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

Autor: 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 Charlesworth, Alexandra 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
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: PLoS Biology, Vol 22, Iss 4, p e3002582 (2024)
Druh dokumentu: article
ISSN: 1544-9173
1545-7885
DOI: 10.1371/journal.pbio.3002582
Popis: 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.
Databáze: Directory of Open Access Journals
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