How the Antioxidant Glutathione Keeps Mitochondria Healthy

As described in a new paper published in Science, Kıvanç Birsoy and his colleagues in Rockefeller’s Laboratory of Metabolic Regulation and Genetics have discovered the first such sensor for an organelle — specifically mitochondria, the cell’s power center. The sensor is part of a protein that does triple duty: it senses, regulates, and delivers the antioxidant glutathione into the mitochondrial interior, where it plays critical roles in tamping down oxidizing reactions and maintaining appropriate iron levels.

Glutathione is an antioxidant produced throughout the body that plays many important roles, including neutralizing unstable oxygen molecules called free radicals, which cause damage to DNA and cells if left unchecked. It also helps repair cellular damage and regulates cell proliferation, and its loss is associated with aging, neurodegeneration, and cancer. As a result, glutathione supplements have become increasingly popular as an over-the-counter approach to wellness.

But how glutathione actually enters mitochondria was unknown until 2021, when Birsoy and his team discovered that a transporter protein called SLC25A39 delivers the package. It also appeared to regulate the amount of glutathione.

The findings strongly suggested that the mitochondria had some sort of way to detect and adjust these fluctuating levels.

The protein’s unique structure may explain its abilities, says Birsoy. When Yuyang Liu, a graduate student in his lab and first author of the study, compared SLC25A39’s structure against others in the SLC family of transporters in the AlphaFold protein structure database, Liu spotted a unique extra loop in the protein. When they snipped it from the protein, its transporter abilities remained intact, but it lost the ability to sense glutathione. “Finding that interesting loop later led to our understanding of the sensing mechanism,” Birsoy says.

Sources:

Yuyang Liu, Shanshan Liu, Anju Tomar, Frederick S. Yen, Gokhan Unlu, Nathalie Ropek, Ross A. Weber, Ying Wang, Artem Khan, Mark Gad, Junhui Peng, Erdem Terzi, Hanan Alwaseem, Alexandra E. Pagano, Søren Heissel, Henrik Molina, Benjamin Allwein, Timothy C. Kenny, Richard L. Possemato, Li Zhao, Richard K. Hite, Ekaterina V. Vinogradova, Sheref S. Mansy, Kıvanç Birsoy. Autoregulatory control of mitochondrial glutathione homeostasis. Science, 2023; DOI: 10.1126/science.adf4154

Rockefeller University. (2023, November 8). How the antioxidant glutathione keeps mitochondria healthy. ScienceDaily. Retrieved November 8, 2023 from www.sciencedaily.com/releases/2023/11/231108114638.htm

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