The N8-Iper agonist of the human muscarinic receptor M2 induces mitochondrial dysfunction in S. cerevisiae

Glioblastoma is a malignant human brain tumor of the astrocytic type. The activation of M2 muscarinic receptor (a G protein-coupled receptor, GPCR) by orthosteric agonist Arecaidine Propargyl Ester (APE) and dualsteric agonist N-8-Iper (N8) caused a significant decrease of cell proliferation and survival in Glioblastoma cancer stem cells and in Glioblastoma stable cell lines. Preliminary data showed the two agonists exerted a mitochondrial damage and an alteration of the lipid pattern in Glioblastoma cells. GPCRs are conserved in evolution from yeast to humans and the yeast system is considered a platform for human GPCR studies. To evaluate if the mitochondrial dysfunction is directly linked to the activation of the M2 muscarinic receptor, we tested the M2 agonists in yeast cells, elucidating the effects on mitochondria in a yeast model system. N8, but not APE, induces a mitochondrial dysfunction in yeast cells in a time and concentration-dependent manner. These results mimic the activity on glioblastoma cell cultures, suggesting a direct effect of the N8 agonist on mitochondrial function.