Oxidative Phosphorylation System: Nuclear Genes and Genetic Disease

Laura Sánchez‐Caballero, Radboud University Medical Center, Nijmegen, The Netherlands
Fabian Baertling, University Children's Hospital Duesseldorf, Heinrich Heine University, Düsseldorf, Germany
Leo Nijtmans, Radboud University Medical Center, Nijmegen, The Netherlands
Jan AM Smeitink, Radboud University Medical Center, Nijmegen, The Netherlands

Published online: October 2017

DOI: 10.1002/9780470015902.a0006029.pub3

Abstract

The mitochondrial oxidative phosphorylation (OXPHOS) system is located in the inner mitochondrial membrane, and it is the major energy provider of the cell. It consists of five multiprotein complexes (complex I–V). Defects in one or several of these enzymes cause mitochondrial disorders. Identifying underlying mutations within the nuclear genome has been an arduous task until the widespread use of whole exome sequencing in recent years. Since then, a big effort has been put into deciphering underlying mutations in nuclear genes that directly or indirectly affect the OXPHOS system. This led to the discovery of a great number of new gene defects involved in these multifaceted diseases. These findings not only improved the diagnostic process but also helped to understand the mechanisms behind mitochondrial diseases and laid the groundwork for novel approaches to therapy.

Key Concepts

  • Mitochondrial diseases are caused by a deficient pyruvate oxidation that involves the Krebs cycle and the oxidative phosphorylation (OXPHOS) system.
  • The OXPHOS system comprises the four respiratory chain enzymes (complexes I–IV) and complex V, also termed ATP synthase.
  • Defects in one or several of these enzymes cause mitochondrial disorders and give rise to a broad spectrum of clinical signs and symptoms ranging from mild adult‐onset myopathy to neonatal-onset fatal multisystem disease.
  • Impairments in OXPHOS functionality can not only be caused by mutations in genes encoding subunits of the respective complex but also by defects in nuclear genes encoding proteins required for OXPHOS complex biogenesis, mitochondrial translation, or mitochondrial redox homeostasis.

Keywords: mitochondria; respiratory chain; nuclear gene defects; human; oxidative phosphorylation; mitochondrial disease

Figure 1. Scheme of the OXPHOS (oxidative phosphorylation) system in mammalian mitochondria. Electrons (e−) from carbon oxidations are transferred via NADH (nicotinamide adenine dinucleotide) into OXPHOS complex I, which is embedded in the lipid bilayer of the mitochondrial inner membrane (IMM), then transported to coenzyme Q (Q). Some electrons from organic‐acid oxidations are transferred, via other flavin‐containing enzyme complexes directly to CoQ. CoQ delivers electrons via complex III and cytochrome c (Cyt c) to the final electron acceptor complex IV. Here, oxygen is reduced to water. The electrons lose free energy at each transfer step, and in complexes I, III and IV, the energy is harnessed and coupled to the movement of H+ from the mitochondrial matrix to the intermembrane space (IMS). The proton gradient thus generated is used for the production of ATP by complex V. Except for complex II, all complexes contain some proteins encoded by the mitochondrial genome and others encoded by the nuclear genome. The number of subunits for each complex is indicated.
close

References

Abrahams JP , Abrahams JP , Leslie AG , Lutter R and Walker JE (1994) Structure at 2.8 A resolution of F1‐ATPase from bovine heart mitochondria. Nature 370 (6491): 621–628.

Alston CL , Rocha MC , Lax NZ , Turnbull DM and Taylor RW (2017) The genetics and pathology of mitochondrial disease. Journal of Pathology 241 (2): 236–250.

Andreu AL , Hanna MG , Reichmann H , et al. (1999) Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. New England Journal of Medicine 341 (14): 1037–1044.

Baertling F , Rodenburg RJ , Schaper J , et al. (2014) A guide to diagnosis and treatment of Leigh syndrome. Journal of Neurology, Neurosurgery and Psychiatry 85 (3): 257–265.

Balsa E , Marco R , Perales‐Clemente E , et al. (2012) NDUFA4 is a subunit of complex IV of the mammalian electron transport chain. Cell Metabolism 16 (3): 378–386.

