The mitochondria are best known as the cell’s powerhouse, but growing evidence suggests these organelles play a far more sinister role in cancer. New research has uncovered that the mitochondrial metabolite glutathione is central to enabling breast cancer cells to detach from the primary tumor, travel through the body, and establish new growths in distant tissues.
The findings, led by scientists at Rockefeller University, mark one of the first direct links between a specific mitochondrial metabolite and metastasis—the process responsible for most cancer-related deaths.
“We hope our work will highlight the critical role of organelles and their metabolites in cancer biology,” said Kivanç Birsoy, head of the Laboratory of Metabolic Regulation and Genetics at Rockefeller.
Cracking the Mystery of Metastasis
Metastasis remains the leading cause of cancer mortality. While researchers have long sought the cellular drivers of this process, the precise mechanisms have remained elusive. Previous studies identified several metabolites—including lactate, pyruvate, glutamine, and serine—as contributors to distinct stages of metastasis. Because mitochondria generate both energy and metabolites, scientists suspected a deeper connection.
“The mitochondria produce thousands of metabolites, making it difficult to pinpoint which specifically drive tumor spread,” Birsoy explained.
Tracking Cells Under Stress
In their study, graduate fellow Nicole DelGaudio and postdoctoral fellow Hsi-wen Yeh applied protein-tagging techniques to distinguish primary breast tumor cells from those that migrated to the lung. By analyzing mitochondrial metabolites, the researchers revealed how cellular metabolism shifts during colonization of new tissues.
The standout compound was glutathione. Known as a potent antioxidant, glutathione levels surged in metastatic cells. Spatial metabolomics confirmed its accumulation in lung tissue where secondary tumors formed.
The team then turned to mitochondrial transporters and identified SLC25A39 as essential for importing glutathione. The discovery directly connected glutathione and its transporter to cancer spread.
Further investigation showed that mitochondrial glutathione does not primarily act as an antioxidant in metastasis. Instead, it activates ATF4, a transcription factor that helps cancer cells survive in low-oxygen environments. This role proved critical during the earliest phases of metastatic colonization.
Building on Past Discoveries
The Birsoy lab has a track record with glutathione research. In 2021, they identified SLC25A39 as the transporter moving glutathione into mitochondria. By 2023, they demonstrated its ability to sense and adjust glutathione levels.
“When this transporter and metabolite emerged in cancer screenings, we knew exactly how to test their roles,” Birsoy noted. “Because we had already developed tools to block glutathione entry, we could immediately explore its impact on metastasis.”
The new findings underscore mitochondria’s pivotal role in cancer biology and open potential avenues for therapies aimed at halting metastasis at its earliest stages.
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