One gene - two proteins: the C-terminus of the prototypical M2 muscarinic receptor localizes to the mitochondria

Muscarinic acetylcholine receptors are G protein-coupled receptors (GPCRs) activated by the endogenous neurotransmitter acetylcholine. We show here that the carboxyl terminal fragment of the muscarinic M(2) receptor, containing the transmembrane regions 6 and 7 (M(2)tail), is expressed by virtue of an internal ribosome entry site. Radioligand binding, biochemical and molecular biology experiments, combined to advanced fluorescence microscopy reveal that the M(2)tail, whose expression is upregulated 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 via reduction of oxidative phosphorylation. Genetic editing of the key methionine where cap-independent translation occurs, reveals the physiological role of this process in influencing cell proliferation and oxygen consumption. The expression of the carboxyl-terminal of a GPCR, capable of regulating mitochondrial function, constitutes a hitherto unknown mechanism that cells may use for controlling their metabolism under variable environmental conditions, notably unrelated to the canonical signalling function of the GPCR at the plasma membrane