Biochemical controls: how mitochondria protect themselves (Introduction)

by David Turell , Friday, November 10, 2023, 19:09 (169 days ago) @ David Turell

They control glutathione levels:

https://www.sciencedaily.com/releases/2023/11/231108114638.htm

"...within every human cell are self-contained, membrane-bound organelles, all of which are equally in need of fuel to carry out important functions. Might they, then, have nutrient sensors of their own?

"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.

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"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.

"The antioxidant is especially abundant in mitochondria, which cannot function without it. "As the respiratory organelle, mitochondria produces energy," Birsoy notes. "But mitochondria can also the source of a lot of oxidative stress," which has been implicated in cancer, diabetes, metabolic disorders, and heart and lung diseases, among others. If glutathione levels aren't precisely maintained in mitochondria, all systems fail. None of us can survive without it.

"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. "When the antioxidants are low, the level of SLC25A39 increases, and when the antioxidant levels are high, the transport level goes down," Birsoy says.

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"To ferret out how the mitochondria does it, the researchers used a combination of biochemical studies, computational methods, and genetic screens to discover that "SLC25A39 is both a sensor and a transporter at the same time," Birsoy explains. "It has two completely independent domains. One domain senses the glutathione, and the other transports it."

"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."

Comment: we are designed to use oxygen to burn our food for fuel/energy. Oxygen, if uncontrolled is therefore dangerous, which is why protective antioxidants are built into the process. Theodicy note: God knew now dangerous oxygen is, therefore, He added antioxidants. Living biochemistry is filled with trade outs.