Skip to main content
SpringerLink
Log in

Disorders of Oxidative Phosphorylation

  • Chapter
Inborn Metabolic Diseases

Zusammenfassung

Disorders of oxidative phosphorylation encompass heterogeneous infantile, childhood and adult onset diseases characterised by variable involvement of high energy requiring organs. The central and peripheral nervous systems, skeletal and cardiac muscle, eyes, ears, kidneys and liver are frequently involved. Some well-characterised mitochondrial syndromes are recognised, but many patients have overlapping features not corresponding to a specific syndrome. Theoretically any organ or tissue or combination of organs may be affected, with onset at any age. Owing to the involvement of two distinct genomes, the nuclear genome and that located within the mitochondrion itself, a range of modes of inheritance of mitochondrial disease has been observed: maternal (mitochondrial DNA), autosomal recessive, autosomal dominant, X-linked and sporadic. Disease mechanisms include mutations affecting OXPHOS subunits and assembly factors, and disorders of mitochondrial DNA maintenance, protein synthesis, cofactor biosynthesis and lipid metabolism. The complexity of underlying disease mechanisms, together with clinical, biochemical and genetic heterogeneity, creates enormous diagnostic challenges. Most mitochondrial diseases, especially childhood-onset forms, are characterised by relentless progression. Specific treatments are available for some extremely rare forms of mitochondrial disease, but the majority of cases lack curative treatments, and the mainstay of treatment is supportive.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and 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

References

  1. Robinson BH (2006) Lactic acidemia and mitochondrial disease. Mol Genet Metab 89:3–13

    Google Scholar 

  2. Rahman S, Blok RB, Dahl HH et al. (1996) Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 39:343–351

    Google Scholar 

  3. Lake NJ, Compton AG, Rahman S, Thorburn DR (2016) Leigh Syndrome: One disorder, more than 75 monogenic causes. Ann Neurol 79:190–203

    Google Scholar 

  4. Peters H, Buck N, Wanders R et al. (2014) ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain 137:2903–2908

    Google Scholar 

  5. Thompson Legault J, Strittmatter L, Tardif J et al. (2015) A metabolic signature of mitochondrial dysfunction revealed through a monogenic form of Leigh Syndrome. Cell Rep 13:981–989

    Google Scholar 

  6. Wortmann SB, Vaz FM, Gardeitchik T et al. (2012) Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet 44:797–802

    Google Scholar 

  7. Broomfield A, Sweeney MG, Woodward CE et al. (2015) Paediatric single mitochondrial DNA deletion disorders: an overlapping spectrum of disease. J Inherit Metab Dis 38:445–457

    Google Scholar 

  8. Rahman S, Poulton J (2009) Diagnosis of mitochondrial DNA depletion syndromes. Arch Dis Child 94:3–5

    Google Scholar 

  9. Saneto RP, Cohen BH, Copeland WC, Naviaux RK (2013) Alpers-Huttenlocher syndrome. Pediatr Neurol 48:167–178

    Google Scholar 

  10. Elo JM, Yadavalli SS, Euro L et al. (2012) Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Hum Mol Genet 21:4521–4529

    Google Scholar 

  11. Sofou K, Kollberg G, Holmstrom M et al. (2015) Whole exome sequencing reveals mutations in NARS2 and PARS2, encoding the mitochondrial asparaginyl-tRNA synthetase and prolyl-tRNA synthetase, in patients with Alpers syndrome. Mol Genet Genomic Med 3:59–68

    Google Scholar 

  12. Wolf NI, Rahman S, Schmitt B et al. (2009) Status epilepticus in children with Alpers’ disease caused by POLG1 mutations: EEG and MRI features. Epilepsia 50:1596–1607

    Google Scholar 

  13. Horvath R, Kemp JP, Tuppen HA et al. (2009) Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 132:3165–3174

    Google Scholar 

  14. Zeharia A, Shaag A, Pappo O et al. (2009) Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet 85:401–407

    Google Scholar 

  15. Desbats MA, Lunardi G, Doimo M, Trevisson E, Salviati L (2015) Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency. J Inherit Metab Dis 38:145–156

    Google Scholar 

  16. Clarke SL, Bowron A, Gonzalez IL et al. (2013) Barth syndrome. Orphanet J Rare Dis 8:23

    Google Scholar 

  17. Haghighi A, Haack TB, Atiq M et al. (2014) Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients. Orphanet J Rare Dis 9:119

