The Human Cytochrome c Oxidase Assembly Factors SCO1 and SCO2 Have Regulatory Roles in the Maintenance of Cellular Copper Homeostasis

Leary, Scot C.; Cobine, Paul A.; Kaufman, Brett A.; Mattman, André; Palaty, Jan; Lockitch, Gillian; Winge, Dennis R.; Rustin, Pierre; Horvath, Rita; Shoubridge, Eric A.

doi:10.1016/j.cmet.2007.04.002

Cited by 35 publications

(60 citation statements)

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“…This indicates that SenC is not only required for cbb 3 -Cox, but also regulates Cu homeostasis. A regulatory role of Sco1 and Sco2 on Cu homeostasis has already been proposed for humans (Leary et al, 2007;Leary, 2010). Here, Sco1 transfers Cu(I) to the Cu A site of CoxII, while Sco2 works as Cu-dependent thiol reductase for the cysteine ligands of CoxII (Morgada et al, 2015).…”

Section: Discussionmentioning

confidence: 95%

Cooperation between two periplasmic copper chaperones is required for full activity of the cbb₃‐type cytochrome c oxidase and copper homeostasis in Rhodobacter capsulatus

Trasnea

Utz²,

Khalfaoui-Hassani

et al. 2016

Molecular Microbiology

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Summary Copper (Cu) is an essential micronutrient that functions as a cofactor in several important enzymes, like respiratory heme-copper oxygen reductases. Yet, Cu is also toxic and therefore cells engage a highly coordinated Cu uptake and delivery system to prevent the accumulation of toxic Cu concentrations. In the current work we analyzed Cu delivery to the cbb3-type cytochrome c oxidase (cbb3-Cox) of Rhodobacter capsulatus. We identified the PCuAC-like periplasmic chaperone PccA and analyzed its contribution to cbb3-Cox assembly. Our data demonstrate that PccA is a Cu-binding protein with a preference for Cu(I), which is required for efficient cbb3-Cox assembly, in particular at low Cu concentrations. By using in vivo and in vitro crosslinking we show that PccA forms a complex with the Sco1-homologue SenC. This complex is stabilized in the absence of the cbb3-Cox specific assembly factors CcoGHIS. In cells lacking SenC, the cytoplasmic Cu content is significantly increased, but the simultaneous absence of PccA prevents this Cu accumulation. These data demonstrate that the interplay between PccA and SenC is not only required for Cu delivery during cbb3-Cox assembly, but that it also regulates Cu homeostasis in R. capsulatus.

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Section: Discussionmentioning

confidence: 95%

Cooperation between two periplasmic copper chaperones is required for full activity of the cbb₃‐type cytochrome c oxidase and copper homeostasis in Rhodobacter capsulatus

Trasnea

Utz²,

Khalfaoui-Hassani

et al. 2016

Molecular Microbiology

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“…Later, the copper-binding features of Sco proteins were described by Winge, Leary and coworkers [42]. The two essential Sco proteins in the human mitochondria were shown to perform complementary roles by Leary and Shoubridge [24,58]. Overall, genetic and physiological studies in different organisms pointed out the presence of one or two Sco-like proteins involved in this process.…”

Section: Discussionmentioning

confidence: 99%

Arabidopsis thaliana Hcc1 is a Sco‐like metallochaperone for Cu_A assembly in Cytochrome c Oxidase

et al. 2019

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The assembly of the CuA site in Cytochrome c Oxidase (COX) is a critical step for aerobic respiration in COX‐dependent organisms. Several gene products have been associated with the assembly of this copper site, the most conserved of them belonging to the Sco family of proteins, which have been shown to perform different roles in different organisms. Plants express two orthologs of Sco proteins: Hcc1 and Hcc2. Hcc1 is known to be essential for plant development and for COX maturation, but its precise function has not been addressed until now. Here, we report the biochemical, structural and functional characterization of Arabidopsis thaliana Hcc1 protein (here renamed Sco1). We solved the crystal structure of the Cu+1‐bound soluble domain of this protein, revealing a tri coordinated environment involving a CxxxCxnH motif. We show that AtSco1 is able to work as a copper metallochaperone, inserting two Cu+1 ions into the CuA site in a model of CoxII. We also show that AtSco1 does not act as a thiol‐disulfide oxido‐reductase. Overall, this information sheds new light on the biochemistry of Sco proteins, highlighting the diversity of functions among them despite their high structural similarities. Database PDB entry http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6N5U (Crystal structure of Arabidopsis thaliana ScoI with copper bound).

