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The C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria and regulates cell respiration under stress conditions
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dc.contributor.author | Fasciani, Irene | |
dc.contributor.author | Petragnano, Francesco | |
dc.contributor.author | Wang, Ziming | |
dc.contributor.author | Edwards, Ruairidh | |
dc.contributor.author | Telugu, Narasimha | |
dc.contributor.author | Pietrantoni, Ilaria | |
dc.contributor.author | Zabel, Ulrike | |
dc.contributor.author | Zauber, Henrik | |
dc.contributor.author | Grieben, Marlies | |
dc.contributor.author | Terzenidou, Maria E | |
dc.contributor.author | Di Gregorio, Jacopo | |
dc.contributor.author | Pellegrini, Cristina | |
dc.contributor.author | Santini, Silvano | |
dc.contributor.author | Taddei, Anna R | |
dc.contributor.author | Pohl, Bärbel | |
dc.contributor.author | Aringhieri, Stefano | |
dc.contributor.author | Carli, Marco | |
dc.contributor.author | Aloisi, Gabriella | |
dc.contributor.author | Marampon, Francesco | |
dc.contributor.author | Charlesworth, Eve | |
dc.contributor.author | Roman, Alexandra | |
dc.contributor.author | Diecke, Sebastian | |
dc.contributor.author | Flati, Vincenzo | |
dc.contributor.author | Giorgi, Franco | |
dc.contributor.author | Amicarelli, Fernanda | |
dc.contributor.author | Tobin, Andrew B | |
dc.contributor.author | Scarselli, Marco | |
dc.contributor.author | Tokatlidis, Kostas | |
dc.contributor.author | Rossi, Mario | |
dc.contributor.author | Lohse, Martin J | |
dc.contributor.author | Annibale, Paolo | |
dc.contributor.author | Maggio, Roberto | |
dc.date.accessioned | 2024-05-23T09:30:05Z | |
dc.date.available | 2024-05-23T09:30:05Z | |
dc.date.issued | 2024-04-29 | |
dc.identifier | 301724374 | |
dc.identifier | b59c9ebb-40e3-4632-8d7c-8fc0e1dbea82 | |
dc.identifier | 38683874 | |
dc.identifier | 85191871863 | |
dc.identifier.citation | Fasciani , I , Petragnano , F , Wang , Z , Edwards , R , Telugu , N , Pietrantoni , I , Zabel , U , Zauber , H , Grieben , M , Terzenidou , M E , Di Gregorio , J , Pellegrini , C , Santini , S , Taddei , A R , Pohl , B , Aringhieri , S , Carli , M , Aloisi , G , Marampon , F , Charlesworth , E , Roman , A , Diecke , S , Flati , V , Giorgi , F , Amicarelli , F , Tobin , A B , Scarselli , M , Tokatlidis , K , Rossi , M , Lohse , M J , Annibale , P & Maggio , R 2024 , ' The C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria and regulates cell respiration under stress conditions ' , PLoS Biology , vol. 22 , no. 4 , e3002582 . https://doi.org/10.1371/journal.pbio.3002582 | en |
dc.identifier.issn | 1544-9173 | |
dc.identifier.other | ORCID: /0000-0003-3208-5347/work/159010708 | |
dc.identifier.uri | https://hdl.handle.net/10023/29922 | |
dc.description | Funding: This study was further supported by European Union’s Horizon2020 Marie Skłodowska-Curie Actions (MSCA) Program under Grant Agreements 641833 and 860229 (ONCORNET and ONCORNET2.0 to MJL (https://oncornet.eu). PA would like to gratefully acknowledge support from the Leverhulme Trust (RL-2022-015) (www.leverhulme.ac.uk). Work in the KT lab was supported by grants UK Research and Innovation-Biotechnology and Biological Sciences Research Council (UKRI-BBSRC) BB/T003804/1, BB/R009031/1, BB/X511948/1 and UKRI-Medical Research Council (UKRI-MRC) MC_PC_19039 (https://www.ukri.org). | en |
dc.description.abstract | 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. | |
dc.format.extent | 36 | |
dc.format.extent | 4617219 | |
dc.language.iso | eng | |
dc.relation.ispartof | PLoS Biology | en |
dc.subject | QH301 Biology | en |
dc.subject | DAS | en |
dc.subject.lcc | QH301 | en |
dc.title | The C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria and regulates cell respiration under stress conditions | en |
dc.type | Journal article | en |
dc.contributor.sponsor | The Leverhulme Trust | en |
dc.contributor.institution | University of St Andrews. School of Physics and Astronomy | en |
dc.identifier.doi | 10.1371/journal.pbio.3002582 | |
dc.description.status | Peer reviewed | en |
dc.identifier.grantnumber | RL-2022-015 | en |
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