Lots of the processes that preserve us alive additionally put us in danger. The energy-producing chemical reactions in our cells, for instance, additionally produce free radicals—unstable molecules that steal electrons from different molecules. When generated in surplus, free radicals could cause collateral injury, doubtlessly triggering malfunctions corresponding to most cancers, neurodegeneration, or heart problems.
Cells resolve this drawback by synthesizing antioxidants, compounds that neutralize free radicals. In a brand new examine, Rockefeller scientists determine a key molecule that ferries glutathione, the physique’s main antioxidant, into the cell’s mitochondria, the place free radicals are produced en masse. The discovery, printed in Nature, opens new potentialities for investigating oxidative stress and its damaging results.
“With the potential transporter recognized, we are able to now management the quantity of glutathione that enters mitochondria and examine oxidative stress particularly at its supply,” says Kivanç Birsoy, Chapman Perelman Assistant Professor at The Rockefeller College.
The shuttle into the mitochondria
To keep away from oxidative stress, cells must correctly stability the degrees of free radicals and antioxidants inside their mitochondria, the place vitality manufacturing occurs. As a result of glutathione is produced exterior of mitochondria, within the cell’s cytosol, the scientists wished to know the way it will get transported into these tiny powerhouses within the first place.
To make clear this course of, Birsoy’s group monitored protein expression in cells in response to glutathione’s ranges. “We hypothesized that glutathione is shuttled by a transporter protein whose manufacturing is regulated by glutathione,” Birsoy says. “So if we decrease the degrees of glutathione, the cell ought to compensate by upregulating the transporter protein.”
The evaluation pointed to SLC25A39, a protein within the mitochondrial membrane whose perform was hitherto unknown. The researchers discovered that blocking SLC25A39 diminished glutathione contained in the mitochondrion, with out affecting its ranges elsewhere within the cell. Different experiments confirmed that mice can’t survive with out SLC25A39. In animals engineered to lack this protein, crimson blood cells rapidly die by oxidative stress as a result of their failure to deliver glutathione into mitochondria.
The identification of the transporter could result in a greater understanding of a wide range of illness pathways linked to oxidative stress, together with these concerned in growing old and neurodegeneration. “These circumstances might doubtlessly be handled or prevented by stimulating antioxidant transport into mitochondria,” Birsoy says.
Furthermore, the group is now exploring whether or not SLC25A39 would possibly maintain promise as a drug goal for most cancers, by serving to to induce deadly oxidative stress in tumor cells. “In most cancers, we might wish to stop antioxidants from moving into mitochondria, and the transporter protein could also be our method to try this,” Birsoy says.
Reference: Wang Y, Yen FS, Zhu XG, et al. SLC25A39 is important for mitochondrial glutathione import in mammalian cells. Nature. 2021;599(7883):136-140. doi: 10.1038/s41586-021-04025-w
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