Loss of function of Sco1 and its interaction with cytochrome c oxidase

2009 ◽  
Vol 296 (5) ◽  
pp. C1218-C1226 ◽  
Author(s):  
Lukas Stiburek ◽  
Katerina Vesela ◽  
Hana Hansikova ◽  
Helena Hulkova ◽  
Jiri Zeman
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Copper Homeostasis ◽  
Copper Binding ◽  
Loss Of Function ◽  
Muscle Mitochondria ◽  
Juxtamembrane Region ◽  
Cellular Copper ◽  
The Impact ◽  
Blue Native

Sco1 and Sco2 are mitochondrial copper-binding proteins involved in the biogenesis of the CuA site in the cytochrome c oxidase (CcO) subunit Cox2 and in the maintenance of cellular copper homeostasis. Human Surf1 is a CcO assembly factor with an important but poorly characterized role in CcO biogenesis. Here, we analyzed the impact on CcO assembly and tissue copper levels of a G132S mutation in the juxtamembrane region of SCO1 metallochaperone associated with early onset hypertrophic cardiomyopathy, encephalopathy, hypotonia, and hepatopathy, assessed the total copper content of various SURF1 and SCO2-deficient tissues, and investigated the possible physical association between CcO and Sco1. The steady-state level of mutant Sco1 was severely decreased in the muscle mitochondria of the SCO1 patient, indicating compromised stability and thus loss of function of the protein. Unlike the wild-type variant, residual mutant Sco1 appeared to migrate exclusively in the monomeric form on blue native gels. Both the activity and content of CcO were reduced in the patient's muscle to ∼10–20% of control values. SCO1-deficient mitochondria showed accumulation of two Cox2 subcomplexes, suggesting that Sco1 is very likely responsible for a different posttranslational aspect of Cox2 maturation than Sco2. Intriguingly, the various SURF1-deficient samples analyzed showed a tissue-specific copper deficiency similar to that of SCO-deficient samples, suggesting a role for Surf1 in copper homeostasis regulation. Finally, both blue native immunoblot analysis and coimmunoprecipitation revealed that a fraction of Sco1 physically associates with the CcO complex in human muscle mitochondria, suggesting a possible direct relationship between CcO and the regulation of cellular copper homeostasis.

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

2007 ◽  
Vol 5 (1) ◽  
pp. 9-20 ◽  
Author(s):  
Scot C. Leary ◽  
Paul A. Cobine ◽  
Brett A. Kaufman ◽  
Guy-Hellen Guercin ◽  
Andre Mattman ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Copper Homeostasis ◽  
Human Cytochrome ◽  
Assembly Factors ◽  
Cellular Copper ◽  
Human Cytochrome C

scholarly journals A genome wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity

2021 ◽  
Author(s):  
Natalie M. Garza ◽  
Aaron T. Griffin ◽  
Mohammad Zulkifli ◽  
Chenxi Qiu ◽  
Craig D. Kaplan ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Adaptor Protein ◽  
Copper Homeostasis ◽  
Growth Media ◽  
Ph Sensing ◽  
Loss Of Function ◽  
Genome Wide ◽  
A Genome ◽  
Vacuolar Ph

Copper is essential for the activity and stability of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Loss-of-function mutations in genes required for copper transport to CcO result in fatal human disorders. Despite the fundamental importance of copper in mitochondrial and organismal physiology, systematic characterization of genes that regulate mitochondrial copper homeostasis is lacking. To identify genes required for mitochondrial copper homeostasis, we performed a genome-wide copper-sensitized screen using DNA barcoded yeast deletion library. Our screen recovered a number of genes known to be involved in cellular copper homeostasis while revealing genes previously not linked to mitochondrial copper biology. These newly identified genes include the subunits of the adaptor protein 3 complex (AP-3) and components of the cellular pH-sensing pathway- Rim20 and Rim21, both of which are known to affect vacuolar function. We find that AP-3 and the Rim mutants impact mitochondrial CcO function by maintaining vacuolar acidity. CcO activity of these mutants could be rescued by either restoring vacuolar pH or by supplementing growth media with additional copper. Consistent with these genetic data, pharmacological inhibition of the vacuolar proton pump leads to decreased mitochondrial copper content and a concomitant decrease in CcO abundance and activity. Taken together, our study uncovered a number of novel genetic regulators of mitochondrial copper homeostasis and provided a mechanism by which vacuolar pH impacts mitochondrial respiration through copper homeostasis.

