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

doi:10.1016/j.chembiol.2023.07.009

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SOMALO-BARRANCO, Gloria
Institut Cochin [IC UM3 (UMR 8104 / U1016)]

PAGANO ZOTTOLA, Antonio
Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale [U1215 Inserm - UB]

ABDULRAHMAN, Abdulrasheed
Institut Cochin [IC UM3 (UMR 8104 / U1016)]

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Cell Chemical Biology. 2023-08-17, vol. 30, n° 8, p. 920-932

Resumen en inglés

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.< Leer menos

Palabras clave en inglés

Melatonin

Melatonin receptors

Mitochondria-targeted caged melatonin ligand

Photopharmacology

Mitochondrial respiration