    Google Scholar 

  18. Rahman S (2012) Mitochondrial disease and epilepsy. Dev Med Child Neurol 54:397–406

    Google Scholar 

  19. Fassone E, Taanman JW, Hargreaves IP et al. (2011) Mutations in the mitochondrial complex I assembly factor NDUFAF1 cause fatal infantile hypertrophic cardiomyopathy. J Med Genet 48:691–697

    Google Scholar 

  20. Lee WS, Sokol RJ (2013) Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and outcomes. J Pediatr 163:942–948

    Google Scholar 

  21. Casey JP, Slattery S, Cotter M et al. (2015) Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS. J Inherit Metab Dis 38:1085–1092

    Google Scholar 

  22. Pitceathly RD, Fassone E, Taanman JW et al. (2011) Kearns-Sayre syndrome caused by defective R1/p53R2 assembly. J Med Genet 48:610–617

    Google Scholar 

  23. El-Hattab AW, Adesina AM, Jones J, Scaglia F (2015) MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 116:4–12

    Google Scholar 

  24. Nesbitt V, Pitceathly RD, Turnbull DM et al. (2013) The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation – implications for diagnosis and management. J Neurol Neurosurg Psychiatry 84:936–938

    Google Scholar 

  25. DiMauro S, Hirano M (2003) MERRF. In: Pagon RA, Adam MP, Ardinger HH et al. (eds.) Gene Reviews, Seattle, Washington (updated 2015)

    Google Scholar 

  26. Thorburn DR, Rahman S (2003) Mitochondrial DNA-Associated Leigh Syndrome and NARP. Gene Reviews, Seattle, Washington (updated 2014)

    Google Scholar 

  27. Pitceathly RD, Murphy SM, Cottenie E et al. (2012) Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology 79:1145–1154

    Google Scholar 

  28. Meyerson C, Van SG, McClelland C (2015) Leber hereditary optic neuropathy: current perspectives. Clin Ophthalmol 9:1165–1176

    Google Scholar 

  29. Stumpf JD, Saneto RP, Copeland WC (2013) Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol 5:a011395

    Google Scholar 

  30. Halter JP, Michael W, Schupbach M et al. (2015) Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Brain 138:2847–2858

    Google Scholar 

  31. Murphy R, Turnbull DM, Walker M, Hattersley AT (2008) Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med 25:383–399

    Google Scholar 

  32. Milone M, Wong LJ (2013) Diagnosis of mitochondrial myopathies. Mol Genet Metab 110:35–41

    Google Scholar 

  33. Stuppia G, Rizzo F, Riboldi G et al. (2015) MFN2-related neuropathies: Clinical features, molecular pathogenesis and therapeutic perspectives. J Neurol Sci 356:7–18

    Google Scholar 

  34. Wallen RC, Antonellis A (2013) To charge or not to charge: mechanistic insights into neuropathy-associated tRNA synthetase mutations. Curr Opin Genet Dev 23:302–309

    Google Scholar 

  35. Hatefi Y (1985) The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem 54:1015–1069

    Google Scholar 

  36. Smits P, Smeitink J, van den Heuvel L (2010) Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol 2010:737385

    Google Scholar 

  37. Mayr JA (2015) Lipid metabolism in mitochondrial membranes. J Inherit Metab Dis 38:137–144

    Google Scholar 

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

    Google Scholar 

  39. Ferdinandusse S, Waterham HR, Heales SJ et al. (2013) HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. Orphanet J Rare Dis 8:188

    Google Scholar 

  40. Pagliarini DJ, Calvo SE, Chang B et al. (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123

    Google Scholar 

  41. Sacconi S, Salviati L, Nishigaki Y et al. (2008) A functionally dominant mitochondrial DNA mutation. Hum Mol Genet 17:1814–1820

    Google Scholar 

  42. Rahman S (2015) Emerging aspects of treatment in mitochondrial disorders. J Inherit Metab Dis 38:641–653

    Google Scholar 

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

    Google Scholar 

  44. Kim HL, Schuster SC (2013) Poor Man’s 1000 Genome project: recent human population expansion confounds the detection of disease alleles in 7,098 complete mitochondrial genomes. Front Genet 4:13

    Google Scholar 

  45. Wedatilake Y, Brown R, McFarland R et al. (2013) SURF1 deficiency: a multi-centre natural history study. Orphanet J Rare Dis 8:96

    Google Scholar 

  46. Haack TB, Haberberger B, Frisch EM et al. (2012) Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J Med Genet 49:277–283

    Google Scholar 

  47. Calvo SE, Compton AG, Hershman SG et al. (2012) Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Trans l Med 4:118ra10

    Google Scholar 

  48. Mayr JA, Feichtinger RG, Tort F, Ribes A, Sperl W (2014) Lipoic acid biosynthesis defects. J Inherit Metab Dis 37:553–563