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“…Consequently, cardiac pathologies are a prevalent outcome of mitochondrial-related disorders [1]. The human SCO2 gene encodes a 266-amino-acid metallochaperone that participates in copper delivery to COX [2], and thus mutations in SCO2 are among the most common causes of COX deficiency [3]. These disorders are characterized by encephalopathy and HCM, collectively leading to death in infancy or early childhood [4].…”

Section: Introductionmentioning

confidence: 99%

Investigating the cardiac pathology of SCO2‐mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell–derived cardiomyocytes

Hallas

Eisen

Shemer

et al. 2017

J Cellular Molecular Medi

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Mutations in SCO2 are among the most common causes of COX deficiency, resulting in reduced mitochondrial oxidative ATP production capacity, often leading to hypertrophic cardiomyopathy (HCM). To date, none of the recent pertaining reports provide deep understanding of the SCO2 disease pathophysiology. To investigate the cardiac pathology of the disease, we were the first to generate induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) from SCO2-mutated patients. For iPSC generation, we reprogrammed skin fibroblasts from two SCO2 patients and healthy controls. The first patient was a compound heterozygote to the common E140K mutation, and the second was homozygote for the less common G193S mutation. iPSC were differentiated into cardiomyocytes through embryoid body (EB) formation. To test the hypothesis that the SCO2 mutation is associated with mitochondrial abnormalities, and intracellular Ca 2+ -overload resulting in functional derangements and arrhythmias, we investigated in SCO2-mutated iPSC-CMs (compared to control cardiomyocytes): (i) the ultrastructural changes; (ii) the inotropic responsiveness to b-adrenergic stimulation, increased [Ca 2+ ] o and angiotensin-II (AT-II); and (iii) the Beat Rate Variability (BRV) characteristics. In support of the hypothesis, we found in the mutated iPSC-CMs major ultrastructural abnormalities and markedly attenuated response to the inotropic interventions and caffeine, as well as delayed afterdepolarizations (DADs) and increased BRV, suggesting impaired SR Ca 2+ handling due to attenuated SERCA activity caused by ATP shortage. Our novel results show that iPSC-CMs are useful for investigating the pathophysiological mechanisms underlying the SCO2 mutation syndrome.

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The Human Cytochrome c Oxidase Assembly Factors SCO1 and SCO2 Have Regulatory Roles in the Maintenance of Cellular Copper Homeostasis

Cited by 35 publications

References 0 publications

Cooperation between two periplasmic copper chaperones is required for full activity of the cbb₃‐type cytochrome c oxidase and copper homeostasis in Rhodobacter capsulatus

Cooperation between two periplasmic copper chaperones is required for full activity of the cbb₃‐type cytochrome c oxidase and copper homeostasis in Rhodobacter capsulatus

Arabidopsis thaliana Hcc1 is a Sco‐like metallochaperone for Cu_A assembly in Cytochrome c Oxidase

Investigating the cardiac pathology of SCO2‐mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell–derived cardiomyocytes

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The Human Cytochrome c Oxidase Assembly Factors SCO1 and SCO2 Have Regulatory Roles in the Maintenance of Cellular Copper Homeostasis

Cited by 35 publications

References 0 publications

Cooperation between two periplasmic copper chaperones is required for full activity of the cbb3‐type cytochrome c oxidase and copper homeostasis in Rhodobacter capsulatus

Cooperation between two periplasmic copper chaperones is required for full activity of the cbb3‐type cytochrome c oxidase and copper homeostasis in Rhodobacter capsulatus

Arabidopsis thaliana Hcc1 is a Sco‐like metallochaperone for CuA assembly in Cytochrome c Oxidase

Investigating the cardiac pathology of SCO2‐mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell–derived cardiomyocytes

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Product

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About

Cooperation between two periplasmic copper chaperones is required for full activity of the cbb₃‐type cytochrome c oxidase and copper homeostasis in Rhodobacter capsulatus

Cooperation between two periplasmic copper chaperones is required for full activity of the cbb₃‐type cytochrome c oxidase and copper homeostasis in Rhodobacter capsulatus

Arabidopsis thaliana Hcc1 is a Sco‐like metallochaperone for Cu_A assembly in Cytochrome c Oxidase