Loss of Wdr23 drives neuronal mitochondrial biogenesis

Abstract

Mitochondrial 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. Wdr23KO also 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. HIGHLIGHTSO_LILoss of Wdr23 increases nuclear-coded mitochondrial resident proteins. C_LIO_LIPromoters of transcripts dysregulated in the hippocampus of Wdr23KO mice are enriched for NRF1 regulatory sequences. C_LIO_LIInsulin degrading enzyme (IDE) expression, which can localize to the mitochondria, is increased in the brain tissues lacking WDR23. C_LIO_LIWdr23KO animals have increased expression of relaxin-3 (RLN3) peptide, but not RLFP3 receptor. C_LI