A new study sheds light on a surprising contributor to breast cancer metastasis: a mitochondrial antioxidant called glutathione. While mitochondria are often referred to as the powerhouses of the cell, recent research continues to show that their role in cancer biology goes far beyond energy production. In breast cancer, the spread of cancer cells to other parts of the body—known as metastasis—is the primary cause of mortality. The latest findings, published in Cancer Discovery, reveal that glutathione, a metabolite produced and stored in mitochondria, plays a central role in enabling cancer cells to survive the transition from the breast to distant organs like the lungs.

This discovery not only deepens our understanding of how cancer spreads but also highlights the importance of looking at specific organelles and their metabolites when studying tumor behavior. The research, led by Kivanç Birsoy at Rockefeller University, identifies a key mechanism by which glutathione supports metastatic colonization, offering potential new avenues for therapeutic intervention. For those following developments in cancer metabolism or mitochondrial function, this study marks a significant step forward.

The team approached the problem by using a novel protein-tagging strategy that allowed them to differentiate between cells from the primary breast tumor and those that had migrated to the lung. By analyzing the mitochondrial metabolites in both cell types, the researchers could identify which compounds were uniquely important for metastasis. Among thousands of metabolites, glutathione stood out. Known for its role in reducing oxidative stress and supporting immune function, glutathione was found in dramatically higher levels in metastatic cells that had settled in the lung.

I found this detail striking: the team didn’t just measure glutathione levels—they visualized them. Through a technique called spatial metabolomics, they were able to map the distribution of glutathione directly within lung tissue. This allowed them to confirm that metastatic cells in the lung had elevated mitochondrial glutathione, offering compelling visual evidence for its role in cancer spread.

But the researchers didn’t stop there. They investigated how glutathione gets into the mitochondria in the first place. The answer lies in a transporter protein called SLC25A39. This protein was previously identified by the same lab as the key gatekeeper for mitochondrial glutathione import. In the current study, SLC25A39 emerged again—this time as a critical enabler of metastasis. When the transporter was blocked, metastatic cells struggled to grow in the lung, confirming its essential role in cancer progression.

Interestingly, the study also found that glutathione’s role in metastasis is not due to its antioxidant properties. Multiple experiments ruled out oxidative stress reduction as the primary mechanism. Instead, glutathione appears to trigger a stress-response pathway by activating a transcription factor called ATF4. This protein helps cancer cells survive in low-oxygen environments, such as those found in new metastatic sites. The activation of ATF4 gives these cells a survival advantage during the early stages of colonization, when they are most vulnerable.

The implications of these findings are significant. By pinpointing both a metabolite and its transporter as key players in metastasis, the study offers a more precise target for future therapies. In contrast to broad-spectrum treatments that affect many cellular processes, a drug designed to block SLC25A39 could potentially limit cancer spread with fewer side effects. The research team also examined patient samples and found that breast cancer patients with lung metastases had higher levels of SLC25A39. Moreover, elevated expression of this transporter was associated with poorer overall survival, reinforcing its relevance in clinical outcomes.

This work builds on earlier discoveries from the Birsoy lab. In 2021, they first identified SLC25A39 as the mitochondrial glutathione transporter. Two years later, they demonstrated that this protein doesn’t just passively transport glutathione—it also senses and regulates its levels within mitochondria. These foundational insights gave the team a head start in investigating its role in cancer. As Birsoy noted, having the tools already in place allowed them to move quickly once the transporter appeared in cancer screenings.

One of the most compelling aspects of the study is its emphasis on cellular compartments. Rather than treating metabolism as a uniform process across the cell, the researchers focused on how specific organelles like mitochondria contribute to disease. “We’re trying to make our knowledge of metabolism more precise,” Birsoy said. “It’s not just about some metabolite levels going up and others going down. We need to look at the organelles, the precise compartments, to understand how metabolites influence human health.”

As the field of cancer research continues to evolve, studies like this one underscore the importance of looking beyond traditional pathways. By examining how mitochondrial function intersects with cancer cell survival, scientists are uncovering new strategies to combat one of the most challenging aspects of cancer: its ability to spread. While more work is needed before these findings can translate into treatments, the identification of glutathione and SLC25A39 as drivers of metastasis offers a promising direction for future research and drug development.

Read more at medicalxpress.com