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

2007 ◽  
Vol 5 (5) ◽  
pp. 403 ◽  
Author(s):  
Scot C. Leary ◽  
Paul A. Cobine ◽  
Brett A. Kaufman ◽  
Guy-Hellen Guercin ◽  
Andre Mattman ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Copper Homeostasis ◽  
Human Cytochrome ◽  
Assembly Factors ◽  
Cellular Copper ◽  
Human Cytochrome C

scholarly journals Essential Roles in Development and Pigmentation for the Drosophila Copper Transporter DmATP7

2006 ◽  
Vol 17 (1) ◽  
pp. 475-484 ◽  
Author(s):  
Melanie Norgate ◽  
Esther Lee ◽  
Adam Southon ◽  
Ashley Farlow ◽  
Philip Batterham ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Cellular Level ◽  
Loss Of Function ◽  
Neuronal Function ◽  
Copper Transporter ◽  
Disease Phenotypes ◽  
In Vivo Analysis ◽  
Cellular Copper ◽  
P Type

Defects in the mammalian Menkes and Wilson copper transporting P-type ATPases cause severe copper homeostasis disease phenotypes in humans. Here, we find that DmATP7, the sole Drosophila orthologue of the Menkes and Wilson genes, is vital for uptake of copper in vivo. Analysis of a DmATP7 loss-of-function allele shows that DmATP7 is essential in embryogenesis, early larval development, and adult pigmentation and is probably required for copper uptake from the diet. These phenotypes are analogous to those caused by mutation in the mouse and human Menkes genes, suggesting that like Menkes, DmATP7 plays at least two roles at the cellular level: delivering copper to cuproenzymes required for pigmentation and neuronal function and removing excess cellular copper via facilitated efflux. DmATP7 displays a dynamic and unexpected expression pattern in the developing embryo, implying novel functions for this copper pump and the lethality observed in DmATP7 mutant flies is the earliest seen for any copper homeostasis gene.

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

2020 ◽  
Vol 21 (19) ◽  
pp. 6983
Author(s):  
Shadi Maghool ◽  
Michael T. Ryan ◽  
Megan J. Maher
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Molecular Mechanisms ◽  
Intermembrane Space ◽  
Copper Binding ◽  
Transport Chain ◽  
Assembly Factor ◽  
Controversial Area ◽  
Thiol Oxidoreductase ◽  
Assembly Activity

Complex IV (cytochrome c oxidase; COX) is the terminal complex of the mitochondrial electron transport chain. Copper is essential for COX assembly, activity, and stability, and is incorporated into the dinuclear CuA and mononuclear CuB sites. Multiple assembly factors play roles in the biogenesis of these sites within COX and the failure of this intricate process, such as through mutations to these factors, disrupts COX assembly and activity. Various studies over the last ten years have revealed that the assembly factor COA6, a small intermembrane space-located protein with a twin CX9C motif, plays a role in the biogenesis of the CuA site. However, how COA6 and its copper binding properties contribute to the assembly of this site has been a controversial area of research. In this review, we summarize our current understanding of the molecular mechanisms by which COA6 participates in COX biogenesis.

scholarly journals Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice

Science ◽  
2020 ◽  
Vol 368 (6491) ◽  
pp. 620-625 ◽  
Author(s):  
Liam M. Guthrie ◽  
Shivatheja Soma ◽  
Sai Yuan ◽  
Andres Silva ◽  
Mohammad Zulkifli ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Small Molecule ◽  
Murine Model ◽  
Copper Deficiency ◽  
Menkes Disease ◽  
Neurological Injury ◽  
Loss Of Function ◽  
Brindled Mouse ◽  
The Brain

Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse—a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.

scholarly journals Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase

2015 ◽  
Vol 26 (13) ◽  
pp. 2385-2401 ◽  
Author(s):  
Manuela Bode ◽  
Michael W. Woellhaf ◽  
Maria Bohnert ◽  
Martin van der Laan ◽  
Frederik Sommer ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Specific Binding ◽  
Hydrophobic Surface ◽  
Cysteine Residue ◽  
Oxidative Modification ◽  
Intermembrane Space ◽  
Copper Binding ◽  
C Protein ◽  
Copper Transfer

Members of the twin Cx9C protein family constitute the largest group of proteins in the intermembrane space (IMS) of mitochondria. Despite their conserved nature and their essential role in the biogenesis of the respiratory chain, the molecular function of twin Cx9C proteins is largely unknown. We performed a SILAC-based quantitative proteomic analysis to identify interaction partners of the conserved twin Cx9C protein Cox19. We found that Cox19 interacts in a dynamic manner with Cox11, a copper transfer protein that facilitates metalation of the Cu(B) center of subunit 1 of cytochrome c oxidase. The interaction with Cox11 is critical for the stable accumulation of Cox19 in mitochondria. Cox19 consists of a helical hairpin structure that forms a hydrophobic surface characterized by two highly conserved tyrosine-leucine dipeptides. These residues are essential for Cox19 function and its specific binding to a cysteine-containing sequence in Cox11. Our observations suggest that an oxidative modification of this cysteine residue of Cox11 stimulates Cox19 binding, pointing to a redox-regulated interplay of Cox19 and Cox11 that is critical for copper transfer in the IMS and thus for biogenesis of cytochrome c oxidase.

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