Spatial metablomic imaging of glutathione in a mouse lung with metastases. (Birsoy lab)
The mitochondria may be the powerhouse of the cell, but mounting evidence suggests this organelle is also a driving force behind cancer. Now, new evidence points to the mitochondrial metabolite glutathione, highlighting its central role in helping breast cancer cells break away from the primary tumor, travel through the body, and take root in other tissues.
The findings are among the first to link a specific mitochondrial metabolite to metastasis, with strong implications for the study of cancer at the cellular level. "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.
A mysterious connection with metastasis
The vast majority of cancer deaths are due to its spread, rather than complications from the original tumor. Knowing that metastasis lies at the heart of cancer mortality, researchers have spent decades trying to identify-and defeat-the specific factors that enable rogue cells to break away from the primary tumor and colonize the rest of the body.
Metabolites play a key role, with prior studies having shown that the metabolites lactate, pyruvate, glutamine, and serine each support distinct stages of metastasis. And since mitochondria within the cancer cell are responsible for not only generating energy but also providing metabolites, it is unsurprising that a handful of recent studies have linked mitochondrial activity to metastasis in breast, renal, and pancreatic cancers.
However, researchers had been unable to identify the precise mechanisms at play. "Mitochondria have thousands of metabolites, and it's been difficult to determine which are important to tumor formation and growth, and which initiate metastasis," says Birsoy.
Cells under stress
In their study, Birsoy and colleagues utilized an innovative strategy that involved protein tagging able to distinguish primary tumor cells and from those that had migrated from the breast to the lung. The team, led by graduate fellow Nicole DelGaudio and postdoctoral fellow Hsi-wen Yeh, then analyzed the metabolites in these organelles to reveal how mitochondrial metabolites shift when cancer cells colonize new sites.
"These techniques allowed us to, in an unbiased manner, see the difference between what's essential in metastasis and what's essential in the primary tumor," DelGaudio says.
Among thousands of mitochondrial compounds, one stood out: glutathione. A major antioxidant involved in reducing oxidative stress, enhancing metabolic detoxification, and regulating the immune system, glutathione levels were found to have skyrocketed in metastatic cancer cells that invaded the lung. To further confirm the findings, the team used a spatial metabolomics technique that allowed them to visualize the distribution of glutathione directly within lung tissues.
They then shifted their focus toward mitochondrial membrane proteins, screening for transporters that stood out as essential for metastatic cells growing in the lung. Once again, a clear frontrunner emerged: SLC25A39, the mitochondrial glutathione transporter. The findings closed the loop, linking a metabolite and its transporter to metastasis by demonstrating that mitochondrial glutathione import via the SLC25A39 transporter is essential for cancer spread.
Birsoy and colleagues also found how mitochondrial glutathione drives cancer spread: not by acting as an antioxidant-an effect ruled out through multiple experiments-but by signaling to activate ATF4, a transcription factor that helps cancer cells survive in low-oxygen conditions. This also pinpointed when glutathione is specifically required: during the early steps of metastatic colonization, when cancer cells adapt rapidly to the stressful environment of a new tissue.
A familiar culprit
This work builds on recent significant work from the Birsoy lab. In 2021, his team was the first to demonstrate that SLC25A39 is the transporter that brings glutathione into the mitochondria; in 2023, they showed that SLC25A39 is not only a transporter but a dynamic sensor that regulates the amount of glutathione in the mitochondria and adjusts those levels accordingly. So when this metabolite and its mitochondrial transporter showed up in cancer screenings, Birsoy knew where to take his experiments next.
"Because we found this transporter earlier and knew how to block the entry of glutathione, we already had the tools necessary to investigate its role in cancer metastasis," he says.
The findings may have clinical implications-especially since the team also found that breast cancer samples from patients whose disease had spread to the lung showed elevated SLC25A39, and that higher SLC25A39 expression was strongly correlated with poorer overall survival in breast cancer patients. One day, a small molecule that targets this metabolite by blocking its transporter could potentially forestall breast cancer metastasis, with fewer side-effects than sweeping therapies that target more general cellular processes.
In the short-term, however, the paper emphasizes the importance of nailing down just how metabolites within different compartments operate within our cells.
"We're trying to make our knowledge of metabolism more precise," Birsoy says. "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."
