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.
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References
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.
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).
Skladal, D., Halliday, J. & Thorburn, D. R. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126, 1905–1912 (2003).
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)
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).
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).
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.
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.
Szklarczyk, R. & Huynen, M. A. Mosaic origin of the mitochondrial proteome. Proteomics 10, 4012–4024 (2010).
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).
Shutt, T. E. & Gray, M. W. Bacteriophage origins of mitochondrial replication and transcription proteins. Trends Genet. 22, 90–95 (2006).
Bourdon, A. et al. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nature Genet. 39, 776–780 (2007).
Tibbetts, A. S. & Appling, D. R. Compartmentalization of mammalian folate-mediated one-carbon metabolism. Annu. Rev. Nutr. 30, 57–81 (2010).
Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012).
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).
Chance, B. & Williams, G. R. A method for the localization of sites for oxidative phosphorylation. Nature 176, 250–254 (1955).
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).
Schagger, H. & von Jagow, G. Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal. Biochem. 199, 223–231 (1991).
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).
Shoubridge, E. A. Supersizing the mitochondrial respiratory chain. Cell Metab. 15, 271–272 (2012).
Efremov, R. G., Baradaran, R. & Sazanov, L. A. The architecture of respiratory complex I. Nature 465, 441–445 (2010).
Hunte, C., Zickermann, V. & Brandt, U. Functional modules and structural basis of conformational coupling in mitochondrial complex I. Science 329, 448–451 (2010).
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).
Nouws, J. et al. Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Cell Metab. 12, 283–294 (2010).
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).
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).
Allen, J. F. The function of genomes in bioenergetic organelles. Phil. Trans. R. Soc. Lond. B 358, 19–37 (2003).
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).
Pierron, D. et al. Cytochrome c oxidase: evolution of control via nuclear subunit addition. Biochim. Biophys. Acta 1817, 590–597 (2012).
Scarpulla, R. C. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 1813, 1269–1278 (2011).
Spiegelman, B. M. Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. Novartis Found. Symp. 287, 60–63 (2007).
MacAskill, A. F. & Kittler, J. T. Control of mitochondrial transport and localization in neurons. Trends Cell Biol. 20, 102–112 (2010).
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).
Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nature Rev. Mol. Cell Biol. 12, 9–14 (2011).
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).
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.
Glancy, B. & Balaban, R. S. Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry 51, 2959–2973 (2012).
Kacser, H. & Burns, J. A. The control of flux. Symp. Soc. Exp. Biol. 27, 65–104 (1973).
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).
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).
Hartwell, L. Genetics. Robust interactions. Science 303, 774–775 (2004).
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).
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.
Wallace, D. C. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427–1430 (1988).
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).
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.
Calvo, S. E. & Mootha, V. K. The mitochondrial proteome and human disease. Annu. Rev. Genomics Hum. Genet. 11, 25–44 (2010).
Koopman, W. J., Willems, P. H. & Smeitink, J. A. Monogenic mitochondrial disorders. N. Engl. J. Med. 366, 1132–1141 (2012).
Park, S. G., Schimmel, P. & Kim, S. Aminoacyl tRNA synthetases and their connections to disease. Proc. Natl Acad. Sci. USA 105, 11043–11049 (2008).
Nishino, I., Spinazzola, A. & Hirano, M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283, 689–692 (1999).
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).
Kornmann, B. et al. An ER–mitochondria tethering complex revealed by a synthetic biology screen. Science 325, 477–481 (2009).
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).
Kirkman, M. A. et al. Gene–environment interactions in Leber hereditary optic neuropathy. Brain 132, 2317–2326 (2009).
Sadun, A. Acquired mitochondrial impairment as a cause of optic nerve disease. Trans. Am. Ophthalmol. Soc. 96, 881–923 (1998).
Bitner-Glindzicz, M. et al. Prevalence of mitochondrial 1555A>G mutation in European children. N. Engl. J. Med. 360, 640–642 (2009).
Prezant, T. R. et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genet. 4, 289–294 (1993).
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).
Viscomi, C. et al. Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nature Med. 16, 869–871 (2010).
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).
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).
Calvo, S. E. et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci. Transl. Med. 4, 118ra110 (2012).
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).
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).
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).
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).
Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).
Butow, R. A. & Avadhani, N. G. Mitochondrial signaling: the retrograde response. Mol. Cell 14, 1–15 (2004).
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).
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).
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).
Haynes, C. M. & Ron, D. The mitochondrial UPR — protecting organelle protein homeostasis. J. Cell Sci. 123, 3849–3855 (2010).
Rugarli, E. I. & Langer, T. Mitochondrial quality control: a matter of life and death for neurons. EMBO J. 31, 1336–1349 (2012).
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.
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).
Mullen, A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385–388 (2012).
Perocchi, F. et al. MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467, 291–296 (2010).
Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).
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).
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).
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).
Wu, H. et al. Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296, 349–352 (2002).
Molkentin, J. D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).
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).
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).
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).
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).
West, A. P., Shadel, G. S. & Ghosh, S. Mitochondria in innate immune responses. Nature Rev. Immunol. 11, 389–402 (2011).
Pfeffer, G., Majamaa, K., Turnbull, D. M., Thorburn, D. & Chinnery, P. F. Treatment for mitochondrial disorders. Cochrane Database Syst. Rev. 4, CD004426 (2012).
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).
Nilsson, R. et al. Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis. Cell Metab. 10, 119–130 (2009).
Stacpoole, P. W. Why are there no proven therapies for genetic mitochondrial diseases? Mitochondrion 11, 679–685 (2011).
Michelakis, E. D. et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34 (2010).
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).
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).
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).
Copeland, J. M. et al. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol. 19, 1591–1598 (2009).
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).
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.
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Vafai, S., Mootha, V. Mitochondrial disorders as windows into an ancient organelle. Nature 491, 374–383 (2012). https://doi.org/10.1038/nature11707
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DOI: https://doi.org/10.1038/nature11707
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