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