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To investigate the potential of astrocytes to consume and metabolize L-proline, we incubated cultured primary rat astrocytes with L-proline in the absence or the presence of other energy substrates and investigated L-proline consumption, cellular ATP content and cell viability. In the absence of glucose, the cells consumed L-proline which allowed the cells to maintain a high cellular ATP level as long as extracellular L-proline was detectable. This L-proline consumption was saturable and followed apparent Michaelis-Menten kinetics with a calculated K\n                    <jats:sub>M<\/jats:sub>\n                    value of around 320 \u00b5M and a V\n                    <jats:sub>max<\/jats:sub>\n                    value of around 100 nmol\/(h x mg). In contrast to L-proline, D-proline was not consumed by the cells and was unable to prevent a cellular ATP loss in starved astrocytes. L-Proline consumption was lowered in a concentration-dependent manner by known inhibitors of proline dehydrogenase. The potential of 1 mM L-proline to maintain a high cellular ATP content in starved astrocytes and to prevent cell death was almost identical to that found for 1 mM glucose and a co-application of both substrates had additive ATP-maintaining effects. The presence of L-proline hardly affected the consumption of glucose, while glucose, glucose-derived lactate as well as other energy substrates severely slowed down the astrocytic L-proline consumption. In addition, application of L-proline prevented the rapid loss in cellular ATP level and the subsequent toxicity induced in glucose-deprived astrocytes in the presence of inhibitors of the mitochondrial uptake of pyruvate and fatty acids. These protective effects of proline were abolished by an inhibitor of proline dehydrogenase. The data presented demonstrate that L-proline is an excellent energy substrate for cultured astrocytes especially for conditions of limited availability of other energy substrates.\n                  <\/jats:p>","DOI":"10.1007\/s11064-025-04618-1","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T09:21:17Z","timestamp":1764148877000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Consumption of L-Proline as Energy Substrate by Cultured Primary Rat Astrocytes"],"prefix":"10.1007","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9082-1274","authenticated-orcid":false,"given":"Paul","family":"Spellerberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7869-1305","authenticated-orcid":false,"given":"Ralf","family":"Dringen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"4618_CR1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0053785","volume":"8","author":"AA Morgan","year":"2013","unstructured":"Morgan AA, Rubenstein E (2013) Proline: the distribution, frequency, positioning, and common functional roles of proline and polyproline sequences in the human proteome. 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