Iron–sulfur Clusters and Oxygen in Human Disease: A Review

Overview

This minireview synthesizes how iron–sulfur (Fe–S) cofactors interface with oxygen across biology, emphasizing oxygen-sensitive Fe–S sensors and Fe–S biogenesis in mammalian cells, pathology (hyperoxia, cancer, Friedreich’s ataxia), and therapeutic implications.

What was studied and how?

The authors collate mechanistic and disease-facing evidence on iron–sulfur clusters and oxygen in human disease, focusing on cellular and tissue contexts as the primary “matrix,” with illustrative microbial and eukaryotic systems. They summarize Fe–S–based oxygen/iron sensing in bacteria (RirA, [4Fe–4S]), yeast (Aft1/2, Yap5), and mammals (IRP1 switching between [4Fe–4S] aconitase and apo-IRP1 RNA-binding; FBXL5 with a redox-active [2Fe–2S] in its LRR domain; NCOA4 as an Fe–S–responsive ferritinophagy receptor; CISD1/mitoNEET carrying a [2Fe–2S] cluster). Disease sections synthesize genetic screens and proteomics under hyperoxia, tumor Fe–S pathway selection (NFS1) in lung adenocarcinoma, and hypoxia interventions in Friedreich’s ataxia models. Evidence spans cultured cells at defined O₂ tensions, mouse models, and in vitro reconstitution; the paper also highlights tissues with distinct oxygen set-points and an image-based summary of sensing and pathology.

Most important findings

Critical point	Details
Fe–S cofactors as O₂/iron sensors	IRP1 retains [4Fe–4S] and functions as cytosolic aconitase under lower O₂; cluster loss under higher O₂/ROS/RNS converts it to RNA-binding IRP1 controlling iron transcripts.
FBXL5 redox gating	An oxygen-responsive [2Fe–2S]^2+ in FBXL5’s LRR domain enables IRP1/2 recognition and proteasomal targeting; oxidative stress amplifies IRP2 degradation.
NCOA4 and ferritinophagy	Fe–S–bound NCOA4 (favored at low O₂/high iron) is ubiquitinated and degraded; apo-NCOA4 (high O₂/low iron) directs ferritin to lysosomal degradation to release iron.
CISD1/mitoNEET transfer	The [2Fe–2S] cluster donates to cytosolic targets (e.g., apo-IRP1) in its oxidized +2 state; oxygen promotes oxidation and affects cluster stability, indicating a redox-gated transfer switch.
Hyperoxia vulnerability	At 80% O₂, Fe–S proteins in purine biosynthesis (PPAT), diphthamide synthesis (DPH1/2), nucleotide excision repair (ERCC2), and ETC complexes I/II destabilize; antioxidants against superoxide do not rescue—implicating O₂ directly.
Tissue O₂ set-points & Fe–S biogenesis	High-O₂ tissues (lung) show stronger dependence on Fe–S biogenesis; genetic essentiality screens highlight Fe–S pathways under high O₂.
NFS1 in lung tumors	NFS1 is positively selected/amplified in lung adenocarcinoma; its suppression under high O₂ sensitizes to ferroptosis and limits growth/metastasis.
FRDA and oxygen	In FXN deficiency, hypoxia (1–11% O₂) rescues Fe–S biogenesis and ataxia phenotypes in models; 55% O₂ accelerates symptoms, indicating oxygen as a disease modifier.

Strengths

The review is tightly focused on oxygen as a variable shaping Fe–S cluster stability, speciation, and signaling, and it translates these principles to clinically relevant contexts (hyperoxia, lung tumors, Friedreich’s ataxia). Mechanistic framing of specific cluster types and oxidation states ([4Fe–4S], [2Fe–2S], and redox state +2) improves interpretability for translational work. Cross-species exemplars (bacteria, yeast, mammal) clarify conserved logic. The integration of genetic screens, proteomics, in vitro reconstitution, and animal models adds multi-level rigor. Figure 1 (p. 3) is an effective visual synthesis mapping oxidation state, protein targets, and disease processes.

Any Limitations

Speciation is discussed at the cofactor level, but detailed metalloproteomics in clinical samples is not provided. Direct microbiome structure–function signatures, patient biofluids, and standardized oxygen exposures across clinical settings are not systematically analyzed here.

Future Perspectives

The synthesis points to actionable directions: strategies to preserve Fe–S clusters during hyperoxia; therapeutic targeting of Fe–S biogenesis (e.g., NFS1) in high-O₂ tumors; and hypoxia or hypoxia-mimicking interventions in Fe–S biogenesis disorders (e.g., Friedreich’s ataxia) with tissue-specific considerations. Mapping the human Fe–S proteome and defining oxygen “set-points” across organs could refine diagnostics and exposure guidance. Carefully designed preclinical and clinical studies controlling O₂ will be essential.

Conclusion

This review positions Fe–S clusters as oxygen-sensitive hubs connecting iron handling, redox biology, and disease. It delineates redox-gated sensing (IRP1, FBXL5, NCOA4, CISD1), identifies Fe–S liabilities under hyperoxia, and highlights tumor (NFS1) and neurocardiac (FRDA) contexts where oxygen modulates outcomes. For microbial metallomics–aware clinicians, the principles generalize: Fe–S speciation and oxidation state under defined O₂ tensions are central to pathogenesis and therapy design.

Citation

Egozi S, Ast T. Rust and redemption: iron–sulfur clusters and oxygen in human disease and health. Metallomics. 2025;17:mfaf022. doi:10.1093/mtomcs/mfaf022