Mitochondria are best known as the “powerhouses” of our cells, generating the energy that keeps us alive.
But scientists are learning that these tiny organelles play a much more complicated role, especially when it comes to cancer.
A new study has found that a mitochondrial compound called glutathione may be a central driver of breast cancer’s deadly ability to spread to other parts of the body.
The spread of cancer, known as metastasis, is responsible for most cancer deaths.
While treatments can sometimes control or even remove the original tumor, once cancer cells travel to distant organs and grow there, the disease becomes far harder to treat.
That’s why researchers have spent decades trying to understand what gives cancer cells the ability to break away and take root in new tissues.
In the past, scientists discovered that certain cellular byproducts, called metabolites, help cancer cells survive and grow during different stages of metastasis.
Compounds such as lactate, pyruvate, glutamine, and serine were each shown to give cancer cells an advantage.
But mitochondria produce thousands of metabolites, and it has been a major challenge to identify which ones matter most for cancer’s spread.
In this new research, published in Cancer Discovery, scientists at Rockefeller University focused on breast tumors in mice that had spread to the lungs.
They used advanced techniques to compare the metabolites inside mitochondria of primary tumor cells with those of metastatic cells. Among thousands of possibilities, one metabolite clearly stood out: glutathione.
Glutathione is usually seen as a protective molecule, helping to reduce oxidative stress and support the immune system. But in this case, its levels were much higher in metastatic cancer cells, particularly in the lungs.
Using a specialized technique called spatial metabolomics, the researchers were able to actually visualize glutathione within lung tissue and confirm that metastatic cells were loaded with it.
The team then turned to mitochondrial proteins and discovered that one transporter, called SLC25A39, was responsible for moving glutathione into the mitochondria of metastatic cancer cells. Blocking this transporter prevented the cancer from spreading, making the connection between glutathione, its transporter, and metastasis clear.
Interestingly, the way glutathione fueled metastasis was not through its usual antioxidant role. Instead, it activated a stress-response protein called ATF4, which helps cancer cells survive when they first arrive in new and oxygen-poor tissues. This survival boost appeared to be crucial during the earliest stages of metastasis, allowing the cells to adapt quickly and establish new tumors.
This discovery builds on earlier work from the same lab. In 2021, the researchers first identified SLC25A39 as the transporter that carries glutathione into mitochondria. In 2023, they showed that the transporter also acts as a sensor, adjusting how much glutathione enters the mitochondria based on the cell’s needs. These insights gave the team the tools to test its role in cancer spread.
The findings may have important clinical implications. Patient samples showed that breast cancers that had spread to the lungs had higher levels of SLC25A39, and patients with higher expression of the transporter had worse survival outcomes. This raises the possibility that future treatments could target this pathway specifically—blocking glutathione’s entry into mitochondria as a way to stop metastasis, with potentially fewer side effects than broader cancer drugs.
For now, the research underscores a broader message: to understand cancer and other diseases, scientists need to study metabolites not just in general, but within the specific compartments of the cell where they operate.
The tiny details inside mitochondria may turn out to be some of the most important clues in the fight against cancer.
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