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

DOI

10.1073/pnas.1705768114

Authors

• 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

Preprint

Link to Free Full Text

Repository Citation

Suofu, Y., Li, W., Jean-Alphonse, F. G., Jia, J., Khattar, N. K., Li, J., Baranov, S. V., Leronni, D., Mihalik, A. C., He, Y., Cecon, E., Wehbi, V. L., Kim, J., Heath, B. E., Baranova, O. V., Wang, X., Gable, M. J., Kretz, E. S., & Di Benedetto, G. (2017). Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proceedings of the National Academy of Sciences of the United States of America, 114 (38), E7997-E8006. https://doi.org/10.1073/pnas.1705768114