Iron sensing and regulation in Saccharomyces cerevisiae: Ironing out the mechanistic details

• Iron-dependent Aft1 nuclear export is not required for iron regulon deactivation.
• High and low iron sensing depends on mitochondrial iron–sulfur cluster biogenesis.
• Disruptions in thiol redox metabolism activate the Aft1/2 iron regulon.
• Cth1/2 cross- and auto-regulation enhances the response to iron deficiency.
• Iron-ome studies highlight iron trafficking between mitochondria and vacuoles.

Regulation of iron metabolism in Saccharomyces cerevisiae is achieved at the transcriptional level by low (Aft1 and Aft2) and high iron-sensing (Yap5) transcription factors, and at the post-transcriptional level by mRNA-binding proteins (Cth1 and Cth2). In this review we highlight recent studies unveiling the critical role that iron–sulfur clusters play in control of Aft1/2 and Yap5 activity, as well as the complex relationship between iron homeostasis and thiol redox metabolism. In addition, new insights into the localization and regulation of Cth1/Cth2 have added another layer of complexity to the cell's adaptation to iron deficiency. Finally, biophysical studies on subcellular iron speciation changes in response to environmental and genetic factors have further illuminated the elaborate control mechanisms required to manage iron bioavailability in the cell.