Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration
Résumé
The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly
recognized. Recently, the presence of Gi/o protein-coupled melatonin MT1 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 MT1 and MT2 but spontaneously
accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous
melatonin recruited b-arrestin 2 toMT1 in mitochondria and inhibited oxygen consumption inmitochondria
isolated from HEK293 cells only when expressing MT1 and from mouse cerebellum of WT mice but not
from MT1-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin
ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT1
receptors.
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