The toxicity of cysteine revealed – it causes iron overload in mitochondria and cell death

[haidut]

Cysteine, despite its importance for the synthesis of glutathione (GSH), is one of the few amino acids with direct toxicity even at physiological concentrations. Conversely, cysteine dietary restriction has been reliably shown to increase both average and maximum lifespan. Ray mentioned cysteine in quite a few of his articles and interviews, and his explanation of cysteine;s toxicity revolved mostly around its role as a reductant and goitrogen. However, there seems to be another toxicity mechanism and the study below finally shines light on it. Namely, iron overload, which Ray also warned against, and believed that iron overload is one of the key drivers of aging and diseases. The study below demonstrates that cysteine sequesters iron from ferritin and this allows iron to accumulate in very high concentrations inside the mitochondria, where it not only leads to lipid peroxidation and formation of reactive oxygen species (ROS), but also directly causes cell death. When either the release of iron from ferritin or its cellular uptake is blocked, cysteine is no longer toxic.

https://www.nature.com/articles/s42255-026-01616-7

https://www.rockefeller.edu/news/40469-cysteine-toxic-glutathione/

“…Cysteine is one of the main building blocks that cells use to make proteins. But this amino acid is a double-edged sword—too much cysteine is toxic to the cell. Cells therefore keep free cysteine levels to a minimum, converting most of the amino acid into the antioxidant glutathione. Now, a new paper explains why cysteine is so toxic at high concentrations. The findings, published in Nature Metabolism, show that cysteine can pry iron from ferritin, the protein complex that normally keeps the metal safely locked away, flooding the cell with iron that accumulates in the mitochondria, leading to cell death. These results resolve a longstanding question in basic biology, and offer the first comprehensive explanation for why cells may have evolved to expend significant energy packaging cysteine into glutathione.”

“…On the other hand, too much cysteine is just as toxic. In fact, cysteine is the only one of the 20 protein-building amino acids that becomes acutely toxic when present in excess. “There are some studies suggesting cysteine supplementation might be beneficial,” Birsoy says. “This should be taken with a grain of salt precisely because of how toxic high cysteine is to cells.”

“…Ferritin normally keeps iron safely locked away, while SLC25A28 transports available iron into mitochondria. Finding SLC25A28 at the center of their genetic screen led the researchers to ask whether excess cysteine was somehow freeing iron from ferritin and sending it into mitochondria. A series of experiments confirmed that cysteine can react directly with iron stored in ferritin, changing it into a form that can escape. Glutathione, despite sharing cysteine’s reactive sulfur-containing group, could not. And when the researchers blocked either the release of iron from ferritin or its transport into mitochondria, high levels of cysteine were no longer toxic—a deft demonstration that its impact on iron’s movement is what explains its toxicity.”

Via: https://haidut.me/?p=3117

[Lejeboca]

@haidut Interesting find -- thankss! Yet another reason to keep the glucose uptake high and to avoid metabolic stess.
From this paper's concluding passages [bold-facing is mine]:

"These results also have implications for therapeutic strategies that
manipulate cyst(e)ine availability. Intracellular cysteine became toxic
at concentrations of approximately 1–1.5 mM (Extended Data Fig. 4l),
substantially above its normal systemic abundance. In fasting human
plasma, free cysteine and cystine are present at approximately 10 µM
and 80 µM, respectively, with total cyst(e)ine reaching ~250 µM (refs.
31,32). Thus, the toxic threshold is unlikely to be reached through bulk plasma exposure but may be approached in cells with unusually high cyst(e)ine uptake or impaired cysteine disposal. One such example would be cancers with constitutive NRF2 activation that accumulate cysteine beyond biosynthetic demand through upregulation of SLC7A11, promoting the formation of cysteine-derived conjugates that may serve as a detoxification route [33]. Cysteine or NAC has also been reported to induce cell death in glioblastoma and other cellular contexts, particularly during metabolic stress¹¹,³⁴. Our study suggests that, when this buffering capacity is exceeded, or under conditions of metabolic stress such as glucose limitation, excess cysteine becomes deleterious. Conversely, cystine supplementation can enhance tissue regeneration and stem-cell function in some settings.³⁵. Such findings are therefore likely to depend on the capacity of the receiving cells to metabolize or safely dispose of the resulting cysteine. Cysteine damages the mitochondrial electron transport chain via iron–sulfur protein loss, leading to cells relying more on glycolysis for ATP production and trying to uptake more glucose (Extended Data Fig. 4b). This would explain why glucose starvation is synthetically lethal with high cyst(e)ine as exemplified by disulfidptosis, although this death cannot be rescued by iron chelation [10]. Although this process shares features with ferroptosis, it occurs despite elevated GSH and suppressed lipid peroxidation, defining a distinct form of mitochondrial iron-dependent cell death (Extended Data Fig. 4m). Together, these results position thiol imbalance as a central metabolic vulnerability and underscore the importance of both limiting cysteine accumulation and promoting its safe disposal to maintain cellular homeostasis. "