Melatonin, the hormone of darkness, is produced in the pineal gland in a circadian manner with peak levels during the night and regulates circadian rhythms, sleep, glucose homeostasis and immune functions. Melatonin, acts primarily on MT1 and MT2 receptors, which are members of the G protein-coupled receptor (GPCR) super-family. Along with the great majority of GPCRs, melatonin receptors are well-known cell-surface receptors that transmit extracellular signals into cells through second messengers and further activation of specific signaling pathways. Increasing evidence supports the ability of GPCRs to promote also signaling from receptors located at intracellular compartments as diverse as endosomes, the Golgi, the nuclear membrane and mitochondria, as shown here.
The team of Ralf Jockers and his co-workers, in collaboration with the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), (Barcelona, Spain) and Inserm U1215 (NeuroCentre Magendie, Bordeaux, France) developed an innovative light-controllable melatonin derivative, MCS-1145, that selectively accumulates in mitochondria and allows spatially restricted release of biologically active melatonin upon light activation. MCS-1145 and melatonin inhibit mitochondrial respiration (i.e. oxygen-consumption rate) by direct activation of MT1 receptors located in mitochondria. In addition, we show for the first time that melatonin induces the recruitment of β-arrestin2, a general signal transducer of GPCRs, in the inner mitochondrial space to MT1 located in the outer mitochondrial membrane as revealed by a new split-NanoBiT BRET assay. Collectively, these data support the functional expression of GPCRs in mitochondria.
Our study expands our understanding of the specific role of intracellular GPCRs and in particular in mitochondria and on mitochondrial respiration. MCS-1145 will allow future investigation on the role of mitochondrial melatonin receptors, and their potential as therapeutic target, in sleep disorders, circadian rhythm dysfunctions and type 2 diabetes.
The subcellular targeting strategy of melatonin is expected to be readily transposable to other ligands acting on GPCR suspected to be located in subcellular compartments.
The mitochondrial split-NanoBiT BRET assay is expected to be of general interest for the GPCR community.
This work was funded by the Fondation pour la Recherche Médicale, Agence Nationale de la Recherche, the National Institute of Health and Medical Research (Inserm), National Center for Scientific Research (CNRS), Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación, ERDF-FEDER European and the Catalan government.
Somalo-Barranco G, Pagano Zottola AC, Abdulrahman AO, El Zein RM, Cannich A, Muñoz L, Serra C, Oishi A, Marsicano G, Masri B, Bellocchio L, Llebaria, Jockers R. Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration. Cell Chemical Biology 30, 1-13, August 17, 2023. http://doi.org/10.1016/j.chembiol.2023.07.009