Mitochondrial LETM1 drives ionic and molecular clock rhythms in circadian pacemaker neurons

The mechanisms that generate robust ionic oscillation in circadian pacemaker neurons are under investigation. Here, we demonstrate critical functions of the mitochondrial cation antiporter leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1), which exchanges K⁺/H⁺ in Drosophila and Ca²⁺/H⁺ in mammals, in circadian pacemaker neurons. Letm1 knockdown in Drosophila pacemaker neurons reduced circadian cytosolic H⁺ rhythms and prolonged nuclear PERIOD/TIMELESS expression rhythms and locomotor activity rhythms. In rat pacemaker neurons in the hypothalamic suprachiasmatic nucleus (SCN), circadian rhythms in cytosolic Ca²⁺ and Bmal1 transcription were dampened by Letm1 knockdown. Mitochondrial Ca²⁺ uptake peaks late during the day were also observed in rat SCN neurons following photolytic elevation of cytosolic Ca²⁺. Since cation transport by LETM1 is coupled to mitochondrial energy synthesis, we propose that LETM1 integrates metabolic, ionic, and molecular clock rhythms in the central clock system in both invertebrates and vertebrates.