. Biomembr. 18, 331–368 (1986).

    Article  CAS  PubMed  Google Scholar 

  16. Chance, B. & Williams, G. R. A method for the localization of sites for oxidative phosphorylation. Nature 176, 250–254 (1955).

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Schagger, H. & Pfeiffer, K. The ratio of oxidative phosphorylation complexes I–V in bovine heart mitochondria and the composition of respiratory chain supercomplexes. J. Biol. Chem. 276, 37861–37867 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Schagger, H. & von Jagow, G. Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal. Biochem. 199, 223–231 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Cruciat, C. M., Brunner, S., Baumann, F., Neupert, W. & Stuart, R. A. The cytochrome bc1 and cytochrome c oxidase complexes associate to form a single supracomplex in yeast mitochondria. J. Biol. Chem. 275, 18093–18098 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Shoubridge, E. A. Supersizing the mitochondrial respiratory chain. Cell Metab. 15, 271–272 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Efremov, R. G., Baradaran, R. & Sazanov, L. A. The architecture of respiratory complex I. Nature 465, 441–445 (2010).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Hunte, C., Zickermann, V. & Brandt, U. Functional modules and structural basis of conformational coupling in mitochondrial complex I. Science 329, 448–451 (2010).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Runswick, M. J., Fearnley, I. M., Skehel, J. M. & Walker, J. E. Presence of an acyl carrier protein in NADH:ubiquinone oxidoreductase from bovine heart mitochondria. FEBS Lett. 286, 121–124 (1991).

    Article  CAS  PubMed  Google Scholar 

  24. Nouws, J. et al. Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Cell Metab. 12, 283–294 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Cogswell, A. M., Stevens, R. J. & Hood, D. A. Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. Am. J. Physiol. 264, C383–C389 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Fannin, S. W., Lesnefsky, E. J., Slabe, T. J., Hassan, M. O. & Hoppel, C. L. Aging selectively decreases oxidative capacity in rat heart interfibrillar mitochondria. Arch. Biochem. Biophys. 372, 399–407 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Allen, J. F. The function of genomes in bioenergetic organelles. Phil. Trans. R. Soc. Lond. B 358, 19–37 (2003).

    Article  CAS  Google Scholar 

  28. Johnson, D. T., Harris, R. A., Blair, P. V. & Balaban, R. S. Functional consequences of mitochondrial proteome heterogeneity. Am. J. Physiol. Cell Physiol. 292, C698–C707 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Pierron, D. et al. Cytochrome c oxidase: evolution of control via nuclear subunit addition. Biochim. Biophys. Acta 1817, 590–597 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Scarpulla, R. C. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 1813, 1269–1278 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Spiegelman, B. M. Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. Novartis Found. Symp. 287, 60–63 (2007).

    CAS  PubMed  Google Scholar 

  32. MacAskill, A. F. & Kittler, J. T. Control of mitochondrial transport and localization in neurons. Trends Cell Biol. 20, 102–112 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Chan, D. C. Fusion and fission: interlinked processes critical for mitochondrial health. Annu. Rev. Genet. http://dx.doi.org/10.1146/annurev-genet-110410-132529 (29 August, 2012).

  34. Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nature Rev. Mol. Cell Biol. 12, 9–14 (2011).

    Article  CAS  Google Scholar 

  35. Balaban, R. S., Kantor, H. L., Katz, L. A. & Briggs, R. W. Relation between work and phosphate metabolite in the in vivo paced mammalian heart. Science 232, 1121–1123 (1986).

    Article  ADS  CAS  PubMed  Google Scholar 

  36. Chance, B. & Williams, G. R. Respiratory enzymes in oxidative phosphorylation. III. The steady state. J. Biol. Chem. 217, 409–427 (1955). This classic paper introduced the 'respiratory states' of isolated mitochondria, providing a conceptual framework for studying mitochondrial energetics.

    Article  CAS  PubMed  Google Scholar 

  37. Glancy, B. & Balaban, R. S. Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry 51, 2959–2973 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Kacser, H. & Burns, J. A. The control of flux. Symp. Soc. Exp. Biol. 27, 65–104 (1973).

    CAS  PubMed  Google Scholar 

  39. Heinrich, R. & Rapoport, T. A. A linear steady-state treatment of enzymatic chains. General properties, control and effector strength. Eur. J. Biochem. 42, 89–95 (1974).

    Article  CAS  PubMed  Google Scholar 

  40. Groen, A. K., Wanders, R. J., Westerhoff, H. V., van der Meer, R. & Tager, J. M. Quantification of the contribution of various steps to the control of mitochondrial respiration. J. Biol. Chem. 257, 2754–2757 (1982).

