Loss of Wdr23 drives neuronal mitochondrial biogenesis

Abstract

ABSTRACTMitochondrial adaptation is important for stress resistance throughout life. Here we show that WDR23 loss results in an enrichment for genes regulated by nuclear respiratory factor 1 (NRF1), which coordinates mitochondrial biogenesis and respiratory functions, and an increased steady state level of nuclear coded mitochondrial resident proteins in the brain.Wdr23KOalso increases the endogenous levels of insulin degrading enzyme (IDE) and the relaxin-3 peptide (RLN3), both of which mediate mitochondrial metabolic and oxidative stress responses. Taken together, these studies reveal an important role for WDR23 as a component of the mitochondrial homeostat in the murine brain.HIGHLIGHTSLoss of Wdr23 increases nuclear-coded mitochondrial resident proteins.Promoters of transcripts dysregulated in the hippocampus ofWdr23KOmice are enriched for NRF1 regulatory sequences.Insulin degrading enzyme (IDE) expression, which can localize to the mitochondria, is increased in the brain tissues lacking WDR23.Wdr23KOanimals have increased expression of relaxin-3 (RLN3) peptide, but not RLFP3 receptor.