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| Item Type: | Article |
|---|---|
| Title: | The C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria and regulates cell respiration under stress conditions |
| Creators: |
Fasciani, I., Petragnano, F., Wang, Z.  ORCID: https://orcid.org/0009-0000-0062-7119, Edwards, R., Telugu, N. ORCID: https://orcid.org/0000-0003-4509-7056, Pietrantoni, I., Zabel, U., Zauber, H. ORCID: https://orcid.org/0000-0003-2595-1147, 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. ORCID: https://orcid.org/0000-0001-9440-9752, Diecke, S. ORCID: https://orcid.org/0000-0002-5219-5992, Flati, V., Giorgi, F., Amicarelli, F., Tobin, A.B., Scarselli, M., Tokatlidis, K., Rossi, M., Lohse, M.J. ORCID: https://orcid.org/0000-0002-0599-3510, Annibale, P. ORCID: https://orcid.org/0000-0003-3208-5347 and Maggio, R. ORCID: https://orcid.org/0000-0003-4436-2356
|
| 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 M(2) receptor, comprising the transmembrane regions 6 and 7 (M(2)tail), 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. |
| Keywords: | Cell Proliferation, Cell Respiration, HEK293 Cells, Induced Pluripotent Stem Cells, Mitochondria, Muscarinic M2 Receptor, Oxidative Phosphorylation, Oxygen Consumption, Physiological Stress, Reactive Oxygen Species, Animals, Mice |
| Source: | PLoS Biology |
| ISSN: | 1544-9173 |
| Publisher: | Public Library of Science |
| Volume: | 22 |
| Number: | 4 |
| Page Range: | e3002582 |
| Date: | 29 April 2024 |
| Official Publication: | https://doi.org/10.1371/journal.pbio.3002582 |
| PubMed: | View item in PubMed |
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