Too Much Cysteine Kills Cells Through a Hidden Iron Overload in Mitochondria

Cysteine has long been celebrated as one of biology’s most protective molecules. As a sulfur-bearing amino acid, it builds proteins, feeds the production of the antioxidant glutathione, and anchors the iron–sulfur clusters that keep the cell’s energy machinery running. When cells are starved of cysteine, they die by ferroptosis, an iron-driven form of lipid peroxidation that has become one of the hottest topics in cancer biology. But cysteine has a darker side that scientists have struggled to explain for decades. In excess, the same molecule becomes a potent poison, and the mechanism behind that toxicity has remained stubbornly obscure. A new study published in Nature Metabolism by Toshitaka Nakamura, Kıvanç Birsoy and colleagues at The Rockefeller University, working with Yatrik Shah’s team at the University of Michigan, now reveals that too much cysteine kills cells through an unexpected route: a catastrophic collapse of iron management inside mitochondria.

The researchers began with an unbiased approach designed to let the cells themselves point to the answer. Using a genome-wide CRISPR screen, they systematically disabled every gene in human cells and then flooded the survivors with high levels of cysteine. If a cell lacking a particular gene suddenly became resistant to cysteine’s lethal effects, that gene was likely part of the killing machinery. The screen delivered a striking and somewhat counterintuitive result: the strongest protective hits were not antioxidant enzymes or detoxification pathways, but the mitochondrial iron transporters SLC25A28 and SLC25A37, also known as mitoferrins. These proteins sit in the inner mitochondrial membrane and shuttle iron into the organelle. When the researchers knocked them out, cells tolerated cysteine doses that would otherwise be fatal, indicating that the import of iron into mitochondria is an essential step in cysteine toxicity.

That finding reframed the problem entirely. Rather than acting as a simple chemical toxin that oxidizes or alkylates cellular components, excess cysteine appears to hijack the cell’s own iron logistics. The team showed that limiting mitochondrial iron availability suppresses cysteine-induced cell death and, crucially, prevents the damage that cysteine inflicts on iron–sulfur cluster proteins and on respiration itself. Iron–sulfur clusters are tiny cofactors assembled inside mitochondria and installed into a wide range of proteins, including components of the respiratory chain that generate cellular energy and enzymes that maintain the genome. When their integrity fails, mitochondria falter, energy production collapses, and the cell begins to die.

To understand how a surplus of an amino acid could destabilize iron in the first place, the researchers traced the metal’s movements through the cell. Their experiments revealed that cysteine mobilizes iron from ferritin, the cell’s principal iron storage cage, expanding the cytosolic pool of freely available iron. That liberated iron is then driven into mitochondria through the mitoferrin transporters, causing the organelles to accumulate iron to dangerous levels. This mechanism echoes classical biochemistry: reductants, including thiols, have been known since the 1970s to release iron from ferritin, and in bacteria, high intracellular cysteine was shown more than twenty years ago to promote oxidative DNA damage by fueling the Fenton reaction, in which iron converts hydrogen peroxide into destructive hydroxyl radicals. The new work shows that in human cells, the consequences of this iron release converge specifically on mitochondria.

Why would extra iron inside mitochondria be so lethal? The answer, according to the study, lies in the delicate redox chemistry of the organelle. The researchers found that the balance between reduced and oxidized glutathione, the cell’s master antioxidant couple, becomes critically imbalanced downstream of iron accumulation. Mitochondria normally maintain a robust pool of reduced glutathione, imported through the transporter SLC25A39, to buffer the reactive chemistry of the respiratory chain. When cysteine overload disrupts this balance, iron–sulfur cluster proteins begin to deteriorate, including respiratory chain components and mitochondrial translation factors that depend on these clusters. Proteomic analysis confirmed that cysteine treatment selectively depletes iron–sulfur cluster-containing proteins from the mitochondrial compartment, and respiration measurements showed corresponding losses of basal and maximal oxygen consumption.

