Document Detail

A targetable fluorescent sensor reveals that copper-deficient SCO1 and SCO2 patient cells prioritize mitochondrial copper homeostasis.
MedLine Citation:
PMID:  21563821     Owner:  NLM     Status:  MEDLINE    
We present the design, synthesis, spectroscopy, and biological applications of Mitochondrial Coppersensor-1 (Mito-CS1), a new type of targetable fluorescent sensor for imaging exchangeable mitochondrial copper pools in living cells. Mito-CS1 is a bifunctional reporter that combines a Cu(+)-responsive fluorescent platform with a mitochondrial-targeting triphenylphosphonium moiety for localizing the probe to this organelle. Molecular imaging with Mito-CS1 establishes that this new chemical tool can detect changes in labile mitochondrial Cu(+) in a model HEK 293T cell line as well as in human fibroblasts. Moreover, we utilized Mito-CS1 in a combined imaging and biochemical study in fibroblasts derived from patients with mutations in the two synthesis of cytochrome c oxidase 1 and 2 proteins (SCO1 and SCO2), each of which is required for assembly and metalation of functionally active cytochrome c oxidase (COX). Interestingly, we observe that although defects in these mitochondrial metallochaperones lead to a global copper deficiency at the whole cell level, total copper and exchangeable mitochondrial Cu(+) pools in SCO1 and SCO2 patient fibroblasts are largely unaltered relative to wild-type controls. Our findings reveal that the cell maintains copper homeostasis in mitochondria even in situations of copper deficiency and mitochondrial metallochaperone malfunction, illustrating the importance of regulating copper stores in this energy-producing organelle.
Sheel C Dodani; Scot C Leary; Paul A Cobine; Dennis R Winge; Christopher J Chang
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-12
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  133     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-01     Completed Date:  2011-09-23     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8606-16     Citation Subset:  IM    
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MeSH Terms
Carrier Proteins / chemistry*,  genetics,  metabolism
Copper / chemistry*,  metabolism
Fibroblasts / chemistry,  metabolism
Fluorescent Dyes / chemistry*
HEK293 Cells
Membrane Proteins / chemistry*,  genetics,  metabolism
Mitochondria / chemistry*,  metabolism
Mitochondrial Proteins / chemistry*,  genetics,  metabolism
Molecular Imaging
Grant Support
GM 083292/GM/NIGMS NIH HHS; GM 79465/GM/NIGMS NIH HHS; R01 GM079465/GM/NIGMS NIH HHS; R01 GM079465-04/GM/NIGMS NIH HHS; R01 GM079465-05/GM/NIGMS NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Carrier Proteins; 0/Fluorescent Dyes; 0/Membrane Proteins; 0/Mitochondrial Proteins; 0/SCO1 protein, human; 0/SCO2 protein, human; 789U1901C5/Copper

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