At a Glance
- Scientists discovered that breast cancer cells accumulate high levels of the metabolite glutathione in their mitochondria, specifically during the process of metastasis to the lung.
- This accumulation is driven by an elevated expression of the mitochondrial transporter protein SLC25A39, which is essential for successful metastatic colonization but not primary tumor growth.
- Mitochondrial glutathione functions by helping to activate the transcription factor ATF4, which enables cancer cells to survive the stressful, low-oxygen environment of a newly formed tissue.
- The study confirmed that glutathione’s role in metastasis is independent of its canonical function as an antioxidant, revealing a novel signaling pathway for the metabolite.
- Higher levels of the SLC25A39 transporter in human breast cancer samples correlate with poorer patient survival, suggesting it as a potential therapeutic target to prevent metastasis.
New research reveals that the spread of cancer may hinge on a single molecule within the cell’s powerhouse, the mitochondria. Scientists have discovered that breast cancer cells need a crucial supply of the metabolite glutathione inside their mitochondria to break away from a primary tumor and successfully establish new colonies in distant organs, a deadly process known as metastasis. This finding provides a new understanding of how cancer exploits the cell’s internal machinery to survive and spread throughout the body.
The study, published in the journal Cancer Discovery, was conducted by researchers at Rockefeller University who sought to identify the specific factors that enable cancer to metastasize. Most cancer-related deaths are caused by metastasis, not the original tumor. Using innovative techniques to tag and compare cells from a primary breast tumor with those that had traveled to the lung, the team analyzed the thousands of metabolites, or small molecules involved in metabolism, inside their mitochondria. This unbiased search revealed one compound that stood out: glutathione levels were dramatically higher in the metastatic cells.
The team then identified the molecular gateway responsible for this buildup. They found that a transporter protein on the mitochondrial membrane, called SLC25A39, was working overtime to import glutathione into the mitochondria of metastatic cells. When the researchers blocked this transporter, cancer cells lost their ability to colonize the lung, confirming that the import of mitochondrial glutathione is essential for metastasis. “We hope that our work will bring more attention to how organelles and their metabolites are relevant to cancer biology,” says Kivanç Birsoy, head of the Laboratory of Metabolic Regulation and Genetics at Rockefeller, in a university press release.
Interestingly, glutathione’s well-known role as an antioxidant was not the reason for its importance in metastasis. Instead, the study showed that mitochondrial glutathione is required to activate a stress-response protein called ATF4. This protein helps cancer cells adapt and survive in the harsh, low-oxygen environments they encounter when colonizing a new organ. The discovery also has clinical significance, as the team found that higher levels of the SLC25A39 transporter in patient tumors strongly correlated with poorer overall survival, marking it as a potential target for future therapies designed to halt cancer’s deadly journey.
References
- Rockefeller University. (2025, August 18). Mitochondrial antioxidant found to drive breast cancer metastasis. Medical Xpress; Rockefeller University. https://medicalxpress.com/news/2025-08-mitochondrial-antioxidant-breast-cancer-metastasis.html
- Yeh, H., DelGaudio, N. Lauren., Uygur, B., Millet, A., Khan, A., Unlu, G., Xiao, M., Timson, R. C., Li, C., Ozcan, K., Smith, K. W., Nascentes Melo, L. Martins., Allies, G., Basturk, O., Sickmann, A., Bayraktar, E. C., Possemato, R., Tasdogan, A., & Birsoy, K. (2025). Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling. Cancer Discovery. https://doi.org/10.1158/2159-8290.CD-24-1556
