Cooperation between COA6 and SCO2 in COX2 Maturation during Cytochrome c Oxidase Assembly Links Two Mitochondrial Cardiomyopathies

Pacheu-Grau, David; Bareth, Bettina; Dudek, Jan; Juris, Lisa; Vögtle, F.-Nora; Wissel, Mirjam; Leary, Scot C.; Dennerlein, Sven; Rehling, Peter; Deckers, Markus

doi:10.1016/j.cmet.2015.04.012

Cited by 69 publications

(90 citation statements)

References 48 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…55 In retrospect, these findings are not that surprising given the relative severity of the copper deficiency in various SCO1 cell types, 45 and the fact that SCO1 catalyzes the transfer of copper to the Cu A site of COX2 in a reaction that is facilitated by SCO2 and COA6. 54, 56, 58, 87 These observations in fact collectively support the idea that SCO1 sits at the head of a mitochondrial pathway, and that its functional status directly impinges upon COX assembly and the generation of a signal that regulates copper homeostasis (Figure 2). 23, 24 The exact identity of this mitochondrial signal and how it is transduced to copper handling machinery localized elsewhere in the cell is not yet known.…”

Section: Mitochondrial Copper Chaperones Play a Key Role In The Regulsupporting

confidence: 63%

The mitochondrion: a central architect of copper homeostasis

2017

View full text Add to dashboard Cite

All known eukaryotes require copper for their development and survival. The essentiality of copper reflects its widespread use as a co-factor in conserved enzymes that catalyze biochemical reactions critical to energy production, free radical detoxification, collagen deposition, neurotransmitter biosynthesis and iron homeostasis. However, the prioritized use of copper poses an organism with a considerable challenge because, in its unbound form, copper can potentiate free radical production and displace iron-sulphur clusters to disrupt protein function. Protective mechanisms therefore evolved to mitigate this challenge and tightly regulate the acquisition, trafficking and storage of copper such that the metal ion is rarely found in its free form in the cell. Findings by a number of groups over the last ten years emphasize that this regulatory framework forms the foundation of a system that is capable of monitoring copper status and reprioritizing copper usage at both the cellular and systemic levels of organization. While the identification of relevant molecular mechanisms and signaling pathways has proven to be difficult and remains a barrier to our full understanding of the regulation of copper homeostasis, mounting evidence points to the mitochondrion as a pivotal hub in this regard in both healthy and diseased states. Here, we review our current understanding of copper handling pathways contained within the organelle and consider plausible mechanisms that may serve to functionally couple their activity to that of other cellular copper handling machinery to maintain copper homeostasis.

show abstract

Section: Mitochondrial Copper Chaperones Play a Key Role In The Regulsupporting

confidence: 63%

The mitochondrion: a central architect of copper homeostasis

2017

View full text Add to dashboard Cite

show abstract

“…The fact that this reaction occurs in the mitochondria strongly suggests that there are other cofactors mediating this process. One possible candidate for this role is protein COA6, recently identified as an essential cofactor for oxidase assembly containing a Cys-rich motif, which was proposed to interact with COX II and Sco2 (43,44).…”

Section: Discussionmentioning

confidence: 99%

Loop recognition and copper-mediated disulfide reduction underpin metal site assembly of Cu _A in human cytochrome oxidase

Morgada

Abriata

Cefaro

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Maturation of cytochrome oxidases is a complex process requiring assembly of several subunits and adequate uptake of the metal cofactors. Two orthologous Sco proteins (Sco1 and Sco2) are essential for the correct assembly of the dicopper Cu A site in the human oxidase, but their function is not fully understood. Here, we report an in vitro biochemical study that shows that Sco1 is a metallochaperone that selectively transfers Cu(I) ions based on loop recognition, whereas Sco2 is a copper-dependent thiol reductase of the cysteine ligands in the oxidase. Copper binding to Sco2 is essential to elicit its redox function and as a guardian of the reduced state of its own cysteine residues in the oxidizing environment of the mitochondrial intermembrane space (IMS). These results provide a detailed molecular mechanism for Cu A assembly, suggesting that copper and redox homeostasis are intimately linked in the mitochondrion.

show abstract

“…5B). In S. cerevisiae cox1 mutants, COX2 has been shown to contain copper (11), which could also be true in the human COX1 mutant cybrids, thus providing an opportunity to analyze COX2 translocation by protease-protection assays. In support of this possibility, COX2 is proteinase K-sensitive in mitoplasts prepared by hypotonic swelling of mitochondria isolated from COX1 cybrid cells (Fig.…”

Section: Cox18 Is Essential For the Translocation Of Cox2 C Terminus mentioning

confidence: 99%

Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module

Bourens¹,

Barrientos

2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by John M. Denu Defects in mitochondrial cytochrome c oxidase or respiratory chain complex IV (CIV) assembly are a frequent cause of human mitochondrial disorders. Specifically, mutations in four conserved assembly factors impinging the biogenesis of the mitochondrion-encoded catalytic core subunit 2 (COX2) result in myopathies. These factors afford stability of newly synthesized COX2 (the dystonia-ataxia syndrome protein COX20), a protein with two transmembrane domains, and maturation of its copper center, Cu A (cardiomyopathy proteins SCO1, SCO2, and COA6). COX18 is an additional COX2 assembly factor that belongs to the Oxa1 family of membrane protein insertases. Here, we used a gene-editing approach to generate a human COX18 knock-out HEK293T cell line that displays isolated complete CIV deficiency. We demonstrate that COX20 stabilizes COX2 during insertion of its N-proximal transmembrane domain, and subsequently, COX18 transiently interacts with COX2 to promote translocation across the inner membrane of the COX2 C-tail that contains the apo-Cu A site. The release of COX18 from this complex coincides with the binding of the SCO1-SCO2-COA6 copper metallation module to COX2-COX20 to finalize COX2 biogenesis. Therefore, COX18 is a new candidate when screening for mitochondrial disorders associated with isolated CIV deficiency.In nucleated human cells, mitochondria are central organelles that harbor the enzymes required for cellular respiration and aerobic energy production through oxidative phosphorylation (OXPHOS).2 These multimeric complexes are formed by subunits encoded in the nuclear and mitochondrial genomes that are assembled into functional units with the assistance of a myriad of nucleus-encoded ancillary proteins, generally called assembly factors. Mutations in OXPHOS subunits or assembly factors result in failure to fulfill the energy demands of most tissues with a major incidence in those with high energy

show abstract

Cooperation between COA6 and SCO2 in COX2 Maturation during Cytochrome c Oxidase Assembly Links Two Mitochondrial Cardiomyopathies

Cited by 69 publications

References 48 publications

The mitochondrion: a central architect of copper homeostasis

The mitochondrion: a central architect of copper homeostasis

Loop recognition and copper-mediated disulfide reduction underpin metal site assembly of Cu _A in human cytochrome oxidase

Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module

Contact Info

Product

Resources

About

Cooperation between COA6 and SCO2 in COX2 Maturation during Cytochrome c Oxidase Assembly Links Two Mitochondrial Cardiomyopathies

Cited by 69 publications

References 48 publications

The mitochondrion: a central architect of copper homeostasis

The mitochondrion: a central architect of copper homeostasis

Loop recognition and copper-mediated disulfide reduction underpin metal site assembly of Cu A in human cytochrome oxidase

Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module

Contact Info

Product

Resources

About

Loop recognition and copper-mediated disulfide reduction underpin metal site assembly of Cu _A in human cytochrome oxidase