Mitochondrial Ferredoxin Determines Vulnerability of Cells to Copper Excess. Issue 10 (19th October 2017)

• Record Type: Journal Article
• Authors: Vallières, Cindy; Holland, Sara L.; Avery, Simon V.
• Is Part Of: Cell chemical biology. Volume 24:Issue 10(2017)
• Page Start: 1228
• Page End: 1237.e3
• Publication Date: 2017-10-19
• Subjects: micronutrient toxicity -- Fdx2 -- iron-sulfur cluster -- Saccharomyces cerevisiae -- myopathy -- Wilson's disease -- oxidative stress; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.08.005
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. 55 Fe 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. Graphical Abstract: Highlights: Expression level of the essential mitochondrial ferredoxin determines Cu resistance Copper targets the FeS domain of yeast Yah1 Copper action at Yah1 affects downstream, essential FeS-protein function The function in copper resistance is conserved in the human ferredoxin, Fdx2 Abstract : Vallières et al. identify the conserved ferredoxin Yah1 (Fdx2 in humans) as an important target of copper excess in cells. Copper targets the FeS domain of the ferredoxin, needed for the essential process of FeS-cluster biogenesis. This knowledge could help in tackling copper-related diseases.