https://phaidra.vetmeduni.ac.at/o:2714 The cation exchanger Letm1, circadian rhythms, and NAD(H) levels interconnect in diurnal zebrafish Dao, Pauline Pauline Dao University of Veterinary Medicine Vienna / University of Vienna / Medical University of Vienna Nowikovsky, Karin Karin Nowikovsky 0000-0001-8435-8410 University of Veterinary Medicine Vienna / Medical University of Vienna Tessmar-Raible, Kristin Kristin Tessmar-Raible 0000-0002-8038-1741 University of Vienna Dinhopl, Nora Nora Dinhopl University of Veterinary Medicine Vienna Orel, Lukas Lukas Orel 0000-0001-6999-5833 University of Vienna Hajny, Stefan Stefan Hajny 0000-0002-4178-7968 Medical University Vienna / University of Vienna Mekis, Ronald Ronald Mekis University of Veterinary Medicine Vienna / Medical University of Vienna Life Science Alliance LLC text eng Mitochondria are fundamental for life and require balanced ion exchange to maintain proper functioning. The mitochondrial cation exchanger LETM1 sparks interest because of its pathophysiological role in seizures in the Wolf Hirschhorn Syndrome (WHS). Despite observation of sleep disorganization in epileptic WHS patients, and growing studies linking mitochondria and epilepsy to circadian rhythms, LETM1 has not been studied from the chronobiological perspective. Here we established a viable letm1 knock-out, using the diurnal vertebrate Danio rerio to study the metabolic and chronobiological consequences of letm1 deficiency. We report diurnal rhythms of Letm1 protein levels in wild-type fish. We show that mitochondrial nucleotide metabolism is deregulated in letm1-/- mutant fish, the rate-limiting enzyme of NAD+ production is up-regulated, while NAD+ and NADH pools are reduced. These changes were associated with increased expression amplitude of circadian core clock genes in letm1-/- compared with wild-type under light/dark conditions, suggesting decreased NAD(H) levels as a possible mechanism for circadian system perturbation in Letm1 deficiency. Replenishing NAD pool may ameliorate WHS-associated sleep and neurological disorders. Critical Region; Hirschhorn; Metabolism; Protein; Gene http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:2714/download 10.26508/lsa.202101194 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Life Science Alliance 5(9) (2022) Life Science Alliance 5 9 2.36 MB 2022