Biogenesis and assembly of eukaryotic cytochrome c oxidase catalytic core

Abstract

Eukaryotic cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. COX is a multimeric enzyme formed by subunits of dual genetic origin which assembly is intricate and highly regulated. The COX catalytic core is formed by three mitochondrial DNA encoded subunits, Cox1, Cox2 and Cox3, conserved in the bacterial enzyme. Their biogenesis requires the action of messenger-specific and subunit-specific factors which facilitate the synthesis, membrane insertion, maturation or assembly of the core subunits. The study of yeast strains and human cell lines from patients carrying mutations in structural subunits and COX assembly factors has been invaluable to identify these ancillary factors. Here we review the current state of knowledge of the biogenesis and assembly of the eukaryotic COX catalytic core and discuss the degree of conservation of the players and mechanisms operating from yeast to human. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes.

Fig. 1. Simplified model for the process of COX assembly

General chaperones and RNA-specific translational activators (not depicted here but see explanation in the text) are required for synthesis of the mtDNA-encoded subunits forming the core. Following their insertion into the inner membrane, Cox1 and Cox2 are matured by addition of metal cofactors. At some point, substrate-specific chaperones bind Cox1 and Cox2 to maintain them in an assembly-competent state. A predicted Cox3 chaperone has not been yet identified. Following Cox1 maturation, the nuclear DNA-encoded Cox5 and 6 subunits are added to Cox1 prior incorporation of the other core subunits and the rest of the accessory subunits to form the holoenzyme.

Fig. 2. Coordination of Cox1 synthesis with COX assembly

The model depicts the roles of Mss51, Cox14, Cox25 and the mtHsp70 chaperone Ssc1 on translational regulation of COX biogenesis (see explanation in the text).

Fig. 3. Biogenesis of Cox2

The scheme depicts the several steps and proteins involved of synthesis, topogenesis, maturation and assembly of Cox2 (see explanation in the text). IMM, inner mitochondrial membrane; IMS, intermembrane space.