Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
School of Medicine, University of Tsinghua, Beijing, China 100084.
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 (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.
G 蛋白偶联受体（GPCRs）通常被描述为将细胞外信号传递到细胞内的细胞表面受体。在这里，我们表明由褪黑素 1 型受体（MT）、其相关 G 蛋白和β-arrestin 组成的 GPCR 信号转导系统的核心组件位于神经元线粒体上和内部。我们发现配体褪黑素仅在线粒体基质中合成，并通过细胞器释放，激活线粒体 MT 信号转导通路，抑制应激介导的细胞色素 c 释放和半胱天冬酶激活。这些发现以及我们观察到线粒体 MT 的过表达可减少小鼠的缺血性脑损伤，描绘了一种线粒体 GPCR 机制，有助于褪黑素的神经保护作用。我们提出了一个新术语，“自动分泌”，类似于当类似现象发生在细胞水平时的“自分泌”，来描述这种出乎意料的细胞内细胞器配体-受体途径，为研究线粒体 GPCR 生物学开辟了新的研究途径。
