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

Autor/innen

  • I. Fasciani
  • F. Petragnano
  • Z. Wang
  • R. Edwards
  • N. Telugu
  • I. Pietrantoni
  • U. Zabel
  • H. Zauber
  • M. Grieben
  • M.E. Terzenidou
  • J. Di Gregorio
  • C. Pellegrini
  • S. Santini
  • A.R. Taddei
  • B. Pohl
  • S. Aringhieri
  • M. Carli
  • G. Aloisi
  • F. Marampon
  • E. Charlesworth
  • A. Roman
  • S. Diecke
  • V. Flati
  • F. Giorgi
  • F. Amicarelli
  • A.B. Tobin
  • M. Scarselli
  • K. Tokatlidis
  • M. Rossi
  • M.J. Lohse
  • P. Annibale
  • R. Maggio

Journal

  • PLoS Biology

Quellenangabe

  • PLoS Biol 22 (4): e3002582

Zusammenfassung

  • 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.


DOI

doi:10.1371/journal.pbio.3002582