The dual-site agonist for human M2 muscarinic receptors Iper-8-naphtalimide induces mitochondrial dysfunction in Saccharomyces cerevisiae

Authors:

Angela Cirigliano1,a, Antonia Amelina2,a, Elena Passarini2, Alessandra Ricelli1, Nicole Balasco1, Mattia Mori3, Bruno Botta4, Maria Egle De Stefano2,5, Claudio Papotto6, Claudia Guerriero2, Ada Maria Tata2,5 and Teresa Rinaldi2,*

doi: 10.15698/mic2025.12.862
Volume 12, pp. 290 to 298, published 12/12/2025.

PDF Download PubMed Link Supplemental Information
Affiliations:

1 Institute of Molecular Biology and Pathology, CNR c/o Department of Chemistry, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy. 2 Department of Biology and Biotechnologies, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy. 3 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy. 4 Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy. 5 Research Centre of Neurobiology “Daniel Bovet”, Sapienza University of Rome, 00185 Rome, Italy. 6 Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy.

Keywords: 

Glioblastoma, M2 muscarinic receptor, orthosteric agonist, dualsteric agonist, ergosterol, mitochondrial DNA, modeling in S. cerevisiae.

Corresponding Author(s):

Teresa Rinaldi, Piazzale A. Moro 5, 00185 Rome, Italy; teresa.rinaldi@uniroma1.it

Conflict of interest statement:

The authors declare no conflicts of interest.

Please cite this article as:

Angela Cirigliano, Antonia Amelina, Elena Passarini, Alessandra Ricelli, Nicole Balasco, Mattia Mori, Bruno Botta, Maria Egle De Stefano, Claudio Papotto, Claudia Guerriero, Ada Maria Tata, Teresa Rinaldi (2025). The dual-site agonist for human M2 muscarinic receptors Iper-8-naphtalimide induces mitochondrial dysfunction in Saccharomyces cerevisiae. Microbial cell 12: 290–298. doi: 10.15698/mic2025.12.862

© 2025 Cirigliano et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

Glioblastoma is a malignant astrocytic tumor of the brain. A significantly decrease of glioblastoma cell proliferation and survival can be achieved by activating the M2 muscarinic acetylcholine receptor (a G protein-coupled receptor, or GPCR) with two agonist molecules, the orthosteric agonist Arecaidine Propargyl Ester (APE) and the dualsteric agonist Iper-8-naphthalimide (N-8-Iper). In glioblastoma cells, these agonists caused mitochondrial damage and an altered lipid profile. To characterize the mitochondrial dysfunction induced by the muscarinic agonists, we tested APE and N-8-Iper in S. cerevisiae, a yeast model system specifically suitable to study the activity of molecules of pharmaceutical interest on mitochondria. N-8-Iper, but not APE, induced mitochondrial dysfunction in S. cerevisiae cells in a time- and concentration-dependent manner. These results suggest that the agonist N-8-Iper on glioblastoma cell cultures has a direct effect on mitochondrial function. Moreover, since
GPCRs are evolutionarily conserved from yeast to humans, these results confirm that the yeast system is a suitable model for studying human GPCRs.