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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 38; pp. E7997 - E8006
• Main Authors: Suofu, Yalikun, Li, Wei, Jean-Alphonse, Frédéric G., Jia, Jiaoying, Khattar, Nicolas K., Li, Jiatong, Baranov, Sergei V., Leronni, Daniela, Mihalik, Amanda C., He, Yanqing, Cecon, Erika, Wehbi, Vanessa L., Kim, JinHo, Heath, Brianna E., Baranova, Oxana V., Wang, Xiaomin, Gable, Matthew J., Kretz, Eric S., Di Benedetto, Giulietta, Lezon, Timothy R., Ferrando, Lisa M., Larkin, Timothy M., Sullivan, Mara, Yablonska, Svitlana, Wang, Jingjing, Minnigh, M. Beth, Guillaumet, Gérald, Suzenet, Franck, Richardson, R. Mark, Poloyac, Samuel M., Stolz, Donna B., Jockers, Ralf, Witt-Enderby, Paula A., Carlisle, Diane L., Vilardaga, Jean-Pierre, Friedlander, Robert M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.09.2017
• Series: PNAS Plus
• Subjects: Animals; Autocrine signalling; Biochemistry, Molecular Biology; Biological Sciences; Brain; Brain Injuries - genetics; Brain Injuries - metabolism; Brain injury; Brain Ischemia - genetics; Brain Ischemia - metabolism; Caspase; Cell Behavior; Cell surface; Cellular Biology; Cytochrome; Cytochrome c; Cytochromes c - genetics; Cytochromes c - metabolism; G protein-coupled receptors; Head injuries; Injury prevention; Ischemia; Life Sciences; Male; Melatonin; Melatonin - biosynthesis; Melatonin - genetics; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Molecular biology; Molecular Networks; Neuroprotection; Pharmaceutical sciences; Pharmacology; PNAS Plus; Receptor, Melatonin, MT1 - genetics; Receptor, Melatonin, MT1 - metabolism; Receptors; Reproductive Biology; Sexual reproduction; Signal Transduction; Studies; G protein-coupled receptor; melatonin; mitochondria; neuroprotection; ischemia
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1705768114

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.