    Article  CAS  PubMed  Google Scholar 

  41. Hartwell, L. Genetics. Robust interactions. Science 303, 774–775 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Rossignol, R., Malgat, M., Mazat, J. P. & Letellier, T. Threshold effect and tissue specificity. Implication for mitochondrial cytopathies. J. Biol. Chem. 274, 33426–33432 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981). This landmark publication reports the sequence and annotation of the human mitochondrial genome.

    Article  ADS  CAS  PubMed  Google Scholar 

  44. Wallace, D. C. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427–1430 (1988).

    Article  ADS  CAS  PubMed  Google Scholar 

  45. Holt, I. J., Harding, A. E. & Morgan-Hughes, J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717–719 (1988). References 44 and 45 report the first disease-causing mutations in the mitochondrial genome (mtDNA).

    Article  ADS  CAS  PubMed  Google Scholar 

  46. Bourgeron, T. et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nature Genet. 11, 144–149 (1995). This paper reports the first nuclear gene mutation that gives rise to a mitochondrial respiratory chain disorder.

    Article  CAS  PubMed  Google Scholar 

  47. Calvo, S. E. & Mootha, V. K. The mitochondrial proteome and human disease. Annu. Rev. Genomics Hum. Genet. 11, 25–44 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Koopman, W. J., Willems, P. H. & Smeitink, J. A. Monogenic mitochondrial disorders. N. Engl. J. Med. 366, 1132–1141 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Park, S. G., Schimmel, P. & Kim, S. Aminoacyl tRNA synthetases and their connections to disease. Proc. Natl Acad. Sci. USA 105, 11043–11049 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nishino, I., Spinazzola, A. & Hirano, M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283, 689–692 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  51. Lieber, D. S. et al. Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease. BMC Med. Genet. 13, 3 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kornmann, B. et al. An ER–mitochondria tethering complex revealed by a synthetic biology screen. Science 325, 477–481 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hobbs, A. E., Srinivasan, M., McCaffery, J. M. & Jensen, R. E. Mmm1p, a mitochondrial outer membrane protein, is connected to mitochondrial DNA (mtDNA) nucleoids and required for mtDNA stability. J. Cell Biol. 152, 401–410 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kirkman, M. A. et al. Gene–environment interactions in Leber hereditary optic neuropathy. Brain 132, 2317–2326 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Sadun, A. Acquired mitochondrial impairment as a cause of optic nerve disease. Trans. Am. Ophthalmol. Soc. 96, 881–923 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Bitner-Glindzicz, M. et al. Prevalence of mitochondrial 1555A>G mutation in European children. N. Engl. J. Med. 360, 640–642 (2009).

    Article  PubMed  Google Scholar 

  57. Prezant, T. R. et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genet. 4, 289–294 (1993).

    Article  CAS  PubMed  Google Scholar 

  58. Cote, H. C. et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N. Engl. J. Med. 346, 811–820 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Viscomi, C. et al. Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nature Med. 16, 869–871 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Reeves, M. B., Davies, A. A., McSharry, B. P., Wilkinson, G. W. & Sinclair, J. H. Complex I binding by a virally encoded RNA regulates mitochondria-induced cell death. Science 316, 1345–1348 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  61. Vasta, V., Merritt, J. L. 2nd, Saneto, R. P. & Hahn, S. H. Next-generation sequencing for mitochondrial diseases reveals wide diagnostic spectrum. Pediatr. Int. 54, 585–601 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Calvo, S. E. et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci. Transl. Med. 4, 118ra110 (2012).

    Article  CAS  Google Scholar 

  63. Vockley, J., Rinaldo, P., Bennett, M. J., Matern, D. & Vladutiu, G. D. Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways. Mol. Genet. Metab. 71, 10–18 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Guan, M. X. et al. Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am. J. Hum. Genet. 79, 291–302 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. von Kleist-Retzow, J. C. et al. Impaired mitochondrial Ca2+ homeostasis in respiratory chain-deficient cells but efficient compensation of energetic disadvantage by enhanced anaerobic glycolysis due to low ATP steady state levels. Exp. Cell Res. 313, 3076–3089 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Trifunovic, A. et al. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl Acad. Sci. USA 102, 17993–17998 (2005).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  68. Butow, R. A. & Avadhani, N. G. Mitochondrial signaling: the retrograde response. Mol. Cell 14, 1–15 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Miceli, M. V., Jiang, J. C., Tiwari, A., Rodriguez-Quinones, J. F. & Jazwinski, S. M. Loss of mitochondrial membrane potential triggers the retrograde response extending yeast replicative lifespan. Front. Genet. 2, 102 (2011).

