Abstract
Aurora kinase A/AURKA is a serine/threonine kinase frequently overexpressed in cancer. Recent discoveries pointed to subcellular pools of AURKA, including at mitochondria. There, AURKA induces organelle clearance by mitophagy together with the autophagy mediator LC3, and its receptor PHB2.
Here, we show that the natural product capsaicin modifies the AURKA/PHB2 interaction. We synthesize 16 capsaicin analogs, and Förster’s Resonance Energy Transfer/Fluorescence Lifetime Imaging Microscopy (FRET/FLIM) in breast cancer cells reveals that compounds 12 and 13 increase the AURKA/PHB2 interaction. Molecular docking shows that they bind to the inhibitory pocket of PHB2 and to the AURKA active site. We demonstrate that compound 13 specifically inhibits mitophagy while leaving AURKA activation unaltered at centrosomes. Our results demonstrate that compound 13 is a PHB ligand acting on the AURKA/PHB2 interaction. Thanks to its specificity, it may lead to the development of anticancer drugs targeting the mitochondrial functions of AURKA.
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Data availability
Source microscopy data are available on Zenodo52 (https://doi.org/10.5281/zenodo.17610406). All other data are available from the corresponding authors (L.D. and G.B.) upon request.
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Acknowledgements
We thank S. Dutertre, X. Pinson, and G. Le Marchand at the Microscopy Rennes Imaging Center (MRic, BIOSIT, Biogenouest) for assistance with FLIM experiments. MRic is a member of the national infrastructure France-BioImaging, supported by the French National Research Agency (ANR-24-INBS-0005 FBI BIOGEN). We thank the Plateforme de chimie biologique integrative (PCBIS, University of Strasbourg) for assistance with cell proliferation and viability experiments. We are grateful to N. Jolivet (IGDR, Rennes) for critical reading of the manuscript, to C. Bertin (IGDR, Rennes) for technical assistance, and to all lab members for helpful comments. This work was supported by the Centre National de la Recherche Scientifique (CNRS), the University of Rennes, the Ligue Contre le Cancer, Comités d’Ille et Vilaine et du Finistère to G.B. C.C was supported by a PhD fellowship from the Ligue Nationale Contre le Cancer (grant n. IP/SC – 17653) and by the Fondation ARC pour la Recherche sur le Cancer.
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CRediT taxonomy: conceptualization (L.D. and G.B.) data curation (A.D., C.C., D.G., V.P., K.F., A.F., L.D., and G.B.), Formal analysis (A.D., C.C., D.G, V.P., K.F., A.F., L.D., and G.B.), Funding acquisition (L.D. and G.B.), Investigation (A.D., C.C., D.G., V.P., K.F., A.F., L.D., and G.B.), Methodology (A.F., L.D., and G.B.), Project administration (L.D. and G.B.), Resources (L.D. and G.B.), Software (C.C., D.G., V.P., A.F., and G.B.), Supervision (A.F, L.D., and G.B.), Validation (L.D. and G.B.), Visualization (C.C., D.G., V.P., A.F., L.D., and G.B.), Writing–original, review and editing (C.C., D.G, A.F., L.D., and G.B.).
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Djehal, A., Caron, C., Giordano, D. et al. Development of capsaicin-derived prohibitin ligands to modulate the Aurora kinase A/PHB2 interaction and mitophagy in cancer cells. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09573-3
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DOI: https://doi.org/10.1038/s42003-026-09573-3
