Systemic Metabolic and Mitochondrial Defects in Rett Syndrome Models.

Neurodevelopmental disorder genes are broadly expressed supporting the concept that these disorders are systemic diseases that impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2 . Transcriptomes and proteomes of organs and brain regions from Mecp2 -null mice and MECP2 -null human cells were assessed. Widespread changes in the transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2 -null male mice and mutant 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 - and MECP2 -sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2 / MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.