Excess cysteine releases iron, overwhelming mitochondria and killing cells

Excess free cysteine can kill cells by releasing iron from ferritin, sending it into mitochondria and damaging the iron-sulfur proteins required for cellular energy production, according to a peer-reviewed experimental study published in Nature Metabolism. The researchers found that high cysteine was no longer toxic when they blocked either the release of iron from ferritin or the transport of available iron into mitochondria, establishing a mechanistic link between cysteine accumulation, mitochondrial iron overload and cell death.

Cysteine is one of the 20 amino acids cells use to build proteins and is also required to produce glutathione and iron-sulfur clusters. Its reactive sulfur-containing group makes it useful but potentially hazardous. Too little cysteine can deplete glutathione and contribute to cell death, while excessive free cysteine is acutely toxic. Cells limit this danger by rapidly converting most free cysteine into glutathione, an antioxidant that can be maintained at much higher concentrations.

The new work addresses a long-standing biochemical puzzle: why do cells tolerate abundant glutathione when both molecules contain a similar reactive sulfur group? A genome-wide CRISPR screen systematically disabled genes to identify genetic changes that allowed experimental cells to survive high cysteine levels. The screen highlighted SLC25A28, which encodes a protein that transports iron into mitochondria, along with receptor proteins involved in breaking down ferritin, the protein complex that normally stores iron in a contained form.

The screen results suggested a previously unrecognized route of toxicity. Rather than acting only through a direct chemical effect, excess cysteine appeared to mobilize iron from its cellular storage and direct it toward mitochondria. Ferritin normally keeps iron safely locked away, whereas SLC25A28 transports available iron into mitochondria. The convergence of these two components in the screen led the team to test whether cysteine could cause the release of iron from ferritin and increase its delivery to mitochondria.

A series of biochemical experiments supported that hypothesis. Cysteine reacted directly with iron stored in ferritin, changing it into a form that could escape the storage complex. Glutathione, despite also containing cysteine’s reactive sulfur-containing group, did not produce the same effect. When the researchers prevented iron from leaving ferritin or from being transported into mitochondria, high cysteine levels were no longer toxic. Those interventions distinguish ferritin-dependent iron release and mitochondrial transport as necessary parts of the damaging pathway.

Tracing the mobilized iron showed that it accumulated inside mitochondria. There, the excess iron damaged iron-sulfur proteins that cells rely on for energy production. With mitochondria overwhelmed by reactive iron and their energy-generating function compromised, cell death followed. The findings therefore connect a change in cysteine availability to three measurable events: liberation of stored iron, accumulation of that iron in mitochondria and disruption of mitochondrial energy production.

“Iron is a very reactive molecule,” said Toshitaka Nakamura, a postdoctoral fellow in Kivanç Birsoy’s Laboratory of Metabolic Regulation and Genetics at Rockefeller University. “It just messes up the mitochondria.” Birsoy said the results explain why keeping free cysteine low may be an evolutionary adaptation that protects cellular energy production: if cells had relied heavily on cysteine instead of glutathione as their primary redox molecule, the consequences for mitochondria could have been catastrophic.

The study is an advance in basic cell biology rather than evidence of a human treatment, clinical benefit or dietary recommendation. It used a genome-wide CRISPR screen and laboratory experiments to investigate the effects of high cysteine levels in experimental cells. The supplied research does not identify a clinical population or establish outcomes in people, and it does not test cysteine supplementation. Birsoy noted that some studies have suggested possible benefits from cysteine supplementation, but said those claims should be treated cautiously because high cysteine concentrations are toxic to cells.

The mechanism may nevertheless offer a specific direction for future disease research. Some cancers rewire their metabolism to take up unusually large amounts of oxidized cysteine. Because the study shows that excess cysteine can mobilize iron and damage mitochondria, the authors propose that such cancer cells may possess adaptations that help them manage cysteine burden and avoid lethal mitochondrial iron accumulation. Identifying and potentially disrupting those adaptations is a future research question, not a demonstrated cancer therapy. The immediate focus remains on understanding how cells sense and manage reactive molecules such as cysteine.

Overall, the findings provide a mechanistic explanation for a central metabolic trade-off. Cysteine supports essential proteins, glutathione production and iron-sulfur clusters, but its free form can also dismantle cellular iron storage. By channeling cysteine into glutathione, cells preserve its useful chemical functions while limiting the iron-dependent damage that high concentrations can cause. The study therefore links cysteine regulation to mitochondrial integrity, energy production and the evolutionary choice of glutathione as the cell’s primary redox molecule, while leaving the therapeutic possibilities for cancer to be investigated.

Subject of Research: Experimental evidence that excess free cysteine causes mitochondrial iron overload and cell death

Article Title: Scientists discover why high levels of the amino acid cysteine are toxic to cells

Article References: Scientists discover why high levels of the amino acid cysteine are toxic to cells. Original publication (Bibliographic details unavailable.)

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Keywords: cysteine toxicity, ferritin, iron metabolism, mitochondria, glutathione, CRISPR screen, iron-sulfur proteins, cell death, cellular redox, metabolic regulation, Scientists, discover