Abstract
SummaryThe 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.
Highlights
Micronutrients that are essential for life create a dilemma for all organisms
FeS Biosynthesis/Delivery Proteins that Confer Copper Resistance Previous work suggested that a key target of Cu toxicity may reside in the FeS-cluster biosynthesis and delivery pathway, upstream of the cytosolic FeS-recipient protein Rli1 (Alhebshi et al, 2012)
Throughout this work, Cu was supplied at concentrations either moderately or barely inhibitory to growth of the wild-type, depending on whether the assay was for increased resistance (i.e., Figure 1) or sensitization, respectively, in the test strain(s). (In vitro assays of cluster turnover [below] required much lower Cu concentrations as these were with purified proteins and in simple buffers, less prone to Cu complexation [Avery et al, 1996; Macomber and Imlay, 2009].) Copper toxicity was rescued by overexpression of Isu1 and Yfh1, and Yah1, of the iron-sulfur cluster (ISC) assembly machinery (Figures 1B and 1C)
Summary
Micronutrients that are essential for life create a dilemma for all organisms. There is a need to balance adequate supply against deleterious effects that inevitably can arise from excess (Heffern et al, 2016; Renwick, 2006). Copper homeostasis is tightly regulated as Cu is highly toxic in excess. Copper homeostasis defects or elevated environmental Cu exposure can result in displacement of other essential metals from cellular constituents, inappropriate protein binding, or provocation of stress from reactive oxygen species (ROS) due to the metal’s redox activity, among other reported effects (Macomber and Imlay, 2009; Pena et al, 1999). Copper toxicity has been widely described in different organisms. In addition to Cu transporters and Cu-requiring enzymes, metalloproteins such as Cu-metallothioneins help to buffer free Cu in cells. When such defenses are inadequate, a key question remains: which molecular target(s) may be the principal ‘‘Achilles’ heel’’ of organisms, accounting for the inhibitory action of copper? Identification of primary cause(s) (rather than effects) of Cu action could open new opportunities for combating Curelated disease
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