Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis
Within the present study we proposed a novel approach for senolysis based on the simultaneous disturbance of the several homeostasis-maintaining systems in senescent cells including intracellular ionic balance, energy production and intracellular utilization of damaged products. Of note, we could no...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/22/14251 |
| _version_ | 1797465041748885504 |
|---|---|
| author | Pavel I. Deryabin Alla N. Shatrova Aleksandra V. Borodkina |
| author_facet | Pavel I. Deryabin Alla N. Shatrova Aleksandra V. Borodkina |
| author_sort | Pavel I. Deryabin |
| collection | DOAJ |
| description | Within the present study we proposed a novel approach for senolysis based on the simultaneous disturbance of the several homeostasis-maintaining systems in senescent cells including intracellular ionic balance, energy production and intracellular utilization of damaged products. Of note, we could not induce senolysis by applying ouabain, amiloride, valinomycin or NH<sub>4</sub>Cl—compounds that modify each of these systems solely. However, we found that ionophore nigericin can disturb plasma membrane potential, intracellular pH, mitochondrial membrane potential and autophagy at once. By affecting all of the tested homeostasis-maintaining systems, nigericin induced senolytic action towards stromal and epithelial senescent cells of different origins. Moreover, the senolytic effect of nigericin was independent of the senescence-inducing stimuli. We uncovered that K<sup>+</sup> efflux caused by nigericin initiated pyroptosis in senescent cells. According to our data, the higher sensitivity of senescent cells compared to the control ones towards nigericin-induced death was partially mediated by the lower intracellular K<sup>+</sup> content in senescent cells and by their predisposition towards pyroptosis. Finally, we proposed an interval dosing strategy to minimize the negative effects of nigericin on the control cells and to achieve maximal senolytic effect. Hence, our data suggest ionophore nigericin as a new senotherapeutic compound for testing against age-related diseases. |
| first_indexed | 2024-03-09T18:16:51Z |
| format | Article |
| id | doaj.art-99a74eaa20f54b49aaa52fec7fe7a429 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:16:51Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-99a74eaa20f54b49aaa52fec7fe7a4292023-11-24T08:41:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221425110.3390/ijms232214251Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for SenolysisPavel I. Deryabin0Alla N. Shatrova1Aleksandra V. Borodkina2Mechanisms of Cellular Senescence Group, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Avenue 4, 194064 Saint-Petersburg, RussiaLaboratory of Intracellular Membranes Dynamic, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Avenue 4, 194064 Saint-Petersburg, RussiaMechanisms of Cellular Senescence Group, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Avenue 4, 194064 Saint-Petersburg, RussiaWithin the present study we proposed a novel approach for senolysis based on the simultaneous disturbance of the several homeostasis-maintaining systems in senescent cells including intracellular ionic balance, energy production and intracellular utilization of damaged products. Of note, we could not induce senolysis by applying ouabain, amiloride, valinomycin or NH<sub>4</sub>Cl—compounds that modify each of these systems solely. However, we found that ionophore nigericin can disturb plasma membrane potential, intracellular pH, mitochondrial membrane potential and autophagy at once. By affecting all of the tested homeostasis-maintaining systems, nigericin induced senolytic action towards stromal and epithelial senescent cells of different origins. Moreover, the senolytic effect of nigericin was independent of the senescence-inducing stimuli. We uncovered that K<sup>+</sup> efflux caused by nigericin initiated pyroptosis in senescent cells. According to our data, the higher sensitivity of senescent cells compared to the control ones towards nigericin-induced death was partially mediated by the lower intracellular K<sup>+</sup> content in senescent cells and by their predisposition towards pyroptosis. Finally, we proposed an interval dosing strategy to minimize the negative effects of nigericin on the control cells and to achieve maximal senolytic effect. Hence, our data suggest ionophore nigericin as a new senotherapeutic compound for testing against age-related diseases.https://www.mdpi.com/1422-0067/23/22/14251senescencenigericinsenolysispyroptosisFOXO4-DRIdasatinib + quercetin |
| spellingShingle | Pavel I. Deryabin Alla N. Shatrova Aleksandra V. Borodkina Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis International Journal of Molecular Sciences senescence nigericin senolysis pyroptosis FOXO4-DRI dasatinib + quercetin |
| title | Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis |
| title_full | Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis |
| title_fullStr | Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis |
| title_full_unstemmed | Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis |
| title_short | Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis |
| title_sort | targeting multiple homeostasis maintaining systems by ionophore nigericin is a novel approach for senolysis |
| topic | senescence nigericin senolysis pyroptosis FOXO4-DRI dasatinib + quercetin |
| url | https://www.mdpi.com/1422-0067/23/22/14251 |
| work_keys_str_mv | AT pavelideryabin targetingmultiplehomeostasismaintainingsystemsbyionophorenigericinisanovelapproachforsenolysis AT allanshatrova targetingmultiplehomeostasismaintainingsystemsbyionophorenigericinisanovelapproachforsenolysis AT aleksandravborodkina targetingmultiplehomeostasismaintainingsystemsbyionophorenigericinisanovelapproachforsenolysis |