Mitochondrial Disorders: Nuclear Gene Mutations


In addition to mutations of mitochondrial deoxyribonucleic acid (mtDNA), many mitochondrial syndromes are due to abnormalities in nuclear genes related to oxidative phosphorylation (OXPHOS). Nuclear genes encode hundreds of proteins directly involved in mitochondrial OXPHOS or linked to other metabolic pathways that are related to OXPHOS, such as the tricarboxylic acid (TCA) cycle and fatty acids β‐oxidation, cell signalling and apoptosis. Although the identification of mutations in mtDNA has become relatively easy because its small size and the nearly complete elucidation of its sequence polymorphisms, the analysis of nuclear disease genes is still a formidable challenge. However, with the recent improvement in technology throughput and bio‐computational power, this scenario is rapidly changing. The discovery of several OXPHOS‐related human genes and the identification of mutations responsible for different clinical syndromes indicate that the majority, but not all, of the inherited mitochondrial disorders are due to nuclear genes encoding proteins targeted to mitochondria.

Key Concepts:

  • Mitochondria are the principal intracellular source of energy through the production of ATP by oxidative phosphorylation (OXPHOS).

  • Mitochondria contain their own genome, a small, circular double‐stranded DNA (mtDNA).

  • mtDNA contains 13 genes encoding subunits of the respiratory chain complexes and 24 genes encoding 2 ribosomal and 22 transfer RNAs, which are necessary to carry out intramitochondrial translation.

  • Mitochondria depend on the nucleus for the supply of all of the other OXPHOS proteins as well as the factors necessary for replication, repair, transcription, translation, maintenance of mtDNA and for the biogenesis, shaping, fusion and fission of the organelles.

  • Mitochondrial‐inherited diseases may present with a vast range of symptoms, severity, age of onset and outcome.

  • Because of its dual genetic control, OXPHOS disorders can be due to mutations in mtDNA or nuclear DNA genes.

  • Recent epidemiological studies show that mitochondrial disorders have a minimal prevalence of 1:5 000.

Keywords: mitochondria; nuclear DNA; mutation; oxidative phosphorylation; respiratory chain

Figure 1.

Brain magnetic resonance images of a patient affected by Leigh Syndrome. (a) Transverse T2‐weighted image showing symmetric hyperintense necrotic lesions in the basal ganglia (arrows). (b) Coronal T2‐weighted image showing cortical atrophy. (c) A 1H‐spectroscopy of the voxels encircled in the brain sections displayed in the upper panels, shows a marked accumulation of lactate (arrow).

Figure 2.

Frequency of biochemical deficiencies in (MRC) complexes. The data were obtained from a total of 239 skeletal muscle biopsies, 75 of which showed reduced activities, analysed in the Unit of Molecular Neurogenetics, Institute of Neurology ‘C. Besta’, Milan, Italy (E. Lamantea, personal communication).

Figure 3.

Southern‐blot analysis of linearised mtDNA samples with (MD), (SD) and mtDNA depleted species (Dep), compared to control samples (Ct).



Allen DA and Ottaway JH (1986) Succinate thiokinase in pigeon breast muscle mitochondria. FEBS Letters 194: 171–175.

Barel O, Shorer Z, Flusser H et al. (2008) Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. American Journal of Human Genetics 82: 1211–1216.

Bayley JP and Devilee P (2010) Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree? Current Opinion in Genetics & Development 20: 324–329.

Bayley JP, Kunst HP, Cascon A et al. (2010) SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncology 11: 366–372.

Bornstein B, Area E, Flanigan KM et al. (2008) Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene. Neuromuscular Disorders 18: 453–459.

Burnichon N, Brière JJ, Libé R et al. (2010) SDHA is a tumor suppressor gene causing paraganglioma. Human Molecular Genetics 19: 3011–3020.

Carrol J, Fearnley IM, Skehel JM et al. (2006) Bovine complex I is a complex of 45 different subunits. Journal of Biological Chemistry 281: 32724–32727.

Cízková A, Stránecký V, Mayr JA et al. (2008) TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nature Genetics 40: 1288–1290.

Davey KM, Parboosingh JS, McLeod DR et al. (2006) Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co‐chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome‐like condition. Journal of Medical Genetics 43: 385–393.