    Google Scholar 

  49. Atkuri KR, Cowan TM, Kwan T, Ng A et al. (2009) Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia. Proc Natl Acad Sci USA 106:3941–3945

    Google Scholar 

  50. Wortmann SB, Kluijtmans LA, Rodenburg RJ et al. (2013) 3-Methylglutaconic aciduria – lessons from 50 genes and 977 patients. J Inherit Metab Dis 36:913–921

    Google Scholar 

  51. Kanabus M, Shahni R, Saldanha JW et al. (2015) Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation. J Inherit Metab Dis 38:211–219

    Google Scholar 

  52. Ostergaard E (2008) Disorders caused by deficiency of succinate-CoA ligase. J Inherit Metab Dis 31:226–229

    Google Scholar 

  53. Rahman S, Clarke CF, Hirano M (2012) 176th ENMC International Workshop: Diagnosis and treatment of coenzyme Q(10) deficiency. Neuromuscul Disord 22:76–86

    Google Scholar 

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

    Google Scholar 

  55. Yatsuga S, Fujita Y, Ishii A et al. (2015) Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol 78:814–823

    Google Scholar 

  56. Pajares S, Arias A, Garcia-Villoria J, Briones P, Ribes A (2013) Role of creatine as biomarker of mitochondrial diseases. Mol Genet Metab 108:119–124

    Google Scholar 

  57. Friedman SD, Shaw DW, Ishak G, Gropman AL, Saneto RP (2010) The use of neuroimaging in the diagnosis of mitochondrial disease. Dev Disabil Res Rev 16:129–135

    Google Scholar 

  58. Bricout M, Grevent D, Lebre AS et al. (2014) Brain imaging in mitochondrial respiratory chain deficiency: combination of brain MRI features as a useful tool for genotype/phenotype correlations. J Med Genet 51:429–435

    Google Scholar 

  59. Calvaruso MA, Smeitink J, Nijtmans L (2008) Electrophoresis techniques to investigate defects in oxidative phosphorylation. Methods 46:281–287

    Google Scholar 

  60. Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF (2012) Treatment for mitochondrial disorders. Cochrane Database Syst Rev 4:CD004426

    Google Scholar 

  61. Kanabus M, Heales SJ, Rahman S (2014) Development of pharmacological strategies for mitochondrial disorders. Br J Pharmacol 171:1798–1817

    Google Scholar 

  62. Gerards M, van den Bosch BJ, Danhauser K et al. (2011) Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain 134:210–219

    Google Scholar 

  63. Ormazabal A, Casado M, Molero-Luis M et al. (2015) Can folic acid have a role in mitochondrial disorders? Drug Discov Today 20:1349–1354

    Google Scholar 

  64. Kerr DS (2013) Review of clinical trials for mitochondrial disorders: 1997–2012. Neurotherapeutics 10:307–319

    Google Scholar 

  65. Smeets HJ, Sallevelt SC, Dreesen JC, de Die-Smulders CE, de Coo IF (2015) Preventing the transmission of mitochondrial DNA disorders using prenatal or preimplantation genetic diagnosis. Ann NY Acad Sci 1350:29–36

    Google Scholar 

  66. Wolf DP, Mitalipov N, Mitalipov S (2015) Mitochondrial replacement therapy in reproductive medicine. Trends Mol Med 21:68–76

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. UCL Institute of Child Health, 30 Guilford Street, WC1N 1EH, London, UK

    Shamima Rahman

  2. Department of Paediatrics, Paracelsus Medical University, Salzburger Landeskliniken SALK, Müllner Hauptstr. 48, 5020, Salzburg, Austria

    Johannes A. Mayr

Authors
  1. Shamima Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johannes A. Mayr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shamima Rahman or Johannes A. Mayr .

Editor information

Editors and Affiliations

  1. Department of Neurology, Neurometabolic Unit, Hôpital Pitié Salpêtrière, Paris, France

    Jean-Marie Saudubray

  2. Division of Metabolism, University Children’s Hospital, Zurich, Switzerland

    Matthias R. Baumgartner

  3. Willink Biochemical Genetics Unit Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK

    John Walter

  4. Central Manchester University Hospitals NHS Foundation Trust, St Mary‘s Hospital, Manchester, UK

    John Walter

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Rahman, S., Mayr, J.A. (2016). Disorders of Oxidative Phosphorylation. In: Saudubray, JM., Baumgartner, M., Walter, J. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-49771-5_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-49771-5_14

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-49769-2

  • Online ISBN: 978-3-662-49771-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation