RT Journal Article
SR Electronic
T1 The cation exchanger Letm1, circadian rhythms, and NAD(H) levels interconnect in diurnal zebrafish
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202101194
DO 10.26508/lsa.202101194
VO 5
IS 9
A1 Dao, Pauline
A1 Hajny, Stefan
A1 Mekis, Ronald
A1 Orel, Lukas
A1 Dinhopl, Nora
A1 Tessmar-Raible, Kristin
A1 Nowikovsky, Karin
YR 2022
UL https://www.life-science-alliance.org/content/5/9/e202101194.abstract
AB 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.