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Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis
Pavel I Deryabin1, Alla N Shatrova2, Aleksandra V Borodkina1
1Mechanisms of Cellular Senescence Group, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Avenue 4, 194064 Saint-Petersburg, Russia.
Abstract:
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 NH4Cl-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+ 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+ 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.
Insights
This study introduces nigericin, an ionophore, as a novel senolytic compound. Nigericin effectively eliminates senescent cells by disrupting multiple cellular systems and inducing pyroptosis, offering a promising approach for age-related diseases.
Area of Science:
- Cell Biology
- Gerontology
- Pharmacology
Background:
- Senescent cells accumulate with age and contribute to age-related diseases.
- Targeting senescent cells (senolysis) is a therapeutic strategy to combat aging.
- Current senolytic approaches often target single pathways, with limited efficacy.
Purpose of the Study:
- To identify novel senolytic compounds targeting multiple homeostasis systems in senescent cells.
- To investigate the senolytic potential of the ionophore nigericin.
- To elucidate the mechanism of nigericin-induced senolysis.
Main Methods:
- Senescent cell models (stromal and epithelial) were established.
- Compounds targeting individual homeostasis systems were tested for senolysis.
- The effect of nigericin on cellular homeostasis (ionic balance, pH, mitochondrial potential, autophagy) was assessed.
- Nigericin-induced cell death pathways (pyroptosis) were analyzed.
- Senescent and control cells were compared for sensitivity to nigericin.
Main Results:
- Single-target compounds failed to induce senolysis.
- Nigericin simultaneously disrupted plasma membrane potential, intracellular pH, mitochondrial membrane potential, and autophagy.
- Nigericin demonstrated senolytic activity across various senescent cell types, independent of senescence induction.
- Nigericin-induced K+ efflux triggered pyroptosis in senescent cells.
- Senescent cells exhibited higher sensitivity to nigericin due to lower intracellular K+ and pyroptosis predisposition.
- An interval dosing strategy was proposed to optimize nigericin's senolytic effect and minimize toxicity.
Conclusions:
- Nigericin is a potent senolytic agent effective against diverse senescent cells.
- The mechanism involves simultaneous disruption of homeostasis and induction of pyroptosis.
- Nigericin shows promise as a senotherapeutic for age-related diseases.
- Optimized dosing strategies are crucial for clinical translation.