Debray FG, Lambert M and Mitchell GA (2008) Disorders of mitochondrial function. Current Opinion in Pediatrics 20: 471–482.

Di Fonzo A, Ronchi D, Lodi T et al. (2009) The mitochondrial disulfide relay system protein GFER is mutated in autosomal‐recessive myopathy with cataract and combined respiratory‐chain deficiency. American Journal of Human Genetics 84: 594–604.

Di Mauro S and De Vivo DC (1996) Genetic heterogeneity in Leigh syndrome. Annals of Neurology 40: 5–7.

Di Mauro S and Schon EA (2003) Mitochondrial respiratory‐chain diseases. New England Journal of Medicine 348: 2656–2668.

Duncan AJ, Bitner‐Glindzicz M, Meunier B et al. (2009) A nonsense mutation in COQ9 causes autosomal‐recessive neonatal‐onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. American Journal of Human Genetics 84: 558–566.

Fernandez‐Vizarra E, Tiranti V and Zeviani M (2009) Assembly of the oxidative phosphorylation system in humans: what we have learned by studying its defects. Biochimica Biophysica Acta 1793: 200–211.

Freisinger P, Futterer N, Lankes E et al. (2006) Hepatocerebral mitochondrial DANN depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations. Archives of Neurology 63: 1129–1134.

Ghezzi D, Goffrini P, Uziel G et al. (2009) SDHAF1, encoding a LYR complex‐II specific assembly factor, is mutated in SDH‐defective infantile leukoencephalopathy. Nature Genetics 41: 654–656.

Ghezzi D, Saada A, D'Adamo P et al. (2008) FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency. American Journal of Human Genetics 83: 415–423.

Ghezzi D, Sevrioukova I, Invernizzi F et al. (2010) Severe X‐linked mitochondrial encephalomyopathy associated with a mutation in apoptosis‐inducing factor. American Journal of Human Genetics 86: 639–649.

Haack TB, Danhauser K, Haberberger B et al. (2010) Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nature Genetics 42: 1131–1134.

Hao HX, Khalimonchuk O, Schraders M et al. (2009) SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 28: 1139–1142.

Hoefs SJ, van Spronsen FJ, Lenssen EW et al. (2010) NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease. European Journal of Human Genetics. December 8 [Epub ahead of print].

Janssen RJ, Nijtmans LG, van den Heuvel LP and Smeitink JA (2006) Mitochondrial complex I: structure, function and pathology. Journal of Inherited Metabolic Disease 29: 499–515.

Kollberg G, Darin N, Benan K et al. (2009) A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion. Neuromuscular Disorders 19: 147–150.

Lagier‐Tourenne C, Tazir M, López LC et al. (2008) ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. American Journal of Human Genetics 82: 661–672.

Levitas A, Muhammad E, Harel G et al. (2010) Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. European Journal of Human Genetics 18: 1160–1165.

Lill R and Mühlenhoff U (2006) Iron‐sulfur protein biogenesis in eukaryotes: components and mechanisms. Annual Review of Cell and Developmental Biology 22: 457–486.

Mandel H, Szargel R, Labay V et al. (2001) The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nature Genetics 29: 337–341.

Massa V, Fernandez‐Vizarra E, Alshahwan S et al. (2008) Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus‐encoded subunit of cytochrome c oxidase. American Journal of Human Genetics 82: 1281–1289.

Musumeci O, Naini A, Slonim AE et al. (2001) Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 56: 849–855.

Nouws J, Nijtmans L, Houten SM et al. (2010) Acyl‐CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Cell Metabolism 12: 283–294.

Ogilvie I, Kennaway NG and Shoubridge EA (2005) A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. Journal of Clinical Investigation 115: 2784–2792.

Okamoto K and Shaw JM (2005) Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annual Review of Genetics 39: 503–536.

Sanadi DR, Langley M and White F (1959) α‐Ketoglutaric dehydrogeanase. VII: the role of thioctic acid. Journal of Biological Chemistry 234: 183–187.

Sasarman F, Brunel‐Guitton C, Antonicka H et al. (2010) LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria. Molecular Biology of the Cell 21: 1315–1323.

Scheper GC, van der Klok T, van Andel RJ et al. (2007) Mitochondrial aspartyl‐tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nature Genetics 39: 534–539.

