Monothiol glutaredoxins in microbial iron metabolism: From iron-sulfur cluster trafficking to iron-dependent regulation.

Iron-sulfur (Fe-S) clusters are essential cofactors that support a wide range of metabolic and regulatory processes across all domains of life. The assembly and distribution of these chemically labile cofactors require tightly coordinated biosynthetic and trafficking systems that respond dynamically to cellular iron availability and redox conditions. Monothiol CGFS-type glutaredoxins (Grxs) have emerged as central components of these networks. Once considered primarily thiol-disulfide oxidoreductases, these proteins are now recognized as versatile Fe-S cluster carriers that coordinate and exchange [2Fe-2S] clusters through glutathione (GSH)-dependent mechanisms. This review synthesizes current understanding of monothiol Grxs across bacteria, fungi, and protists, highlighting both conserved biochemical functions and lineage-specific adaptations. In all systems, CGFS Grxs function as intermediates in Fe-S cluster trafficking pathways, facilitating the transfer of clusters from assembly machineries to downstream targets. In fungi, these proteins have been further co-opted into regulatory circuits, where Grxs alone or in partnership with BolA proteins directly couple mitochondrial Fe-S cluster biogenesis to nuclear transcriptional control of iron homeostasis. In contrast, bacterial and protist systems exhibit more indirect or emerging regulatory roles, often integrating Fe-S metabolism with broader redox and stress-response networks. We propose a unifying model in which monothiol Grxs act as dynamic Fe-S "rheostats" that sense and redistribute labile clusters in response to cellular conditions, thereby linking iron metabolism to physiological adaptation. Understanding how this conserved molecular framework is differentially deployed across organisms provides new insight into microbial iron homeostasis and reveals potential targets for therapeutic intervention in pathogenic systems.