Oxidative Phosphorylation System: Nuclear Genes and Genetic Disease


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.


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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/

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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]