Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release
Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release
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DOI：
10.1073/pnas.1705768114
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发表时间：
2017-09-19
影响因子：
11.1
通讯作者：
Friedlander, Robert M.
中科院分区：
文献类型：
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作者：
Suofu, Yalikun;Li, Wei;Friedlander, Robert M.
G蛋白偶联受体（GPCR）是一种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，一个GPCR信号系统的褪黑激素1型受体（MT 1），其相关的G蛋白，β-arrestins组成的中央组件和神经元线粒体内。我们发现，配体褪黑激素是专门在线粒体基质中合成和释放的细胞器激活线粒体MT 1信号转导途径抑制应激介导的细胞色素c释放和caspase激活。这些发现加上我们的观察，线粒体MT 1过表达减少小鼠缺血性脑损伤描绘了线粒体GPCR机制，有助于褪黑激素的神经保护作用。我们提出了一个新的术语，“automitocrine”，类似于“自分泌”，当一个类似的现象发生在细胞水平上，描述这种意想不到的细胞内细胞器配体受体途径，打开了一个新的研究途径调查线粒体GPCR生物学。
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 beta-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.