Mechanisms of iron sensing and regulation in the yeast Saccharomyces cerevisiae

Abstract

Iron is a redox active element that functions as an essential cofactor in multiple metabolic pathways, including respiration, DNA synthesis and translation. While indispensable for eukaryotic life, excess iron can lead to oxidative damage of macromolecules. Therefore, living organisms have developed sophisticated strategies to optimally regulate iron acquisition, storage and utilization in response to fluctuations in environmental iron bioavailability. In the yeast Saccharomyces cerevisiae, transcription factors Aft1/Aft2 and Yap5 regulate iron metabolism in response to low and high iron levels, respectively. In addition to producing and assembling iron cofactors, mitochondrial iron-sulfur (Fe/S) cluster biogenesis has emerged as a central player in iron sensing. A mitochondrial signal derived from Fe/S synthesis is exported and converted into an Fe/S cluster that interacts directly with Aft1/Aft2 and Yap5 proteins to regulate their transcriptional function. Various conserved proteins, such as ABC mitochondrial transporter Atm1 and, for Aft1/Aft2, monothiol glutaredoxins Grx3 and Grx4 are implicated in this iron-signaling pathway. The analysis of a wide range of S. cerevisiae strains of different geographical origins and sources has shown that yeast strains adapted to high iron display growth defects under iron-deficient conditions, and highlighted connections that exist in the response to both opposite conditions. Changes in iron accumulation and gene expression profiles suggest differences in the regulation of iron homeostasis genes.

Iron-dependent cleavage of ribosomal RNA during oxidative stress in the yeast Saccharomyces cerevisiae

“…Eukaryotes have developed complex systems for iron uptake, utilization and storage (48)(49)(50). Disruption of these systems can result in either iron shortage or overload, with mitochondrial defects often playing a major role in the iron homeostasis disturbances (49).…”

Iron–sulfur clusters: from metals through mitochondria biogenesis to disease

“…The studies made on A. vinelandii were crucial to the discovery of Fe–S biogenesis mechanism as three operons dedicated to the Fe–S biogenesis were found, one of them being the nif operon, involved in the biogenesis of nitrogenase [22]. Since then, the iron–sulfur cluster synthesis and assembly pathways have begun to be described, in addition to the sensing iron-level mechanisms, providing a better understanding of the complicated chemistry of iron [23, 24]. Bacteria Fe–S cluster biogenesis machineries have been reviewed elsewhere [25, 26], and thus, are not the focus of this review.…”

“…Another example is in Saccharomyces cerevisiae , where the iron metabolism is regulated by the transcription factors Aft1/Aft2 and Yap5, in accordance to the available iron levels [24, 36]. The first two are implicated with the activation of genes when the iron levels are low, while Yap5 is involved when the iron levels are extremely high.…”

Iron toxicity in yeast: transcriptional regulation of the vacuolar iron importer Ccc1

“…Alterations in these parameters can result in iron-limited growth or iron toxicity and death. Saccharomyces cerevisiae has evolved complex mechanisms to obtain iron and to protect itself from the toxic effects of excess cellular iron [for review see (Martinez-Pastor et al 2017; Outten and Albetel 2013; Philpott et al 2012)]. Fungi and plants store iron in the vacuole to protect themselves from toxicity as they do not express the cytosolic iron-binding protein ferritin (Bode et al 1995; Gollhofer et al 2014; Kim et al 2006; Li et al 2001; Portnoy et al 2000; Singh et al 2007; Szczypka et al 1997; Urbanowski and Piper 1999).…”

“…These genes encode for proteins involved in plasma membrane iron acquisition, vacuolar iron export, mitochondrial iron import and iron–sulfur cluster synthesis along with proteins involved in iron metabolism [for review see (Martinez-Pastor et al 2017; Outten and Albetel 2013)]. These transcription factors, Aft1 and Aft2, predominantly respond to the levels of mitochondrial iron-sulfur (Fe–S) cluster biogenesis and not to cytosolic iron levels.…”