Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies

Abstract

Mitochondrial disorders are a heterogeneous group of often multisystemic and early fatal diseases, which are amongst the most common inherited human diseases. These disorders are caused by defects in the oxidative phosphorylation (OXPHOS) system, which comprises five multisubunit enzyme complexes encoded by both the nuclear and the mitochondrial genomes. Due to the multitude of proteins and intricacy of the processes required for a properly functioning OXPHOS system, identifying the genetic defect that underlies an OXPHOS deficiency is not an easy task, especially in the case of combined OXPHOS defects. In the present communication we give an extensive overview of the proteins and processes (in)directly involved in mitochondrial translation and the biogenesis of the OXPHOS system and their roles in combined OXPHOS deficiencies. This knowledge is important for further research into the genetic causes, with the ultimate goal to effectively prevent and cure these complex and often devastating disorders.

Figure 1

Schematic overview of the processes involved in mitochondrial translation and the biogenesis of the OXPHOS system. Before translation can take place in the mitochondrion, the mtDNA needs to be maintained, replicated and transcribed and numerous nDNA-encoded proteins have to be imported into the mitochondrion for these processes and for mitochondrial translation itself (see Figure 2 for more details on mitochondrial translation and its components depicted here). For the formation of the OXPHOS system, the nDNA- and mtDNA-encoded subunits need to be synthesized, imported, inserted into the inner membrane and assembled into enzyme complexes. The 13 mRNAs depicted refer to 9 monocistronic and 2 dicistronic transcripts. Proteins implicated in mitochondrial disorders are mentioned in brackets (also see Table 1). CI–CV  =  complex I–V of the OXPHOS system; TIM and TOM  =  translocase of the inner and outer mitochondrial membranes.

Figure 2

Diagram of human mitochondrial protein synthesis. The three phases of mitochondrial translation—initiation, elongation and termination—and all translation factors involved are represented in this figure. See Section 3.2 in the text for a detailed description of all steps (numbered in boxes) of the mitochondrial translation process. Initiation, elongation and termination factors are represented by green, purple and red ovals, respectively. GTP and GDP are shown in yellow and beige circles, respectively.