Mitochondrial Proteome Changes in Rett Syndrome

SIMPLE SUMMARY: Rett syndrome (RTT) is a genetic disorder caused by mutations in the X-chromosome. These mutations distort the function of a protein (methyl-CpG-binding protein 2), which controls the expression of several other genes. The resulting pathology, which manifests mostly in female patients, is associated with a number of deficits in brain functioning and development. On the cellular level, the defective functioning of mitochondria—the powerplants of the cells—is one of several hallmarks of RTT. Mitochondria contain more than 1000 different proteins, and their composition differs among tissues. Our study aims to reveal differences between the mitochondrial proteomes of a mouse model of RTT and wild-type (WT) mice. Two brain regions were studied, the hippocampus and neocortex, both of which are pivotal for cognitive function. Indeed, numerous differences were identified, which are not only mouse strain (genotype)-specific but also brain-region-specific. These differentially expressed proteins could affect mitochondrial dynamics, oxidative phosphorylation, and other important aspects of mitochondrial functioning. The data obtained will contribute to improving our understanding of mitochondrial malfunctioning during the progression of RTT, and they will pave the way for further translational medicine research. ABSTRACT: Rett syndrome (RTT) is a genetic neurodevelopmental disorder with mutations in the X-chromosomal MECP2 (methyl-CpG-binding protein 2) gene. Most patients are young girls. For 7–18 months after birth, they hardly present any symptoms; later they develop mental problems, a lack of communication, irregular sleep and breathing, motor dysfunction, hand stereotypies, and seizures. The complex pathology involves mitochondrial structure and function. Mecp2(−/y) hippocampal astrocytes show increased mitochondrial contents. Neurons and glia suffer from oxidative stress, a lack of ATP, and increased hypoxia vulnerability. This spectrum of changes demands comprehensive molecular studies of mitochondria to further define their pathogenic role in RTT. Therefore, we applied a comparative proteomic approach for the first time to study the entity of mitochondrial proteins in a mouse model of RTT. In the neocortex and hippocampus of symptomatic male mice, two-dimensional gel electrophoresis and subsequent mass-spectrometry identified various differentially expressed mitochondrial proteins, including components of respiratory chain complexes I and III and the ATP-synthase FoF1 complex. The NADH-ubiquinone oxidoreductase 75 kDa subunit, NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, NADH dehydrogenase [ubiquinone] flavoprotein 2, cytochrome b-c1 complex subunit 1, and ATP synthase subunit d are upregulated either in the hippocampus alone or both the hippocampus and neocortex of Mecp2(−/y) mice. Furthermore, the regulatory mitochondrial proteins mitofusin-1, HSP60, and 14-3-3 protein theta are decreased in the Mecp2(−/y) neocortex. The expressional changes identified provide further details of the altered mitochondrial function and morphology in RTT. They emphasize brain-region-specific alterations of the mitochondrial proteome and support the notion of a metabolic component of this devastating disorder.