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.
Extracellular vesicles are involved in the occurrence, progression and metastasis of glioblastoma (GBM). GBM can secrete a variety of tumour-derived extracellular vesicles (TDEVs) with high immunosuppressive activity that remotely suppress the systemic immune system, and therapy targeting TDEVs has potential efficacy. In this study, we detected a higher concentration of CD73+ TDEVs enriched in exosomes in central and peripheral body fluids of GBM patients than in those of patients with other brain tumours (low-grade glioma or brain metastases from melanoma or non-small-cell lung cancer). High CD73 expression was detected on the surface of T cells, and this CD73 was derived from TDEVs secreted by GBM cells. In vitro, we observed that CD73+ TDEVs released by GBM cell lines could be taken up by T cells. Moreover, excess adenosine was produced by AMP degradation around T cells and by adenosine receptor 2A (A2AR)-dependent inhibition of aerobic glycolysis and energy-related metabolic substrate production, thereby inhibiting the cell cycle entry and clonal proliferation of T cells. In vivo, defects in exosomal synthesis and CD73 expression significantly inhibited tumour growth in GBM tumour-bearing mice and restored the clonal proliferation of T cells in the central and peripheral regions. These data indicate that CD73+ TDEVs can be used as a potential target for GBM immunotherapy.
Long noncoding RNAs (lncRNAs) have emerged as an important class of molecules that have been associated with brain function and neurological disease, but the expression profiles of lncRNAs after intracerebral hemorrhage (ICH) remain to be elucidated. In this study, we determined the expression pattern of nuclear factor-k-gene binding (NF-kB) interacting lncRNA (NKILA) after ICH and examined its respective effects on the endoplasmic reticulum stress (ERS)/autophagy pathway, hippocampal neuron loss, and the NF-kB pathway after type VII collagenase-induced ICH in rats. The regulatory mechanisms of NKILA were investigated by an intraperitoneal injection of small interfering (siRNA) against NKILA into rats after ICH. NKILA inhibition mediated by siRNA against NKILA was shown to significantly reduce ERS and autophagy, activate the NF-kB pathway, decrease neurological deficits, brain edema, and injury, and induce blood-brain barrier breakdown, further leading to hippocampal neuron loss and the production of inflammation cytokines. Taken together, the demonstration that NKILA induces the ERS/autophagy pathway and inhibits the NF-kB pathway after ICH supports the concept that NKILA functions as a novel target that is required for the attenuation of brain injuries after ICH.
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