Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 PARIS, France; MCS, Laboratory of Medicinal Chemistry & Synthesis, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
INSERM, U1215 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France.
Cell Chem Biol. 2023 Aug 17;30(8):920-932.e7. doi: 10.1016/j.chembiol.2023.07.009.
The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of G protein-coupled melatonin MT receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearing a triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzyl group releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT and MT but spontaneously accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous melatonin recruited β-arrestin 2 to MT in mitochondria and inhibited oxygen consumption in mitochondria isolated from HEK293 cells only when expressing MT and from mouse cerebellum of WT mice but not from MT-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT receptors.
越来越多的研究表明，信号传导功能完备的 G 蛋白偶联受体存在于细胞内区室中。除了质膜，最近还发现 G 蛋白偶联褪黑素 MT 受体存在于线粒体中。褪黑素具有很高的细胞通透性，能够同等地激活质膜和线粒体受体。在这里，我们介绍了 MCS-1145，这是一种带有三苯基膦阳离子的褪黑素衍生物，用于特异性的线粒体靶向，以及一个光解的邻硝基苄基基团，在光照时释放褪黑素。MCS-1145 对 MT 和 MT 具有低亲和力，但会自发地积累在线粒体中，并且在那里它不易被冲洗掉。非笼状 MCS-1145 和外源性褪黑素将β-arrestin 2募集到线粒体中的 MT 上，并抑制从 HEK293 细胞分离的线粒体中的耗氧量，只有在表达 MT 且来自 WT 小鼠的小脑而不是 MT 敲除小鼠时才会抑制。总的来说，我们开发了第一个线粒体靶向光激活型褪黑素配体，并证明褪黑素通过线粒体 MT 受体抑制线粒体呼吸。
