Mitochondrial disorders caused by mutations in respiratory chain assembly factors

Abstract

Mitochondrial diseases involve the dysfunction of the oxidative phosphorylation (OXPHOS) system. This group of diseases presents with heterogeneous clinical symptoms affecting mainly organs with high energy demands. Defects in the multimeric complexes comprising the OXPHOS system have a dual genetic origin, mitochondrial or nuclear DNA. Although many nuclear DNA mutations involve genes coding for subunits of the respiratory complexes, the majority of mutations found to date affect factors that do not form part of the final complexes. These assembly factors or chaperones have multiple functions ranging from cofactor insertion to proper assembly/stability of the complexes. Although significant progress has been made in the last few years in the discovery of new assembly factors, the function of many remains elusive. Here, we describe assembly factors or chaperones that are required for respiratory chain complex assembly and their clinical relevance.

Figure 1

BCS1L is encoded by eight exons with the start codon in exon 2 and the stop codon in exon 8. Mutations in the 5′UTR region causing complex III deficiency are shown. In the BCS1L protein three functional domains, the import domain, the BCS1L_N-specific domain and the AAA_ATPase domain can be identfied. BCS1L mutations are indicated by their respective amino acid exchange. Mutations occur in all domains of the protein but cause a wide spectrum of symptoms ranging from mild complex III deficiency and Björnstad syndrome (shown above the BCS1L protein) to mutations causing mainly hepatopathy (bold, italic), mainly encephalopathy (underlined) or hepatopathy and encephalopathy (bold, italic and underlined) (shown below the BCS1L protein). BCS1L mutations are indicated by their respective amino acid exchange. Patients identified so far are either homozygous for mutations (P99L, S277N, S78G, T50A, G129R) or compound heterozygotes (R45C/R56ter, V327A/R56ter, G35R/184C, S78G/144Q, R73C/F368I, R155P/V353M).