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

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 muscari...

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Published in:	PLoS biology Vol. 22; no. 4; p. e3002582
Main Authors:	Fasciani, Irene, Petragnano, Francesco, Wang, Ziming, Edwards, Ruairidh, Telugu, Narasimha, Pietrantoni, Ilaria, Zabel, Ulrike, Zauber, Henrik, Grieben, Marlies, Terzenidou, Maria E, Di Gregorio, Jacopo, Pellegrini, Cristina, Santini, Jr, Silvano, Taddei, Anna R, Pohl, Bärbel, Aringhieri, Stefano, Carli, Marco, Aloisi, Gabriella, Marampon, Francesco, Charlesworth, Eve, Roman, Alexandra, Diecke, Sebastian, Flati, Vincenzo, Giorgi, Franco, Amicarelli, Fernanda, Tobin, Andrew B, Scarselli, Marco, Tokatlidis, Kostas, Rossi, Mario, Lohse, Martin J, Annibale, Paolo, Maggio, Roberto
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 29-04-2024 Public Library of Science (PLoS)
Subjects:	Acetylcholine receptors (muscarinic) Animal models Animals Biology and Life Sciences C-Terminus Cell Proliferation Cell Respiration Cell surface receptors Cellular stress response CRISPR Environmental conditions G protein-coupled receptors HEK293 Cells Human influences Humans Hypotheses Induced Pluripotent Stem Cells - metabolism Internal ribosome entry site Membranes Methionine Mice Mitochondria Mitochondria - metabolism Muscarinic receptors Oxidative Phosphorylation Oxygen Oxygen Consumption Phosphorylation Physical Sciences Physiological aspects Plasma Pluripotency Polypeptides Proteins Reactive oxygen species Reactive Oxygen Species - metabolism Receptor, Muscarinic M2 - genetics Receptor, Muscarinic M2 - metabolism Receptors Research and Analysis Methods Respiration Stem cells Stress, Physiological Yeasts Germany
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Summary:	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.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1545-7885 1544-9173 1545-7885
DOI:	10.1371/journal.pbio.3002582