Cytochrome c oxidase biogenesis – from translation to early assembly of the core subunit COX1

Abstract

Mitochondria are the powerhouses of the cell as they produce the majority of ATP with their oxidative phosphorylation (OXPHOS) machinery. The OXPHOS system is composed of the F1Fo ATP synthase and four mitochondrial respiratory chain complexes, the terminal enzyme of which is the cytochrome c oxidase (complex IV) that transfers electrons to oxygen, generating water. Complex IV comprises of 14 structural subunits of dual genetic origin: while the three core subunits are mitochondrial encoded, the remaining constituents are encoded by the nuclear genome. Hence, the assembly of complex IV requires the coordination of two spatially separated gene expression machinery. Recent efforts elucidated an increasing number of proteins involved in mitochondrial gene expression, which are linked to complex IV assembly. Additionally, several COX1 biogenesis factors have been intensively biochemically investigated and an increasing number of structural snapshots shed light on the organization of macromolecular complexes such as the mitoribosome or the cytochrome c oxidase. Here, we focus on COX1 translation regulation and highlight the advanced understanding of early steps during COX1 assembly and its link to mitochondrial translation regulation.

Coordinating mitochondrial translation with assembly of the OXPHOS complexes

“…The assembly of complex IV proceeds through the subsequent association of modular subassemblies. Initially, the COX1 module, whose assembly is facilitated through the MITRAC (Mitochondrial Translation Regulation Assembly intermediate of Cytochrome c oxidase) complex, comes together with the COX4-COX5A module [ 24 , 25 ]. Successively, the COX2 module and COX3 module follow.…”

More than Just Bread and Wine: Using Yeast to Understand Inherited Cytochrome Oxidase Deficiencies in Humans

“…The assembly of a functional COX complex requires the carefully coordinated action of at least 30 proteins, in addition to the 14 subunit constituents [12]. The exact roles for many of these subunits remain unclear, and investigations into the mechanisms behind the assembly of the holoenzyme are ongoing.…”

“…The catalytic core of the complex is made up of the three mitochondrial-encoded subunits-COX1, COX2, COX3. Each of these are assembled into the mitochondrial inner membrane with the assistance of their distinct sets of assembly factors that stabilize the assembling apoenzyme in the membrane and ensure the appropriate insertion of essential cofactors [12]. Early research into COX assembly described the process as being linear, with subunits being added onto COX1 one after another [13].…”

“…The linear assembly model, which was supported by results that demonstrated that COX1 acted as a seed to which other subunits could join, has been largely replaced by the concept of modular COX assembly [14,15], wherein each of the three catalytic subunits is formed separately with the assistance of its own dedicated set of assembly factors [16]. These modules are then added to a seed module of nuclear assembly factors in a linear manner [12], with the distinct steps of the process referred to as S1-S4. S1 involves the formation of the COX1 module, which then joins the nuclear seed module in S2.…”

“…Early studies of oxa1 null mutants revealed an impairment of the processing and insertion of COX2 into the mitochondrial inner membrane [112,130], with OXA1 being required for the proper export of both the N-and C-termini of COX2. While initial observations suggested OXA1 was specific to COX assembly, further work in both yeast and humans has revealed a broader role for OXA1 in mitochondrial membrane insertion processes [12], including the import of the members of the mitochondrial metabolite carrier family of proteins [131]. Indeed, OXA1 has been shown to be a member of the YidC/Oxa1/Alb3 protein family, with roles in membranes from bacteria to thylakoids and mitochondria [132].…”