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Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E7997-E8006. doi: 10.1073/pnas.1705768114. Epub 2017 Sep 5.

Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release.

Author information

1
Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
2
School of Medicine, University of Tsinghua, Beijing, China 100084.
3
Laboratory for G-Protein Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
4
Xiangya Second Hospital, Central South University, Hunan Province, China 410008.
5
Inserm, U1016, Institut Cochin, 75014 Paris, France.
6
CNRS UMR 8104, Paris, France.
7
University of Paris Descartes, 75006 Paris, France.
8
Neuroscience Institute, Italian National Research Council, 35121 Padova, Italy.
9
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261.
10
Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261.
11
Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213.
12
Small Molecule Biomarker Core, University of Pittsburgh, Pittsburgh, PA 15213.
13
Institut de Chimie Organique et Analytique, Universite d'Orleans, UMR CNRS 7311, 45067 Orleans, France.
14
Brain Modulation Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
15
Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282.
16
Laboratory for G-Protein Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261; friedlanderr@upmc.edu jpv@pitt.edu.
17
Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213; friedlanderr@upmc.edu jpv@pitt.edu.

Abstract

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.

KEYWORDS:

G protein-coupled receptor; ischemia; melatonin; mitochondria; neuroprotection

PMID:
28874589
PMCID:
PMC5617277
DOI:
10.1073/pnas.1705768114
[Indexed for MEDLINE]
Free PMC Article

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