Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence

Cell Death Discov. 2026 Feb 19. doi: 10.1038/s41420-026-02967-6. Online ahead of print.

ABSTRACT

Mitochondria integrate senescence and apoptotic fates, yet it is unclear whether their ability to oxidize different fuels for energy production influences their vulnerability to senolytics in therapy-induced senescence (TIS). Using MitoPlates™ technology, we functionally mapped the mitophenotypes of TIS cancer cells by quantifying electron transport chain (ETC) flux from various NADH/FADH2 substrates. We then related these profiles to the responsiveness of TIS cancer cells to BCL-xL-targeting BH3 senolytics, as well as to inflammatory SASP signaling sensed by an NF-κB/miR-146a reporter. Mechanistically distinct senogenic stressors produced markedly different bioenergetic outputs and substrate diversity, establishing mitochondria as an emergent, stress-encoded property of TIS phenomena. Increased mitochondrial bioenergetic flexibility corresponded with senolytic permissiveness within each cell lineage. However, the magnitude of the senolytic response was largely limited by the pre-senescent bioenergetic configuration of the parental mitochondria, and baseline succinate oxidation served as a functional indicator of this inherited threshold. TIS SASPs were restricted by the secretome of the cell-of-origin, but only the miR146a-positive, fatty acid β-oxidation-related inflammatory SASP states were senolytically responsive. Inflachromene, an inhibitor of the chromatin remodelers HMGB1/2, decoupled mitochondrial bioenergetics from senolytic susceptibility, yielding SASP-null/miR146a-negative senescent cancer cells that were completely resistant to ABT-263/navitoclax and A1331852 despite extensive mitochondrial reprogramming. Thus, the senolytic response is governed by a layered circuit in which mitochondrial bioenergetic heritage establishes the senolytic ceiling, TIS-acquired bioenergetic flexibility fine-tunes the amplitude of the senolytic response, and establishing a mitochondria-inflammatory SASP crosstalk is required for BH3-mediated senolysis. These results support using functional readouts that integrate mitochondrial metabolic flexibility and inflammatory SASP to predict and potentially enhance senolytic efficacy in TIS cancer cells.

PMID:41714592 | DOI:10.1038/s41420-026-02967-6