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In the 1990s, several studies in the Neurobiology field led to the widely accepted notion that astrocytes produce large amounts of glutathione that serve to feed neurons with precursors for glutathione synthesis. This assumption has important implications for health and disease since a reduction in this supply from astrocytes could compromise the capacity of neurons to cope with oxidative stress. However, at first glance, this shuttling would imply a large energy expenditure to get to the same point in a nearby cell. Thus, are there additional underlying reasons for this expensive mechanism? Are neurons unable to import and\/or synthesize the three non-essential amino acids that are the glutathione building blocks? The rather oxidizing extracellular environment favors the presence of cysteine (Cys) as cystine (Cis), less favorable for neuronal import. Therefore, it has also been proposed that astrocytic GSH efflux could induce a change in the redox status of the extracellular space nearby the neurons, locally lowering the Cis\/Cys ratio. This astrocytic glutathione release would also increase their demand for precursors, stimulating Cis uptake, which these cells can import, further impacting the local decline of the Cis\/Cys ratio, in turn, contributing to a more reduced extracellular environment and subsequently favoring neuronal Cys import. Here, we revisit the experimental evidence that led to the accepted hypothesis of astrocytes acting as suppliers of neuronal glutathione precursors, considering recent data from the Human Protein Atlas. In addition, we highlight some potential drawbacks of this hypothesis, mainly supported by heterogeneous cellular models. Finally, we outline additional and more cost-efficient possibilities by which astrocytes could support neuronal glutathione levels, including its shuttling in extracellular vesicles.<\/jats:p>","DOI":"10.3390\/ijms24098059","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T13:54:46Z","timestamp":1682949286000},"page":"8059","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Appraising the Role of Astrocytes as Suppliers of Neuronal Glutathione Precursors"],"prefix":"10.3390","volume":"24","author":[{"given":"Dolores","family":"P\u00e9rez-Sala","sequence":"first","affiliation":[{"name":"Department of Structural and Chemical Biology, Centro de Investigaciones Biol\u00f3gicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4714-9051","authenticated-orcid":false,"given":"Mar\u00eda A.","family":"Pajares","sequence":"additional","affiliation":[{"name":"Department of Structural and Chemical Biology, Centro de Investigaciones Biol\u00f3gicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.neuron.2015.03.035","article-title":"A cellular perspective on brain energy metabolism and functional imaging","volume":"86","author":"Magistretti","year":"2015","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/j.1749-6632.1996.tb34449.x","article-title":"Cellular mechanisms of brain energy metabolism. 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