The iron–thiol–oxygen nexus for iron flux from bare and ferritin-caged minerals and safeguarding DNA: the impact of the thiol structure and protein coat

The interplay between iron, sulfur, and oxygen underpins the redox regulation of iron across biological and geochemical systems. Prior to the great oxygenation event (GOE), sulfur fostered a reducing environment essential for Fe²⁺ bioavailability. Post-GOE, the advent of the oxidative environment depleted iron-bioavailability and likely spurred the evolution of ferritin, a nanocage protein that detoxifies Fe²⁺ and catalytically synthesizes the ferrihydrite bio-mineral. Biological iron usage necessitates its reduction and mobilization from bio-minerals, where thiols can play a critical role as electron donors. This study probes the efficacy of various cellular and synthetic thiols in mediating Fe³⁺/Fe²⁺ redox-cycling, O₂ consumption, and the dissolution/mobilization of iron minerals from bare and ferritin protein-encapsulated ferrihydrites to correlate their structure-activity relationship. Furthermore, the antioxidative properties of thiols were assessed through DNA protection and radical scavenging assays. This work reports the formation of thiol-specific transient species upon interaction of thiols with Fe³⁺, which exhibit synergistic O₂ consumption, rapidly generating a hypoxic microenvironment. The thiol-mediated iron mobilization is influenced by the mineral accessibility/size (Na₂S/TG <i>vs.</i> GSH), O₂ consumption ability and iron chelating feature (-SH/-COO^-<i>vs.</i> -NH₃⁺: TG/DHLA <i>vs.</i> Cys/GSH), highlighting entropic contributions (higher efficacy of dithiols over monothiol: DTT/DHLA <i>vs.</i> 2-ME) and restriction posed by protein encapsulation (bare <i>vs.</i> encapsulated ferrihydrites). Inclusion of ferritin cage-variants offers a perspective on evolutionary upgradation of the protein coat, showing how the stability of a mineral core is governed by the specific design of its inorganic-protein interface. These findings underscore the crucial role of cooperativity among iron-sulfur-oxygen interactions in cellular homeostasis, providing quintessential insights into therapeutic strategies for regulating iron metabolism and oxidative stress mitigation.