    PubMed  Google Scholar 

  70. Owusu-Ansah, E., Yavari, A., Mandal, S. & Banerjee, U. Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nature Genet. 40, 356–361 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Mandal, S., Guptan, P., Owusu-Ansah, E. & Banerjee, U. Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila. Dev. Cell 9, 843–854 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Haynes, C. M. & Ron, D. The mitochondrial UPR — protecting organelle protein homeostasis. J. Cell Sci. 123, 3849–3855 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Rugarli, E. I. & Langer, T. Mitochondrial quality control: a matter of life and death for neurons. EMBO J. 31, 1336–1349 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shaham, O. et al. A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells. Proc. Natl Acad. Sci. USA 107, 1571–1575 (2010). This paper reports the application of metabolite profiling to systematically characterize the biochemical ripples that ensue from defined lesions to the mitochondrial respiratory chain, some of which are also mirrored in the plasma of patients with mitochondrial disease.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  75. Morais, R., Guertin, D. & Kornblatt, J. A. On the contribution of the mitochondrial genome to the growth of Chinese hamster embryo cells in culture. Can. J. Biochem. 60, 290–294 (1982).

    Article  CAS  PubMed  Google Scholar 

  76. Mullen, A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385–388 (2012).

    Article  ADS  CAS  Google Scholar 

  77. Perocchi, F. et al. MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467, 291–296 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  78. Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  79. De Stefani, D., Raffaello, A., Teardo, E., Szabo, I. & Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  80. Biswas, G. et al. Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter-organelle crosstalk. EMBO J. 18, 522–533 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Arnould, T. et al. CREB activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation. EMBO J. 21, 53–63 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wu, H. et al. Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296, 349–352 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  83. Molkentin, J. D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ward, S. M. et al. Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. J. Physiol. 525, 355–361 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Brini, M. et al. A calcium signalling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency. Nature Med. 5, 951–954 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Kaftan, E. J., Xu, T., Abercrombie, R. F. & Hille, B. Mitochondria shape hormonally induced cytoplasmic calcium oscillations and modulate exocytosis. J. Biol. Chem. 275, 25465–25470 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Suomalainen, A. et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol. 10, 806–818 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. West, A. P., Shadel, G. S. & Ghosh, S. Mitochondria in innate immune responses. Nature Rev. Immunol. 11, 389–402 (2011).

    Article  CAS  Google Scholar 

  89. Pfeffer, G., Majamaa, K., Turnbull, D. M., Thorburn, D. & Chinnery, P. F. Treatment for mitochondrial disorders. Cochrane Database Syst. Rev. 4, CD004426 (2012).

    Google Scholar 

  90. Hoppins, S. et al. A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria. J. Cell Biol. 195, 323–340 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Nilsson, R. et al. Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis. Cell Metab. 10, 119–130 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Stacpoole, P. W. Why are there no proven therapies for genetic mitochondrial diseases? Mitochondrion 11, 679–685 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Michelakis, E. D. et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Kirby, D. M. & Thorburn, D. R. Approaches to finding the molecular basis of mitochondrial oxidative phosphorylation disorders. Twin Res. Hum. Genet. 11, 395–411 (2008).

    Article  PubMed  Google Scholar 

  95. Owen, M. R., Doran, E. & Halestrap, A. P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607–614 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gohil, V. M. et al. Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nature Biotechnol. 28, 249–255 (2010).

    Article  CAS  Google Scholar 

  97. Copeland, J. M. et al. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol. 19, 1591–1598 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Lee, S. S. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nature Genet. 33, 40–48 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to the many authors whose work we were unable to cite because of space limitations. We offer special thanks to D. Thorburn for careful review of the manuscript and his help with compiling an updated list of disease genes. We are grateful to S. Calvo, M. Jain, E. Rosen, V. Siegel and M. Gray for thoughtful feedback on the manuscript; J-.P. Mazat for providing a figure; M. Fleming, A. Sadun, M. Seidman, R. Mitchell, R. Saneto, D. McGuone and L. Rodriguez for providing clinical images; and G. Perkins and M. Ellisman for providing electron micrographs. We thank the National Institutes of Health for ongoing grant support.

Author information

Authors and Affiliations

  1. Departments of Molecular Biology and Medicine, Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Scott B. Vafai & Vamsi K. Mootha

  2. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Scott B. Vafai & Vamsi K. Mootha

  3. Department of Systems Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Vamsi K. Mootha

Authors
  1. Scott B. Vafai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vamsi K. Mootha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vamsi K. Mootha.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at www.nature.com/reprints.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vafai, S., Mootha, V. Mitochondrial disorders as windows into an ancient organelle. Nature 491, 374–383 (2012). https://doi.org/10.1038/nature11707

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11707

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research