Barth PG , Scholte HR , Berden JA , et al. (1983) An X‐linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes. Journal of Neurological Sciences 62 (1–3): 327–355.

Bayley JP , Kunst HP , Cascon A , et al. (2010) SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncology 11 (4): 366–372.

Bourgeron T (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nature Genetics 11: 144–149. DOI: 10.1038/ng1095-144

Crofts AR , Holland JT , Victoria D , et al. (2008) The Q‐cycle reviewed: how well does a monomeric mechanism of the bc(1) complex account for the function of a dimeric complex? Biochimica et Biophysica Acta 1777 (7–8): 1001–1019.

Crosby AH , Patel H , Chioza BA , et al. (2010) Defective mitochondrial mRNA maturation is associated with spastic ataxia. American Journal of Human Genetics 87 (5): 655–660.

De Meirleir L , Seneca S , Lissens W , et al. (2004) Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. Journal of Medical Genetics 41 (2): 120–124.

Fornuskova D , Stiburek L , Wenchich L , et al.(2010) Novel insights into the assembly and function of human nuclear‐encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b. Biochemical Journal 428 (3): 363–374.

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 (3): 415–423.

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 (6): 654–656.

Ghezzi D , Baruffini E , Haack TB , et al. (2012) Mutations of the mitochondrial‐tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. American Journal of Human Genetics 90 (6): 1079–1087.

Guerrero‐Castillo S , Baertling F , Kownatzki D , et al. (2017) The assembly pathway of mitochondrial respiratory chain complex I. Cell Metabolism 25 (1): 128–139.

Haack TB , Haberberger B , Frisch EM , et al. (2012) Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. Journal of Medical Genetics 49 (4): 277–283.

Hoekstra AS and Bayley JP (2013) The role of complex II in disease. Biochimica et Biophysica Acta 1827 (5): 543–551.

Holt IJ and Jacobs HT (2014) Unique features of DNA replication in mitochondria: a functional and evolutionary perspective. Bioessays 36 (11): 1024–1031.

Holzerova E , Danhauser K , Haack TB , et al. (2016) Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early‐onset neurodegeneration. Brain 139 (Pt 2): 346–354.

Houstek J , Klement P , Floryk D , et al. (1999) A novel deficiency of mitochondrial ATPase of nuclear origin. Human Molecular Genetics 8 (11): 1967–1974.

Iwata S , Lee JW , Okada K , et al. (1998) Complete structure of the 11‐subunit bovine mitochondrial cytochrome bc1 complex. Science 281 (5373): 64–71.

Jiko C , Davies KM , Shinzawa‐Itoh K , et al. (2015) Bovine F1Fo ATP synthase monomers bend the lipid bilayer in 2D membrane crystals. eLife 4: e06119.

Kaukonen J , Juselius JK , Tiranti V , et al. (2000) Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289 (5480): 782–785.

Lightowlers RN , Taylor RW and Turnbull DM (2015) Mutations causing mitochondrial disease: what is new and what challenges remain? Science 349 (6255): 1494–1499.

Lim SC , Smith KR , Stroud DA , et al. (2014) A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome. American Journal of Human Genetics 94 (2): 209–222.

Longley MJ , Clark S and Wai CY (2006) Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. American Journal of Human Genetics 78 (6): 1026–1034.

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 (3): 337–341.

Mayr JA , Haack TB , Graf E , et al. (2012) Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. American Journal of Human Genetics 90 (2): 314–320.

Mayr JA , Haack TB , Freisinger P , et al. (2015) Spectrum of combined respiratory chain defects. Journal of Inherited Metabolic Disease 38 (4): 629–640.

Mohr J and Mageroy K (1960) Sex‐linked deafness of a possibly new type. Acta Genetica et Statistica Medica 10: 54–62.

Mordaunt DA , Jolley A , Balasubramaniam S , et al. (2015) Phenotypic variation of TTC19‐deficient mitochondrial complex III deficiency: a case report and literature review. American Journal of Medical Genetics. Part A 167 (6): 1330–1336.

