Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration

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Somalo-Barranco, Gloria | Pagano Zottola, Antonio | Abdulrahman, Abdulrasheed | El Zein, Rami | Cannich, Astrid | Muñoz, Lourdes | Serra, Carme | Oishi, Atsuro | Marsicano, Giovanni | Masri, Bernard | Bellocchio, Luigi | Llebaria, Amadeu | Jockers, Ralf

Edité par CCSD ; Cell Press -

International audience. The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasinglyrecognized. Recently, the presence of Gi/o protein-coupled melatonin MT1 receptors in mitochondriahas been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasmamembrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearinga triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzylgroup releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT1 and MT2 but spontaneouslyaccumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenousmelatonin recruited b-arrestin 2 toMT1 in mitochondria and inhibited oxygen consumption inmitochondriaisolated from HEK293 cells only when expressing MT1 and from mouse cerebellum of WT mice but notfrom MT1-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatoninligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT1receptors.

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