Many of the processes that keep us alive also put us at risk. The
energy-producing chemical reactions in our cells, for example, also produce
free radicals—unstable molecules that steal electrons from other molecules.
When generated in surplus, free radicals can cause collateral damage,
potentially triggering malfunctions such as cancer, neurodegeneration, or
cardiovascular disease.
Cells solve this problem by synthesizing antioxidants, compounds that
neutralize free radicals. In a new study, Rockefeller scientists identify a
key molecule that ferries glutathione, the body's major antioxidant, into
the cell's mitochondria, where free radicals are produced en masse. The
discovery, published in Nature, opens new possibilities for investigating
oxidative stress and its damaging effects.
"With the potential transporter identified, we can now control the amount of
glutathione that enters mitochondria and study oxidative stress specifically
at its source," says Kivanç Birsoy, Chapman Perelman Assistant Professor at
The Rockefeller University.
The shuttle into the mitochondria
To avoid oxidative stress, cells need to properly balance the levels of free
radicals and antioxidants within their mitochondria, where energy production
happens. Because glutathione is produced outside of mitochondria, in the
cell's cytosol, the scientists wanted to know how it gets transported into
these tiny powerhouses in the first place.
To shed light on this process, Birsoy's team monitored protein expression in
cells in response to glutathione's levels. "We hypothesized that glutathione
is shuttled by a transporter protein whose production is regulated by
glutathione," Birsoy says. "So if we lower the levels of glutathione, the
cell should compensate by upregulating the transporter protein."
The analysis pointed to SLC25A39, a protein in the mitochondrial membrane
whose function was hitherto unknown. The researchers found that blocking
SLC25A39 reduced glutathione inside the mitochondrion, without affecting its
levels elsewhere in the cell. Other experiments showed that mice cannot
survive without SLC25A39. In animals engineered to lack this protein, red
blood cells quickly die by oxidative stress due to their failure to bring
glutathione into mitochondria.
The identification of the transporter may lead to a better understanding of
a variety of disease pathways linked to oxidative stress, including those
involved in aging and neurodegeneration. "These conditions could potentially
be treated or prevented by stimulating antioxidant transport into
mitochondria," Birsoy says.
Moreover, the team is now exploring whether SLC25A39 might hold promise as a
drug target for cancer, by helping to induce fatal oxidative stress in tumor
cells. "In cancer, we would want to prevent antioxidants from getting into
mitochondria, and the transporter protein may be our way to do that," Birsoy
says.
Reference:
Ying Wang et al, SLC25A39 is necessary for mitochondrial glutathione import
in mammalian cells, Nature (2021).
DOI: 10.1038/s41586-021-04025-w
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Biology & Health