Nouws J , Nijtmans LG , Smeitink JA and Vogel RO (2012) Assembly factors as a new class of disease genes for mitochondrial complex I deficiency: cause, pathology and treatment options. Brain 135 (Pt 1): 12–22.

Ostergaard E , Christensen E , Kristensen E , et al. (2007) Deficiency of the alpha subunit of succinate‐coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. American Journal of Human Genetics 81 (2): 383–387.

Ostergaard E , Weraarpachai W , Ravn K , et al. (2015) Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature. Journal of Medical Genetics 52 (3): 203–207.

Sanchez‐Caballero L , Ruzzenente B , Bianchi L , et al. (2016) Mutations in complex I assembly factor TMEM126B result in muscle weakness and isolated complex I deficiency. American Journal of Human Genetics 99 (1): 208–216.

Schagger H , Brandt U , Gencic S and von Jagow G (1995) Ubiquinol‐cytochrome‐c reductase from human and bovine mitochondria. Methods in Enzymology 260: 82–96.

Sengers RC , Trijbels JM , Willems JL , Daniels O and Stadhouders AM (1975) Congenital cataract and mitochondrial myopathy of skeletal and heart muscle associated with lactic acidosis after exercise. Journal of Pediatrics 86 (6): 873–880.

Spelbrink JN , Li FY , Tiranti V , et al. (2001) Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4‐like protein localized in mitochondria. Nature Genetics 28 (3): 223–231.

Stroud DA , Surgenor EE , Formosa LE , et al. (2016) Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature 538 (7623): 123–126.

Timmers HJ , Gimenez‐Roqueplo AP , Mannelli M and Pacak K (2009) Clinical aspects of SDHx‐related pheochromocytoma and paraganglioma. Endocrine‐Related Cancer 16 (2): 391–400.

Van Goethem G , Dermaut B , Lofgren A , Martin JJ and Van Broeckhoven C (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature Genetics 28 (3): 211–212.

Van Vranken JG , Na U , Winge DR and Rutter J (2015) Protein‐mediated assembly of succinate dehydrogenase and its cofactors. Critical Reviews in Biochemistry and Molecular Biology 50 (2): 168–180.

Vidoni S , Harbour ME , Guerrero‐Castillo S , et al. (2017) MR‐1S interacts with PET100 and PET117 in module‐based assembly of human cytochrome c oxidase. Cell Reports 18 (7): 1727–1738.

Vreken P , Valianpour F , Nijtmans LG , et al. (2000) Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome. Biochemical and Biophysical Research Communications 279 (2): 378–382.

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. Nature Genetics 44 (7): 797–802.

Xia D , Esser L , Tang WK , et al. (2013) Structural analysis of cytochrome bc1 complexes: implications to the mechanism of function. Biochimica et Biophysica Acta 1827 (11–12): 1278–1294.

Zara V , Conte L and Trumpower BL (2009) Biogenesis of the yeast cytochrome bc1 complex. Biochimica et Biophysica Acta 1793 (1): 89–96.

Zhu J , Vinothkumar KR and Hirst J (2016) Structure of mammalian respiratory complex I. Nature 536 (7616): 354–358.

Further Reading

Web Links

mt DNA and mitochondrial diseases: http://www.nature.com/scitable/topicpage/mtdna‐and‐mitochondrial‐diseases‐903

MITOMAP A human mitochondrial genome database: http://www.mitomap.org/

The MitoProteome Human Mitochondrial Protein Database. Mitochondrial Proteome Database for mitochondria‐related genes, proteins and diseases: http://www.mitoproteome.org/

Related Sub-Topics:

DNA Structure and Function | Molecular Genetics of Common and Complex Disease | Mutational Mechanisms of Genetic Disease | Cell Compartments and Cellular Organelles | Cell Energetics | Mitochondrial Diseases
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Oxidative Phosphorylation System: Nuclear Genes and Genetic Disease
 
How to Cite close
Sánchez‐Caballero, Laura, Baertling, Fabian, Nijtmans, Leo, and Smeitink, Jan AM(Oct 2017) Oxidative Phosphorylation System: Nuclear Genes and Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006029.pub3]