Molecular Genetics of OXPHOS Disorders

Abstract

Abstract 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.