Elsevier

Mitochondrion

Volume 5, Issue 6, December 2005, Pages 363-388
Mitochondrion

Review
Biogenesis of cytochrome c oxidase

https://doi.org/10.1016/j.mito.2005.08.002Get rights and content

Abstract

Cytochrome c oxidase (COX), the terminal enzyme of electron transport chains in some prokaryotes and in mitochondria, has been characterized in detail over many years. Recently, a number of new data on structural and functional aspects as well as on COX biogenesis emerged. COX biogenesis includes a variety of steps starting from translation to the formation of the mature complex. Each step involves a set of specific factors that assist translation of subunits, their translocation across membranes, insertion of essential cofactors, assembly and final maturation of the enzyme. In this review, we focus on the organization and biogenesis of COX.

Introduction

Cytochrome c oxidase (common abbreviations: CO, CcO, COX, or complex IV) is the terminal enzyme of electron transport chains in eukaryotes and some prokaryotes. It belongs to the family of heme-copper enzymes, and as all its members COX not only reduces dioxygen to water, but also acts as a proton pump (Pereira et al., 2001). Eukaryotic COX is a complex enzyme, which consists of 11–13 subunits depending on the organism. Prokaryotic homologues usually have a less complex organization. The core of the eukaryotic enzyme is formed by three subunits, which are encoded by mitochondrial (mt) DNA and translated on mt ribosomes. The three core subunits are highly conserved between different organisms. Their prokaryotic homologues constitute the functional enzyme. They contain a couple of redox-active metal centers which play a key role in the assembly steps and function of the enzyme. The low-spin heme a and a bimetallic site composed of high-spin heme a3 and a copper ion (CuB) reside in subunit Cox1p. The latter two form the oxygen reduction site termed CuB center. The binuclear CuA center is coordinated by subunit Cox2p and—together with heme a—constitutes the entry site for electrons which are channeled through the respiratory chain to COX.

The other subunits are encoded by the nuclear genome. Compared with their mt counterparts they show relatively low levels of conservation. Nevertheless, most of them are indispensable for the proper assembly and function of the enzyme. The nuclear-encoded COX subunits appear not to originate from the genome of the ancestral endosymbiont. Neither in Rickettsia prowazekii nor in the primitive eukaryotic organisms Reclinomonas americana or Giardia sp. (Lang et al., 1997, Das et al., 2004) putative homologues are detected, suggesting that the nuclear COX genes evolved after the invasion of the endosymbiont.

Besides the above mentioned metal centers, COX contains magnesium, sodium and zinc ions. Only few data are available on the role of these metals for COX function.

Mitochondria evolved sophisticated mechanisms of simultaneously recruiting both nuclearly and mitochondrially encoded subunits, thus allowing the coordinated assembly of proteins and cofactors of different origins into one complex. COX formation requires multiple proteins which facilitate and assist its assembly. Their number exceeds by far that of the COX subunits which represent only a minor part of mt proteome (Sickmann et al., 2003). Although some of these assisting proteins are also involved in other processes, a large number of them is exclusively dealing with COX. Many of them are required for delivery, formation and insertion of the cofactors and metal ions. A less discovered group of proteins is engaged in chaperoning the subunits during delivery or in stabilizing immature COX pre-complexes.

Our knowledge of the COX assembly process is still limited despite of a bulk of data describing structural and functional features of this complicated process. The main aspects of this review will encompass the question of COX organization (including protein composition, organization of the CuA and CuB centers and of the other groups important for COX function), essential aspects of COX assembly, formation and insertion of the heme moieties, delivery of metal ions and formation of the metal centers, and formation of the mature, active COX. In addition we will also briefly summarize novel findings regarding COX expression. Most of the reviewed literature originated from studies on eukaryotic COX, especially of bovine heart and yeast. However, important data from studies on bacterial homologues will also be highlighted. It should be noted that the nomenclature of COX proteins differs between the organisms. We will specify the cases, where such differences exist.

Section snippets

Organization of COX

Cytochrome c oxidase (ferrocytochrome c: oxygen oxidoreductase, EC 1.9.3.1) is the terminal enzyme of the eukaryotic respiratory chain. The membrane-embedded complex, which acts as a dimer (Frey and Murray, 1994, Tsukihara et al., 1995), faces both the mt intermembrane space (IMS) and the matrix, slightly more emerging to the IMS side (Tsukihara et al., 1995, Carr and Winge, 2003). COX plays a key role in the electron transport chain; it catalyzes the reduction of molecular oxygen to water and

Assembly of COX

The assembly of COX is a sequential process that involves a number of accessory proteins (Nijtmans et al., 1998) (Table 2). Prior to assembly the mt-translated subunits need to be processed and inserted into the lipid bilayer of IMM. The nuclearly encoded subunits must be translocated to the site of assembly in the IMM. Only after these processes are successfully accomplished, assembly can occur.

Formation of active COX

Assembly of subunits and insertion of cofactors is not the final step in COX biogenesis. Formation of fully active COX requires additional maturation steps, which include the post-translational linkage of the Cu-coordinating histidine with a highly conserved adjacent tyrosine. This modification was proposed to play a role in the stabilization of the CuB site by scaffolding of CuB ligands (Das et al., 1998, Buse et al., 1999). Later it was suggested that this modification may fix the positions

Regulation of COX expression

Biogenesis of COX as of the other repiratory enzymes requires coordinated regulation of the mt and nuclearly encoded subunits. Coordination of expression of the nuclear genes is achieved by diverse transcriptional activators and repressors that are targets of various signaling pathways. In the past few years, microarray data combined with conventional methods led to the identification of some transcriptional regulators in yeast and mammals (Eisen et al., 1998, Epstein et al., 2001, Traven et

Summary

In this review, we tried to summarize relevant data on COX biogenesis. Because of the huge amount of available information it was not possible to consider all publications. One obvious conclusion that can be drawn is that there are still a number of gaps in our understanding of how functional COX is assembled. Recent mitoproteomic studies led to the identification of many so far uncharacterized proteins which may be engaged in the formation and regulation of respiratory complexes. Our current

Acknowledgements

We are grateful to Dennis R. Winge (Salt Lake City, UT) for critical reading and helpful comments on the manuscript and for providing data prior to publication.

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