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Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release
Ist Teil von
Proceedings of the National Academy of Sciences - PNAS, 2017-09, Vol.114 (38), p.E7997-E8006
Ort / Verlag
United States: National Academy of Sciences
Erscheinungsjahr
2017
Quelle
MEDLINE
Beschreibungen/Notizen
G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT₁), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT₁ signal-transduction pathway inhibiting stress-mediated cytochrome c release and caspase activation. These findings coupled with our observation that mitochondrial MT₁ overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, “automitocrine,” analogous to “autocrine” when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand–receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology.