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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries / genetics
  • Brain Injuries / metabolism*
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism*
  • Cytochromes c / genetics
  • Cytochromes c / metabolism
  • Male
  • Melatonin / biosynthesis*
  • Melatonin / genetics
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Receptor, Melatonin, MT1 / genetics
  • Receptor, Melatonin, MT1 / metabolism*
  • Signal Transduction*


  • Receptor, Melatonin, MT1
  • Cytochromes c
  • Melatonin