What Role Does COA6 Play in Cytochrome C Oxidase Biogenesis: A Metallochaperone or Thiol Oxidoreductase, or Both?

Maghool, Shadi; Ryan, Michael; Maher, M.J.

doi:10.3390/ijms21196983

Cited by 14 publications

(14 citation statements)

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“…Elucidating the biochemical function of these CcO assembly factors has remained a major bottleneck in our understanding of the biogenesis of CcO, with the role of COA6 in Cu A site formation being a case in point. A recent review article debated the potential role of COA6 as a metallochaperone or a thiol-disulfide oxidoreductase (disulfide reductase) in the copper delivery process [ 35 ]. Upon critical analysis of literature, we find that the current experimental data favors the disulfide reductase activity of COA6 and leads to a model where COA6 acts on its client proteins—COX2 and SCO1—by reducing the disulfide bond between their copper-coordinating cysteines to allow for copper binding ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

“…The structure of the human recombinant COA6 protein has been determined by both X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. Both the structures show COA6 as a helical protein with coiled-coil-helix-coiled-coil-helix (CHCH) fold domain [ 24 , 35 , 36 ]. COA6 contains three α-helices where the first two helices—helix 1 (H1) and helix 2 (H2)—form a CHCH domain stabilized by two disulfide bonds between the cysteine pairs of its CX 9 C-CX 10 C motif ( Figure 3 a,b) [ 24 , 36 ].…”

Section: Structure Of Coa6mentioning

confidence: 99%

“…COA6 contains three α-helices where the first two helices—helix 1 (H1) and helix 2 (H2)—form a CHCH domain stabilized by two disulfide bonds between the cysteine pairs of its CX 9 C-CX 10 C motif ( Figure 3 a,b) [ 24 , 36 ]. Despite these similarities between the solution and crystal structures, a number of differences exist, as described in detail in a recent review [ 35 ]. Briefly, the length of the H1 and H2 helices in the crystal structure is significantly longer than those in the solution structure ( Figure 3 a,b).…”

Section: Structure Of Coa6mentioning

confidence: 99%

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The Role of COA6 in the Mitochondrial Copper Delivery Pathway to Cytochrome c Oxidase

Swaminathan

Gohil

2022

Biomolecules

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Copper is essential for the stability and activity of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Copper is bound to COX1 and COX2, two core subunits of CcO, forming the CuB and CuA sites, respectively. Biogenesis of these two copper sites of CcO occurs separately and requires a number of evolutionarily conserved proteins that form the mitochondrial copper delivery pathway. Pathogenic mutations in some of the proteins of the copper delivery pathway, such as SCO1, SCO2, and COA6, have been shown to cause fatal infantile human disorders, highlighting the biomedical significance of understanding copper delivery mechanisms to CcO. While two decades of studies have provided a clearer picture regarding the biochemical roles of SCO1 and SCO2 proteins, some discrepancy exists regarding the function of COA6, the new member of this pathway. Initial genetic and biochemical studies have linked COA6 with copper delivery to COX2 and follow-up structural and functional studies have shown that it is specifically required for the biogenesis of the CuA site by acting as a disulfide reductase of SCO and COX2 proteins. Its role as a copper metallochaperone has also been proposed. Here, we critically review the recent literature regarding the molecular function of COA6 in CuA biogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Structure Of Coa6mentioning

confidence: 99%

Section: Structure Of Coa6mentioning

confidence: 99%

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The Role of COA6 in the Mitochondrial Copper Delivery Pathway to Cytochrome c Oxidase

Swaminathan

Gohil

2022

Biomolecules

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“…However, more recent studies have suggested that COA6 is a thiol-reductase binding SCO1 and/or SCO2 and catalyzing the reduction of critical Cys residues in SCO1 and/or SCO2 as well as MT-CO2 allowing the transfer and binding of Cu to MT-CO2 ( Soma et al, 2019 ; Pacheu-Grau et al, 2020 ). The exact COA6 binding partners and mechanisms are still not completely clear as the interpretation of the results varied in different laboratories depending on the experimental approach used ( Maghool et al, 2020 ).…”

Section: Redox-regulation Of Oxphos Components and Biogenesis Factorsmentioning

confidence: 99%

Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells

Geldon

Fernández-Vizarra

Tokatlidis

2021

Front. Cell Dev. Biol.

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Mitochondria are double-membrane organelles that contain their own genome, the mitochondrial DNA (mtDNA), and reminiscent of its endosymbiotic origin. Mitochondria are responsible for cellular respiration via the function of the electron oxidative phosphorylation system (OXPHOS), located in the mitochondrial inner membrane and composed of the four electron transport chain (ETC) enzymes (complexes I-IV), and the ATP synthase (complex V). Even though the mtDNA encodes essential OXPHOS components, the large majority of the structural subunits and additional biogenetical factors (more than seventy proteins) are encoded in the nucleus and translated in the cytoplasm. To incorporate these proteins and the rest of the mitochondrial proteome, mitochondria have evolved varied, and sophisticated import machineries that specifically target proteins to the different compartments defined by the two membranes. The intermembrane space (IMS) contains a high number of cysteine-rich proteins, which are mostly imported via the MIA40 oxidative folding system, dependent on the reduction, and oxidation of key Cys residues. Several of these proteins are structural components or assembly factors necessary for the correct maturation and function of the ETC complexes. Interestingly, many of these proteins are involved in the metalation of the active redox centers of complex IV, the terminal oxidase of the mitochondrial ETC. Due to their function in oxygen reduction, mitochondria are the main generators of reactive oxygen species (ROS), on both sides of the inner membrane, i.e., in the matrix and the IMS. ROS generation is important due to their role as signaling molecules, but an excessive production is detrimental due to unwanted oxidation reactions that impact on the function of different types of biomolecules contained in mitochondria. Therefore, the maintenance of the redox balance in the IMS is essential for mitochondrial function. In this review, we will discuss the role that redox regulation plays in the maintenance of IMS homeostasis as well as how mitochondrial ROS generation may be a key regulatory factor for ETC biogenesis, especially for complex IV.

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“…COX assembly factor 6 (COA6), a small intermembrane space-located protein, plays a role in the biogenesis of COX, as described in an interesting review by Maghool and coauthors [9], which discusses the current understanding of the molecular mechanisms by which COA6 participates in COX biogenesis. In particular, some evidence has indicated that COA6 binds copper, essential for COX assembly, activity, and stability; at the same time, COA6 possesses a thiol oxidoreductase activity, which could correlate with copper binding.…”

mentioning

confidence: 99%

Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease

Ferramosca

2020

IJMS

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What Role Does COA6 Play in Cytochrome C Oxidase Biogenesis: A Metallochaperone or Thiol Oxidoreductase, or Both?

Cited by 14 publications

References 65 publications

The Role of COA6 in the Mitochondrial Copper Delivery Pathway to Cytochrome c Oxidase

The Role of COA6 in the Mitochondrial Copper Delivery Pathway to Cytochrome c Oxidase

Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells

Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease

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