Fig. 4

SUL-138 shifts the metabolic proteome. A Venn diagram of significantly regulated mitochondrial proteins for the three relevant comparisons APP VEH vs. WT VEH, APP SUL vs. APP VEH and WT SUL vs. WT VEH (FDR, q ≤ 0.05). B MitoXplorer analysis of all mitochondrial proteins with significant regulation in at least one comparison. The graph indicates the number of proteins per mitochondrial process for each comparison; significant MitoXplorer enrichment is indicated (*p ≤ 0.05). C Pairs contrast graph of differential mitochondrial protein expression in APP VEH vs. WT VEH (x-axis) and APP SUL vs. WT VEH (y-axis) comparisons. A general upregulation of mitochondrial proteins involved in multiple metabolic processes is observed in APP/P1 mice (APP VEH vs. WT VEH), whereas only the levels of proteins involved in amino acid metabolism, FAD and FAO and glycolysis are further increased by SUL-138 treatment. The inset shows expression levels of all mitochondrial proteins, without statistical cut-off, and indicates that the observed upregulation of several mitochondrial processes is not due to a general upregulation of all mitochondrial proteins. D Pairs contrast graph of differential mitochondrial protein expression in WT SUL vs. WT VEH (x-axis) and APP SUL vs. APP VEH (y-axis) comparisons showing a clear separation of mitochondrial protein regulation, with FAD and FAO regulated more strongly in WT mice and amino acid metabolism and glycolysis in APP/PS1 mice. E–G Schematic summary of genotype and SUL-138 treatment on the three main metabolic inputs (glycolysis, FAD and FAO, and amino acid metabolism) towards the TCA cycle and the oxidative phosphorylation (OXPHOS) complex. In red and blue significantly upregulated and downregulated proteins (FDR, q ≤ 0.05) are indicated