The most elegant experiment in the paper demonstrates that this redox collapse is not merely a side effect but a causal driver of death. The researchers engineered cells to express a bacterial enzyme, GshF, that synthesizes glutathione, targeting it either to the cytosol or specifically to mitochondria. Boosting glutathione reductase activity within mitochondria alone restored redox balance downstream of iron accumulation and protected cells from cysteine toxicity by preserving iron–sulfur cluster integrity. Cytosolic glutathione enhancement, by contrast, offered far less protection. In other words, the battle over life and death is fought inside the mitochondrial matrix, where the glutathione pool must keep pace with the iron-driven chemical storm that excess cysteine ignites.

The study also clarifies how this newly defined death pathway differs from the better-known forms of regulated cell death. Ferroptosis, discovered in 2012, occurs when cysteine depletion lowers glutathione, inactivating the lipid-repair enzyme GPX4 and allowing iron-dependent lipid peroxidation to shred cellular membranes. Disulfidptosis, described in 2023, arises under glucose starvation when high cysteine levels promote aberrant disulfide bonds in actin cytoskeleton proteins. The pathway described by Nakamura and colleagues is mechanistically distinct: it requires mitochondrial iron import, proceeds through ferritin mobilization and glutathione redox imbalance, and culminates in the loss of iron–sulfur clusters rather than lipid peroxidation or cytoskeletal collapse. The authors propose that this represents a distinct mitochondrial iron-dependent cell death triggered under conditions of thiol imbalance.

The findings carry weight well beyond basic cell biology. Cells keep their cysteine levels remarkably low, a fact that has long hinted at the molecule’s intrinsic toxicity, and the new work explains why: maintaining low cysteine safeguards mitochondrial iron homeostasis. That principle has clinical echoes. Elevated plasma cysteine has been associated with vascular disease and is disturbed in cirrhosis, and recent studies have shown that cysteine depletion can drive dramatic weight loss by triggering adipose tissue thermogenesis, while dietary cysteine influences intestinal stemness through immune signaling. Cancer adds another layer of relevance. Some tumors, particularly those with NRF2 activation, appear vulnerable to excess cysteine through conjugate formation, and D-cysteine has been shown to impair tumor growth by inhibiting the iron–sulfur cluster assembly enzyme NFS1. A therapy that deliberately pushes cysteine above toxic thresholds, or that blocks mitochondrial glutathione reduction to sensitize cells to thiol stress, could exploit this newly mapped vulnerability.

There are also implications for aging. Earlier work from the same scientific lineage showed that cysteine toxicity drives age-related mitochondrial decline by altering iron homeostasis, and the new mechanistic framework gives that observation a concrete molecular basis: ferritin mobilization, mitoferrin-mediated iron import, and glutathione redox failure inside mitochondria. As organisms age, mitochondrial iron handling becomes increasingly error-prone, and thiol metabolism shifts in ways that could tip vulnerable cells toward this death pathway. Understanding the checkpoints along that route, from ferritin release to SLC25A28 and SLC25A37 activity to mitochondrial glutathione reductase capacity, offers a series of potential intervention points.

What makes the study especially compelling is its demonstration that a nutrient’s protective and poisonous faces are governed by the same underlying chemistry. Cysteine supports iron–sulfur cluster biogenesis when dosed correctly and dismantles it when dosed in excess, with the difference determined by how much iron the mitochondria admit and how much reducing power they retain. The Rockefeller-led team has thus turned a decades-old puzzle into a coherent mechanism, one that connects amino acid metabolism, metal trafficking and redox biology into a single lethal circuit. As researchers now test whether this mitochondrial iron-dependent death operates in tissues and diseases where thiol levels run high, the humble amino acid that every biology student learns to love may gain a reputation as one of the cell’s most dangerous tenants when it overstays its welcome.

Subject of Research: Mechanism of cysteine-induced mitochondrial iron-dependent cell death

Article Title: Cysteine excess triggers a mitochondrial iron-dependent cell death

Article References: Nakamura, T., Inoki, A., Das, N. K., Chen, B., Khan, A., Liu, Y., Uygur, B., Yen, F. S., Unlu, G., Shah, Y. M., & Birsoy, K. (2026). Cysteine excess triggers a mitochondrial iron-dependent cell death. Nature Metabolism. https://doi.org/10.1038/s42255-026-01616-7

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01616-7

Keywords: cysteine, mitochondria, iron homeostasis, cell death, iron–sulfur clusters, glutathione, ferritin, mitoferrin, ferroptosis, redox balance, metabolism, CRISPR screen