Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 38, Pages E7997-E8006Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705768114
Keywords
mitochondria; G protein-coupled receptor; melatonin; ischemia; neuroprotection
Categories
Funding
- NIH [R01NS039324, R01NS077748, R01 DK087688, R01 DK102495]
- David Scaife Family Charitable Foundation
- Cotswold Foundation Fellowship Award
- Agence Nationale de la Recherche (ANR) [ANR-12-RPIB-0016 MED-HET-REC-2]
- Fondation de la Recherche Medicale Equipe [FRM DEQ20130326503]
- INSERM
- CNRS
- ANR Who am I? Laboratory of Excellence Grant [ANR-11-LABX-0071]
- ANR [ANR-11-IDEX-0005-01]
- La Region Centre [APR2009-LOIREMEL, APR2012-LIFERMEL]
- Labex SynOrg [ANR-11-LABX-0029]
- Marie-Clement Rodier CSSp Endowed Chair Funds (PAW-E)
- University of Pittsburgh Center for Biologic Imaging NIH [1S10RR019003, 1S10RR025488]
- Agence Nationale de la Recherche (ANR) [ANR-11-LABX-0071] Funding Source: Agence Nationale de la Recherche (ANR)
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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 beta-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.
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