Systemic Proteome Phenotypes Reveal Defective Metabolic Flexibility in Mecp2 Mutants

Abstract

AbstractGenes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations inMECP2. Transcriptomes and proteomes of organs and brain regions fromMecp2-null mice as well as diverseMECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomaticMecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular,Mecp2- andMECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways.MECP2mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations inMecp2/MECP2perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.