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Fluorizoline-induced apoptosis requires prohibitins in nematodes and human cells

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Abstract

We previously showed that fluorizoline, a fluorinated thiazoline compound, binds to both subunits of the mitochondrial prohibitin (PHB) complex, PHB1 and PHB2, being the expression of these proteins required for fluorizoline-induced apoptosis in mouse embryonic fibroblasts. To investigate the conservation of this apoptotic mechanism, we studied the effect of PHB downregulation on fluorizoline activity on two human cell lines, HEK293T and U2OS. Then, we asked whether PHBs mediate the effect of fluorizoline in a multicellular organism. Interestingly, reduced levels of PHBs in the human cells impaired the induction of apoptosis by fluorizoline. We observed that fluorizoline has a detrimental dose-dependent effect on the development and survival of the nematode model Caenorhabditis elegans. Besides, such effects of fluorizoline treatment in living nematodes were absent in PHB mutants. Finally, we further explored the apoptotic pathway triggered by fluorizoline in human cell lines. We found that the BH3-only proteins NOXA, BIM and PUMA participate in fluorizoline-induced apoptosis and that the induction of NOXA and PUMA is dependent on PHB expression.

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Acknowledgements

We thank the CERCA Program/Generalitat de Catalunya for their institutional support. We also thank the Scientific and Technological Centers of Bellvitge Campus at the University of Barcelona.

Funding

This work was supported by grants from the Agencia Estatal de Investigación (Ministerio de Ciencia e Innovación), European Regional Development Fund (ERDF), the European Research Council, the Junta de Andalucía and the Instituto de Salud Carlos III (ISCIII) (SAF2017-83178-R to J.G.; PID2019-107991RB-I00 to R.L.; ERC-2011-StG-281691 and C2A ID: 42571/Exp: 70806 to M.A-S; PI15-00895 to J.C.). J.S-E and I.S-V are recipients of research fellowships from the Ministerio de Ciencia e Innovación. S.N-V is recipient of a research fellowship from Universitat de Barcelona. MD.M-B was supported by the Plan de Empleo Juvenil (EJP09) from the Junta de Anadalucía. D.K has a FI AGAUR fellowship from Generalitat de Catalunya.

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Authors and Affiliations

  1. Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona-IDIBELL (Institut d’Investigació Biomèdica de Bellvitge), L’Hospitalet de Llobregat, Barcelona, Spain

    José Saura-Esteller, Ismael Sánchez-Vera, Sonia Núñez-Vázquez, Judith Jabalquinto-Carrasco, Ana M. Cosialls, Gabriel Pons, Daniel Iglesias-Serret & Joan Gil

  2. Laboratory of Medical Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Medicine (IBUB), University of Barcelona, Barcelona, Spain

    Lorena Mendive-Tapia & Rodolfo Lavilla

  3. Modeling Human Diseases in C. Elegans Group. Genes, Disease and Therapy Program, IDIBELL (Institut d’Investigació Biomèdica de Bellvitge), L’Hospitalet de Llobregat, Barcelona, Spain

    Dmytro Kukhtar & Julián Cerón

  4. Andalusian Center for Developmental Biology, Consejo Superior de Investigaciones Científicas/Junta de Andalucía, Universidad Pablo de Olavide, Seville, Spain

    Manuel D. Martínez-Bueno & Marta Artal-Sanz

  5. Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain

    Manuel D. Martínez-Bueno & Marta Artal-Sanz

  6. Facultat de Medicina, Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Vic, Barcelona, Spain

    Daniel Iglesias-Serret

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  1. José Saura-Esteller
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Contributions

Conceptualization, JS-E, JC, MA-S, GP, DI-S and JG; Funding acquisition, RL, JC, MA-S and JG; Investigation, JS-E, JJ-C, DK, MDM-B and GP; Resources, LM-T and RL; Supervision, JG; Writing—original draft, JS-E, JC, MA-S, DI-S and JG; Writing—review & editing, IS-V, SN-V, JJ-C, AMC, LM-T, DK, MDM-B, RL and GP.

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Correspondence to Joan Gil.

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Daniel Iglesias-Serret and Joan Gil shares senior co-authorship.

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Saura-Esteller, J., Sánchez-Vera, I., Núñez-Vázquez, S. et al. Fluorizoline-induced apoptosis requires prohibitins in nematodes and human cells. Apoptosis 26, 83–95 (2021). https://doi.org/10.1007/s10495-020-01651-z

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