1. The C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria and regulates cell respiration under stress conditions.
- Author
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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, and Charlesworth, Eve
- Subjects
CELL respiration ,MUSCARINIC receptors ,G protein coupled receptors ,MUSCARINIC acetylcholine receptors ,CELL membranes ,MITOCHONDRIA - 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 (M2 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 M2 tail, 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. The muscarinic M2 receptor is a prototypical G-protein-coupled receptor that mediates a wide range of extracellular signals. These authors show that the C-terminal fragment of M2 localizes to the mitochondrial inner membrane and is upregulated upon stress exposure, reducing cellular respiration and ROS to protect cells against variable environmental conditions. [ABSTRACT FROM AUTHOR]- Published
- 2024
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