Cells Dying via the AP-3 Complex-Dependent Regulated Death Pathway Support the Surviving Cells under Amino Acid Deficiency Conditions

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Svyatoslav S. Sokolov^1,a*, Ekaterina A. Smirnova¹, Natalia A. Kireeva¹, Alexandr L. Ksenofontov¹, Vadim N. Tashlitsky¹, and Fedor F. Severin¹

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

^* To whom correspondence should be addressed.

Received: December 3, 2024; Revised: July 6, 2025; Accepted: July 6, 2025

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Starvation can initiate a programmed death in unicellular organisms. It is believed that cells committing suicide via this mechanism support surviving cells with their nutrients. It was recently discovered that heating Saccharomyces cerevisiae yeast cells to 51°C kills the cells though a special pathway that starts with the decomposition of the lysosomal membrane followed by the loss of the plasma membrane integrity a few hours later. Since lysosomes contain hydrolases of nitrogen-containing biopolymers, this programmed death pathway could help the survivors during nitrogen starvation. The loss of the plasma membrane integrity significantly alters the water/salt composition of the cytosol, which in turn can lead to the aggregation of nitrogen-containing macromolecules (proteins and nucleic acids). The pores of the yeast cell wall are too small to let such aggregates through. We showed that cells killed by heating at 52°C stimulated the growth of living cells under conditions of amino acid deficiency, while mutant cells deficient by the AP-3 complex, which were unable to destroy the lysosomal membrane, lacked this ability. Yeast cells killed by boiling also did not support the growth of surviving cells under amino acid deficiency conditions. Unexpectedly, the medium from the cells killed by boiling contained, on average, higher amounts of each amino acid than the medium from the cells killed by heating to 52°C. At the same time, according spectrophotometry and mass spectrometry analysis, the medium obtained by cell heating to 52°C contained higher amount of substances absorbing in a short-wavelength range. We speculate that the compounds supporting the growth of surviving cells under the nitrogen deficiency conditions are generated by hydrolysis of nucleic acids.

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KEY WORDS: AP-3 complex, nitrogen starvation, programmed cell death, vacuole, yeast

DOI: 10.1134/S0006297924604386

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