Format

Send to

Choose Destination
Cell Chem Biol. 2017 Oct 19;24(10):1228-1237.e3. doi: 10.1016/j.chembiol.2017.08.005. Epub 2017 Aug 31.

Mitochondrial Ferredoxin Determines Vulnerability of Cells to Copper Excess.

Author information

1
School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
2
School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK. Electronic address: Simon.Avery@nottingham.ac.uk.

Abstract

The essential micronutrient copper is tightly regulated in organisms, as environmental exposure or homeostasis defects can cause toxicity and neurodegenerative disease. The principal target(s) of copper toxicity have not been pinpointed, but one key effect is impaired supply of iron-sulfur (FeS) clusters to the essential protein Rli1 (ABCE1). Here, to find upstream FeS biosynthesis/delivery protein(s) responsible for this, we compared copper sensitivity of yeast-overexpressing candidate targets. Overexpression of the mitochondrial ferredoxin Yah1 produced copper hyper-resistance. 55Fe turnover assays revealed that FeS integrity of Yah1 was particularly vulnerable to copper among the test proteins. Furthermore, destabilization of the FeS domain of Yah1 produced copper hypersensitivity, and YAH1 overexpression rescued Rli1 dysfunction. This copper-resistance function was conserved in the human ferredoxin, Fdx2. The data indicate that the essential mitochondrial ferredoxin is an important copper target, determining a tipping point where plentiful copper supply becomes excessive. This knowledge could help in tackling copper-related diseases.

KEYWORDS:

Fdx2; Saccharomyces cerevisiae; Wilson's disease; iron-sulfur cluster; micronutrient toxicity; myopathy; oxidative stress

PMID:
28867595
PMCID:
PMC5654725
DOI:
10.1016/j.chembiol.2017.08.005
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center