A Path to Increasing Glutathione Levels in Mitochondria
Glutathione is an interesting cellular antioxidant, as increased levels can improve health in humans and slow aging in animal models. You might recall recent small human trials of high dose supplementation of glutathione precursors in order to achieve upregulation of glutathione, and corresponding studies in mice. It is thought that glutathione upregulation may largely improve health via mitochondrial function, as mitochondria are a prominent source of oxidative stress in aging cells. Here, researchers find a mechanism that regulates the amount of glutathione that enters the mitochondria, and thus a possible target to increase this level without the need for global upregulation. Whether not it is capable of producing greater benefits remains to be seen.
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. The antioxidant is especially abundant in mitochondria, which cannot function without it. As the respiratory organelle, mitochondria produces energy, but mitochondria can also the source of a lot of oxidative stress, 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.
How glutathione actually enters mitochondria was unknown until 2021, when researchers 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. Somehow a mitochondrion figures out how much antioxidant it has, and depending on that amount, it regulates the amount of antioxidant it lets inside."
To ferret out how mitochondria do it, 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. It has two completely independent domains. One domain senses the glutathione, and the other transports it. Now that the researchers know how SLC25A39's package delivery system operates, they can experiment with manipulating it. "This particular transporter protein is upregulated in a group of cancers. People have tried to change overall glutathione levels, but now we have a way to change it in mitochondria without impacting other parts of the cell. This kind of targeted therapy could potentially lower the number of side effects that can come with altering glutathione levels across the whole body."
Link: https://www.rockefeller.edu/news/34956-how-the-antioxidant-glutathione-keeps-mitochondria-healthy/
Bad side effects from systemic glutathione? Most of us either take it, inject it, spray it on, or pop precursors. How do we know how much is too much?
Quote from the study covered here:
"We believe maintaining the glutathione-to-iron ratio is very important, because if you have too little glutathione, then iron becomes very reactive, and if you have too much glutathione, the iron will not be usable."
https://pubmed.ncbi.nlm.nih.gov/10448900/
Glutathione homeostasis in response to exercise training and nutritional supplements
Abstract
Glutathione plays a central role in the maintenance of tissue antioxidant defenses and in the regulation of redox sensitive signal transduction. In muscle cells, the level and redox status of GSH regulates activity of the redox sensitive transcription factor NF-kappaB. Physical exercise may cause oxidation of GSH in tissues such as the blood, skeletal muscle and liver. Endurance training strengthened GSH dependent tissue antioxidant defenses in most studies. Although studies investigating the effect of sprint training are few, current results show that sprint training may also have a beneficial effect on tissue GSH homeostasis. Skeletal muscle GSH level appears to be tightly regulated by the state of physical activity. Regular exercise enhances and chronic inactivity decreases the level of GSH in this tissue.
N-acetyl-L-cysteine (NAC) and alpha-lipoic acid (LA) are two antioxidant dietary supplements that are able to enhance cellular GSH levels.
Because LA can be recycled to its potent dithiol form, dihydrolipoate, by enzymes present in the human cell it has a clear advantage over NAC. Recently an improved form of LA, a positively charged analogue (LA-Plus), has been discovered. LA-Plus has more potent immuno-modulatory activity compared to LA. Both LA and NAC have been shown to have beneficial effects in protecting tissue GSH homeostasis against exercise induced oxidative stress.
So in this trial LA came out better than NAC at increasing Glutathione, why use NAC?