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Many of the processes that keep our bodies alive are also dangerous. Free radicalsunstable molecules, which steal electrons from other molecules, are also produced by energy-producing chemical reactions within our cells. Free radicals, when generated in excess, can cause collateral damage that could lead to malfunctions like cancer, neurodegeneration or cardiovascular disease.
This problem is solved by cells synthesizing antioxidants. These compounds neutralize free radicals. Rockefeller scientists have identified a key molecule which transports glutathione (the body's main antioxidant) into cells' mitochondria. Free radicals are then produced in large quantities. Nature published the discovery. It opens up new avenues for studying oxidative stress and its harmful effects.
"We can now control how much glutathione enters mitochondria, and study oxidative stresses specifically at its source," said Kivan Birsoy (Chaptman Perelman Assistant Professor, The Rockefeller University).
The shuttle to the mitochondria
Cells must balance levels of antioxidants and free radicals in their mitochondria to avoid oxidative stress. This is where energy production takes place. The scientists were interested in how glutathione gets into these small powerhouses, since it is not produced in mitochondria.
Birsoy's research team examined the response of glutathione levels to protein expression in cells to shed light on the process. Birsoy explains, "We hypothesized glutathione was shuttled by a transportation protein whose production can be regulated by glutathione." "So, if we reduce the level of glutathione in the cells, it should compensate by increasing the transporter protein."
SLC25A39 was identified as a protein found in the mitochondrial membrane. Its function was unknown. Researchers found that SLC25A39 blocking reduced glutathione in the mitochondrion without affecting other levels. Other experiments revealed that mice can't survive without SLC25A39. Red blood cells in animals that lack this protein quickly succumb to oxidative stress. This is due to the failure of glutathione to enter mitochondria.
The identification of this transporter could lead to better understanding of many disease pathways that are linked to oxidative stresses, such as those related to neurodegeneration and aging. Birsoy states that these conditions could be prevented or treated by stimulating antioxidant transport to mitochondria.
The team is also exploring whether SLC25A39 could be a potential drug target for cancer by inducing fatal oxidative stress within tumor cells. Birsoy states that in cancer we want to prevent antioxidants getting into mitochondria and that the transporter protein might be our way.
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More information: Ying Wang et. al., SLC25A39 required for mitochondrial glutathione export in mammalian cell, Nature (2021). Information from Nature Ying Wang and colleagues, SLC25A39 is required for mitochondrial glutathione export in mammalian cell, (2021). DOI: 10.1038/s41586-021-04025-w
