Pathways to increase mitochondrial glutathione levels

Glutathione is an interesting cellular antioxidant because in animal models, increased levels of glutathione have been shown to improve human health and slow aging.

You may recall recent small human trials in which high-dose glutathione precursors were supplemented to achieve glutathione upregulation, and corresponding studies in mice.

It is thought that upregulation of glutathione may largely improve health through mitochondrial function, as mitochondria are a major source of oxidative stress in aging cells.

Here, the researchers discovered a mechanism that regulates the amount of glutathione that enters the mitochondria, making it a possible target to boost glutathione levels without the need for global upregulation.

Whether it will yield greater benefits remains to be seen.

Glutathione is an antioxidant produced throughout the body that plays a number of important roles, including neutralizing unstable oxygen molecules called free radicals, which can cause damage to DNA and cells if left unchecked.

It also helps repair cell damage and regulate cell proliferation, the loss of which has been linked to aging, neurodegeneration and cancer.

As a result, glutathione supplements are gaining popularity as an over-the-counter approach to health.

Antioxidants are especially abundant in mitochondria, which cannot function without it.

As respiratory organelles, mitochondria produce energy, but mitochondria can also be the source of a lot of oxidative stress, which has been linked to cancer, diabetes, metabolic disorders, cardiorespiratory diseases, and more.

If glutathione levels in the mitochondria are not precisely maintained, all systems fail. None of us can survive without it.

How glutathione actually gets into the mitochondria, it wasn't until 2021 that researchers discovered that a transporter called SLC25A39 provided this encapsulation.

It also seems to regulate the amount of glutathione. "When antioxidant levels are low, SLC25A39 levels increase, and when antioxidant levels are high, transport levels decrease.

The mitochondria somehow figures out how many antioxidants it has and regulates the amount of antioxidants it puts into the body based on that amount."

To figure out how mitochondria do this, the researchers used a combination of biochemical studies, computational methods, and genetic screening to find that SLC25A39 is both a sensor and a transporter.

It has two completely independent domains. One domain senses glutathione and the other transports glutathione.

Now that researchers know how SLC25A39's package delivery system works, they can try to manipulate it.

This particular transport protein is upregulated in one group of cancers. People have tried to change the overall level of glutathione, but now we have a way to change the level of glutathione in the mitochondria without affecting the rest of the cell.

This targeted therapy could potentially reduce the number of side effects associated with altering whole-body glutathione levels.

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