Iron-Sulfur Clusters and Oxygen in Human Disease

What the review examined

This minireview by Shany Egozi and Tslil Ast, published in Metallomics in July 2025, synthesizes how the biology of iron-sulfur (Fe-S) clusters intersects with molecular oxygen across human health and disease. Fe-S clusters are among the most ancient prosthetic groups in biology, built from iron and inorganic sulfide, and they serve as electron carriers, catalytic centers, and structural elements in hundreds of proteins spanning the electron transport chain, the citric acid cycle, DNA replication and repair, and gene regulation.

The central theme is a fundamental chemical conflict: the same redox reactivity that makes Fe-S clusters superb electron shuttles also makes them intrinsically fragile in the presence of oxygen and reactive oxygen species. The review traces how cells build, protect, and sense these clusters, and how the balance between Fe-S supply and oxidative demand tips toward disease. It draws together examples in which too much oxygen damages Fe-S proteins and, strikingly, cases in which lowering oxygen restores Fe-S biogenesis and rescues cellular function.

Fe-S clusters as sensors of iron and oxygen

Beyond their catalytic roles, Fe-S clusters act as built-in sensors that couple cellular metabolism to iron and oxygen availability. The review highlights regulators such as IRP1 (aconitase), the ubiquitin-ligase adaptor FBXL5, the ferritinophagy receptor NCOA4, and the outer-mitochondrial protein CISD1, whose activities shift depending on whether their clusters are intact, degraded, or oxidatively modified.

Through these sensors, the assembly state of Fe-S clusters is read out as a proxy for iron sufficiency and redox status. When cluster biogenesis falters, cells activate an iron-starvation response even when total iron is adequate, altering iron import, storage, and utilization. This sensing logic makes Fe-S proteins a hub where mismetallation, oxidative stress, and iron homeostasis converge, and it explains why disruptions in cluster assembly reverberate through iron metabolism as a whole.

Hyperoxia injures Fe-S-dependent pathways

Because Fe-S clusters are directly attacked by oxygen and reactive oxygen species, tissues exposed to elevated oxygen tension suffer disproportionate damage to Fe-S-dependent enzymes. The review catalogs vulnerable pathways including purine metabolism, diphthamide synthesis, nucleotide excision repair, and the mitochondrial electron transport chain, all of which rely on cluster-bearing proteins that can be oxidatively degraded.

This mechanism is clinically relevant to hyperoxia, the supraphysiological oxygen exposure encountered during supplemental oxygen therapy and mechanical ventilation. Damage to solvent-exposed clusters can outpace repair, crippling metabolic and DNA-repair capacity and contributing to oxygen toxicity. The framing reframes hyperoxic injury not merely as generic oxidative stress but as a targeted failure of iron-based cofactor chemistry.

NFS1, oxygen, and lung cancer

The lung is the body's most oxygen-rich tissue, and the review connects this environment to cancer biology through the cysteine desulfurase NFS1, the enzyme that mobilizes sulfur for Fe-S cluster assembly. Work by Alvarez and colleagues (Nature, 2017) showed that NFS1 lies in a genomic region amplified in lung adenocarcinoma, undergoes positive selection in lung tumors, and is most highly expressed in well-differentiated adenocarcinomas.

Mechanistically, high oxygen tension in the lung threatens tumor-cell Fe-S clusters, and elevated NFS1 activity shields cells by sustaining cluster supply. Suppressing NFS1 activates the iron-starvation response and, together with impaired glutathione synthesis or cysteine transport, drives ferroptosis, an iron-dependent form of regulated cell death. This positions Fe-S biogenesis as a selective vulnerability that could be exploited therapeutically in oxygen-rich tumors.

Friedreich ataxia: when less oxygen helps

The mirror image of hyperoxic injury is the counterintuitive benefit of hypoxia in Friedreich ataxia (FRDA), a neurodegenerative disease caused by deficiency of frataxin (FXN), a protein that supports Fe-S cluster assembly. Ast and colleagues (Cell, 2019) demonstrated that yeast, human cells, and nematodes lacking frataxin are viable at 1% oxygen but not at atmospheric oxygen, establishing oxygen as a decisive environmental modifier of the disease.

Hypoxia restores steady-state Fe-S cluster levels and normalizes disease-associated signaling through ATF4, NRF2, and IRP2, apparently by increasing iron bioavailability and accelerating cluster synthesis via oxygen-sensitive, HIF-independent mechanisms. In vivo, mice breathing 11% oxygen showed attenuated ataxia, while hyperoxia accelerated decline. These findings motivate chronic hypoxia and oxygen-modulating strategies as potential therapeutic avenues for FRDA.

Fitting into the metal-microbiome-disease axis

This review is primarily a study of human cellular iron biochemistry rather than the microbiome, and it does not directly test heavy-metal exposure or microbial community effects. Presented honestly, its relevance to the metal-microbiome-disease axis is contextual: it underscores that iron is a tightly controlled, redox-active metal whose handling sits at the center of both host physiology and host-microbe competition.

The iron-starvation response and iron-withholding programs described here echo the logic of nutritional immunity, in which the host restricts metal availability to control microbes, and disruptions to iron homeostasis can reshape the metabolic terrain that gut and tissue microbes occupy. Fe-S biology also links to broader metallostasis: perturbations in iron trafficking, oxidative stress, and mismetallation can propagate to microbial iron acquisition via siderophores and metallophores. The paper is best read as mechanistic grounding for why iron dysregulation matters to disease, a foundation on which microbiome-focused work in the metallomics field can build, rather than as direct evidence that metal exposure reshapes the microbiome.