bims-mignad 2025-11-30 papers

Issue of 2025–11–30
two papers selected by
Melisa Emel Ermert, Amsterdam UMC

Neurochem Res. 2025 Nov 26. 51(1): 1

Consumption of L-Proline as Energy Substrate by Cultured Primary Rat Astrocytes.

The catabolism of the proteinogenic amino acid L-proline in mammalian cells is mediated by mitochondrial enzymes that can oxidize proline to provide energy for mitochondrial ATP regeneration. 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 KM value of around 320 µM and a Vmax 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.

Keywords: ATP; Astrocytes; Energy; Metabolism; Mitochondria; Proline

DOI: https://doi.org/10.1007/s11064-025-04618-1

bioRxiv. 2025 Oct 31. pii: 2025.10.30.685682. [Epub ahead of print]

Glycolytic ATP production enables rapid mammalian cell growth.

Matthew A Kukurugya, Shuying Zhang, Brandon T Ha, Alex E Ekvik, Denis V Titov.

Proliferating cells must produce ATP rapidly enough to meet the energy demands of growth and maintenance. While microbes show a linear coupling between ATP production rate and growth, whether this principle holds in mammalian cells has remained unclear and it has been suggested that most ATP is allocated to cell maintenance, regardless of growth rate. Here, we quantified lactate production, oxygen consumption, and proliferation across twelve mammalian cell lines and found a strong linear relationship between total ATP production and growth with the majority of ATP allocated to macromolecular synthesis. By inhibiting glycolysis, inhibiting respiration, or reducing translation, cells shift along this ATP-growth line in predictable directions, indicating bidirectional coupling between ATP supply and demand. A genetically encoded ATP hydrolysis sink increased ATP turnover yet slowed proliferation, demonstrating that ATP production capacity can limit growth. Together, these results show that respiration alone cannot generate enough ATP to support the growth rates of rapidly dividing cells, whereas glycolysis can. Our results provide a quantitative rationale for the Warburg Effect, where cells rely on glycolysis to achieve doubling times faster than 30 hours. Our results establish ATP production rate as a quantitative constraint on growth across species.

DOI: https://doi.org/10.1101/2025.10.30.685682