Molecular Genetics of OXPHOS Disorders


OXPHOS disorders are a common (estimated prevalence 1:5.000) clinically heterogeneous group of genetic disorders caused by dysfunction of the oxidative phosphorylation system, which is the main cellular source of adenosine triphosphate (ATP). Mutations in genes encoded by either nuclear deoxyribonucleic acid (nDNA) or mitochondrial deoxyribonucleic acid (mtDNA) are the underlying molecular cause. Maternal inheritance, mtDNA heteroplasmia and random mitotic segregation contribute to the phenotypic expression of mtDNA mutations. Most OXPHOS disorders are recognized to be caused by nuclear genes. Mutations in genes encoding structural and assembly factors of OXPHOS system cause isolated OXPHOS complex deficiencies and frequently severe paediatric diseases. mtDNA stability nuclear disorders produce secondary mtDNA depletion or multiple mtDNA deletions. Emerging types of OXPHOS disorders are originated by mutations in nuclear genes involved in mitochondrial transcription and translation and in Fe–S cluster biogenesis. Next‐generation sequencing approaches are paving the way to the identification of molecular defects underlying OXPHOS diseases.

Key Concepts

  • Mitochondrial OXPHOS disorders are caused by mutations in genes encoded by two genomes: mitochondrial DNA (mtDNA) and nuclear – chromosomal – DNA (nDNA).
  • Most OXPHOS disorders are caused by nuclear genes, mainly in paediatric OXPHOS patients.
  • Mitochondrial DNA contains 13 genes encoding subunits of electron transport chain complexes I, III and IV, and FoF1‐ATP synthase (complex V). The four complex II subunits are encoded by nDNA.
  • mtDNA genetics key points are as follows: 16,5 kb long, polyplasmy (several copies per cell), maternal inheritance, mitotic segregation, absence of introns, polycistronic transcription and polymorphic.
  • mtDNA disorders could be caused by heteroplasmic or homoplasmic mutations that could be sporadic or maternal inherited.
  • Nuclear OXPHOS defects are caused by genes involved in highly heterogeneous biological pathways.
  • Mutations in genes encoding structural and assembly factors of OXPHOS system cause mainly, but not always, isolated complex defects of mitochondrial respiratory chain (MRC), and cause commonly severe paediatric diseases, being the most common Leigh syndrome.
  • mtDNA stability/maintenance disorders cause secondary mtDNA depletion or multiple mtDNA deletions by mutations in genes with roles in mtDNA replication/repair, mitochondrial dNTP pool preservation and mitochondrial dynamics.
  • Mitochondrial transcription and translational defects by mutations in genes involved in different steps may cause combined MRC defects, with numerous novel nuclear disease‐causing genes recently discovered.
  • High rates of novel nuclear disease‐causing‐genes detection involved in different OXPHOS biogenesis and functions owing to next‐generation sequencing approaches have expanded the spectrum of genes and pathways associated with OXPHOS dysfunction.

Keywords: mitochondrial disorders; respiratory chain; mitochondrial DNA; rare disease; mitochondrial translation; assembly factors; mtDNA maintenance; nuclear OXPHOS genes; heteroplasmy; maternal inheritance

Figure 1. Mitochondrial DNA disorders. Schematic diagram of the 16.5‐kb circular, double‐stranded human mtDNA. The outer circle represents the heavy (H) strand of the genome and the inner circle the light (L) strand. The D‐loop region, or noncoding control region, is key for the initiation of mtDNA replication and transcription. The two ribosomal RNAs are shown in red and 22 tRNAs are shown in black and denoted by their single letter abbreviations. The genes encoding subunits of complex I (MTND1–MTND6 and MTND4L) are shown in blue; cytochrome b (MTCYB) subunit of complex III is shown in green; catalytic subunits of cytochrome c oxidase (MTCO1–MTCO3) are shown in orange and the subunits of the ATP synthase (complex V) (MTATP6 and MTATP8) are shown in purple. The positions of mutations referred in text are marked by pink lines and arrows. LHON, Leber's hereditary optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes; MIDD, maternally inherited diabetes and deafness; CPEO, chronic progressive external ophthalmoplegia; LS, Leigh syndrome; NARP, neurogenic weakness, ataxia and retinitis pigmentosa; MILS, maternally inherited Leigh syndrome; MERFF, myoclonic epilepsy and ragged red fibres; KSS, Kearns–Sayre syndrome; PS, Pearson syndrome; HSP, H‐strand promotor; LSP: L‐strand promotor; OH, origin of H‐strand replication; OL, origin of L‐strand replication and kb, kilobase.
Figure 2. OXPHOS nuclear disorders. Different pathways affected by mutations in nuclear‐encoded genes associated with mitochondrial OXPHOS disorders are depicted in the different compartments of mitochondrion and cytosol. Illustrative genes and the biological processes disturbed when they are mutated are shown in boxes. See text for explanation.


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Blázquez, Alberto, Arenas, Joaquín, and Martín, Miguel A(Mar 2016) Molecular Genetics of OXPHOS Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025341]