Genetic compensations for letm1 deficiency

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 to 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.