The C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria and regulates cell respiration under stress conditions

Irene Fasciani, Francesco Petragnano, Ziming Wang, Ruairidh Edwards, Narasimha Telugu, Ilaria Pietrantoni, Ulrike Zabel, Henrik Zauber, Marlies Grieben, Maria E Terzenidou, Jacopo Di Gregorio, Cristina Pellegrini, Silvano Santini, Anna R Taddei, Bärbel Pohl, Stefano Aringhieri, Marco Carli, Gabriella Aloisi, Francesco Marampon, Eve CharlesworthAlexandra Roman, Sebastian Diecke, Vincenzo Flati, Franco Giorgi, Fernanda Amicarelli, Andrew B Tobin, Marco Scarselli, Kostas Tokatlidis, Mario Rossi, Martin J Lohse, Paolo Annibale, Roberto Maggio

Research output: Contribution to journalArticlepeer-review


Muscarinic acetylcholine receptors are prototypical G protein-coupled receptors (GPCRs), members of a large family of 7 transmembrane receptors mediating a wide variety of extracellular signals. We show here, in cultured cells and in a murine model, that the carboxyl terminal fragment of the muscarinic M2 receptor, comprising the transmembrane regions 6 and 7 (M2tail), is expressed by virtue of an internal ribosome entry site localized in the third intracellular loop. Single-cell imaging and import in isolated yeast mitochondria reveals that M2tail, whose expression is up-regulated in cells undergoing integrated stress response, does not follow the normal route to the plasma membrane, but is almost exclusively sorted to the mitochondria inner membrane: here, it controls oxygen consumption, cell proliferation, and the formation of reactive oxygen species (ROS) by reducing oxidative phosphorylation. Crispr/Cas9 editing of the key methionine where cap-independent translation begins in human-induced pluripotent stem cells (hiPSCs), reveals the physiological role of this process in influencing cell proliferation and oxygen consumption at the endogenous level. The expression of the C-terminal domain of a GPCR, capable of regulating mitochondrial function, constitutes a hitherto unknown mechanism notably unrelated to its canonical signaling function as a GPCR at the plasma membrane. This work thus highlights a potential novel mechanism that cells may use for controlling their metabolism under variable environmental conditions, notably as a negative regulator of cell respiration.

Original languageEnglish
Article numbere3002582
JournalPLoS Biology
Issue number4
Early online date29 Apr 2024
Publication statusE-pub ahead of print - 29 Apr 2024


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