Schmitz‐Linneweber C and Small I (2008) Pentatricopeptide repeat proteins: a socket set for organelle gene expression. Trends in Plant Science 13: 663–670.

Spinazzola A and Zeviani M (2009) Disorders from perturbations of nuclear‐mitochondrial intergenomic cross‐talk. Journal of Internal Medicine 265: 174–192.

Tiranti V, Viscomi C, Hildebrandt T et al. (2009) Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nature Medicine 15: 200–205.

Triepels RH, Van Den Heuvel LP, Trijbels JM and Smeitink JA (2001) Respiratory chain complex I deficiency. American Journal of Medical Genetics 106: 37–45.

Tyynismaa H, Ylikallio E, Patel M et al. (2009) A heterozygous truncating mutation in RRM2B causes autosomal‐dominant progressive external ophthalmoplegia with multiple mtDNA deletions. American Journal of Human Genetics 85: 290–295.

Valayannopoulos V, Haudry C, Serre V et al. (2010) New SUCLG1 patients expanding the phenotypic spectrum of this rare cause of mild methylmalonic aciduria. Mitochondrion 10: 335–341.

Van Coster R, Seneca S, Smet J et al. (2003) Homozygous Gly555Glu mutation in the nuclear‐encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II. American Journal of Medical Genetics. Part A 120A: 13–18.

Weraarpachai W, Antonicka H, Sasarman F et al. (2009) Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late‐onset Leigh syndrome. Nature Genetics 41: 833–837.

Zeviani M (2001) The expanding spectrum of nuclear gene mutations in mitochondrial disorders. Seminars in Cell and Developmental Biology 12: 407–416.

Zeviani M (2008) OPA1 mutations and mitochondrial DNA damage: keeping the magic circle in shape. Brain 131: 314–317.

Zeviani M and Carelli V (2007) Mitochondrial disorders. Current Opinion in Neurology 20: 564–571.

Zeviani M and Klopstock T (2001) Mitochondrial disorders. Current Opinion in Neurology 14: 553–560.

Zeviani M and Lamantea E (2006) Genetic disorders of the mitochondrial OXPHOS system. Science & Medicine 10: 154–167.

Zordan MA, Cisotto P, Benna C et al. (2006) Post‐transcriptional silencing and functional characterization of the Drosophila melanogaster homolog of human Surf1. Genetics 172: 229–241.

Zuchner S, Mersiyanova IV, Muglia M et al. (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot–Marie–Tooth neuropathy type 2A. Nature Genetics 36: 449–451.

Further Reading

Calvo S, Jain M, Xie X et al. (2006) Systematic identification of human mitochondrial disease genes through integrative genomics. Nature Genetics 38: 576–582.

Fontanesi F, Soto IC, Horn D and Barrientos A (2006) Assembly of mitochondrial cytochrome c‐oxidase, a complicated and highly regulated cellular process. American Journal of Physiology. Cell Physiology 291: C1129–C1147.

Haas RH, Parikh S, Falk MJ et al. (2008) The in‐depth evaluation of suspected mitochondrial disease. Molecular Genetics and Metabolism 94: 16–37.

Koene S and Smeitink J (2009) Mitochondrial medicine: entering the era of treatment. Journal of Internal Medicine 265: 193–209.

McFarland R and Turnbull DM (2009) Batteries not included: diagnosis and management of mitochondrial disease. Journal of Internal Medicine 265: 210–228.

Schapira AH (2006) Mitochondrial disease. Lancet 368: 70–82.

Smeitink JA, Zeviani M, Turnbull DM and Jacobs HT (2006) Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders. Cell Metabolism 3: 9–13.

Thorburn DR, Sugiana C, Salemi R et al. (2004) Biochemical and molecular diagnosis of mitochondrial respiratory chain disorders. Biochimica Biophysica Acta 1659: 121–128.

Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annual Review of Genetics 39: 359–407.

Wiedemann N, Frazier AE and Pfanner N (2004) The protein import machinery of mitochondria. Journal of Biological Chemistry 279: 14473–14476.

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Ghezzi, Daniele, and Zeviani, Massimo(Apr 2011) Mitochondrial Disorders: Nuclear Gene Mutations. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005540.pub2]