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

DOI

10.1073/pnas.1705768114

Yalikun Suofu, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Wei Li, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Frédéric G. Jean-Alphonse, Laboratory for G-Protein Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
Jiaoying Jia, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Nicolas K. Khattar, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Jiatong Li, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Sergei V. Baranov, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Daniela Leronni, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Amanda C. Mihalik, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Yanqing He, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Erika Cecon, Inserm, U1016, Institut Cochin, 75014 Paris, France.
Vanessa L. Wehbi, Laboratory for G-Protein Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261.
JinHo Kim, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Brianna E. Heath, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Oxana V. Baranova, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Xiaomin Wang, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Matthew J. Gable, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Eric S. Kretz, Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
Giulietta Di Benedetto, Neuroscience Institute, Italian National Research Council, 35121 Padova, Italy.

Document Type

Journal Article

Publication Date

9-19-2017

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

114

Issue

38

First Page

E7997

Last Page

E8006

Keywords

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

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 (MT), 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 MT signal-transduction pathway inhibiting stress-mediated cytochrome release and caspase activation. These findings coupled with our observation that mitochondrial MT 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.

Open Access

OA

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