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within a chromatin loop domain encompassing the insulin-like growth factor 2 (IGF2) gene. IGF2 may act through the PI3K-Akt-FOXO pathway to modulate energy metabolism (Feinberg, 2007; Wallace and Fan, 2010).

Rett syndrome and the laminopathies may be epigenomic diseases that act in trans to affect mitochondrial function. Rett syndrome is caused by mutations in the methyl-CpG binding protein 2 (MeCP2), which binds to meCpG islands throughout the chromosomes (Loat et al., 2008). As abnormal mitochondria and mitochondrial function have been reported in several Rett patient studies, loss of MeCP2 might disrupt the coordinate regulation of nDNA energy gene expression (Wallace and Fan, 2010). The laminopathies are caused by mutations in the laminin A/C gene (LMNA), which disrupt the nuclear architecture and potentially transcriptional islands. Mutations in the LMNA gene have been found to produce similar phenotypes to those found in mtDNA mutations and a study of cells harboring LMNA mutations revealed mitochondrial defects. Therefore, various epigenomic defects may affect mitochondrial function, implying that an important function of the epigenome is to coordinate the expression of the dispersed bioenergetic genes (Wallace and Fan, 2010).

Bioenergetic Regulation of Signal Transduction and Metabolism

To respond to more rapid energy environment fluctuations, animal cells modify transcription factors and signal transduction systems via high-energy intermediates. High and low blood sugar results in the secretion of insulin by the pancreatic β cells and glucagon by the pancreatic α cells, respectively. Insulin binds to the insulin receptor, which signals, through phosphatidylinositol-3-kinase (PI3K) and Akt/PKB, to phosphorylate and inactivate the FOXO transcription factor. When not phosphorylated, FOXO binds to the PCG-1α promoter and increases PGC-1α expression, which up-regulates mitochondrial biogenesis and OXPHOS. Thus, in the presence of glucose, FOXO is inactivated, OXPHOS is down-regulated, and glycolysis is favored. In the absence of glucose FOXO is active and OXPHOS is up-regulated to burn fat. Similarly, glucacon binds to the glucagon receptor to activate adenylylcyclase, and the resulting cAMP activates protein kinase A (PKA) to phosphorylate CREB. Activated CREB also binds to the PGC-1α promoter and up-regulates OXPHOS. Low glucose thus doubly induces OXPHOS by inhibiting insulin signaling and enhancing glucagon signaling (Wallace, 2007).

The PI3K pathway is also linked via the tuberous sclerosis protein complex (TSC) to the mTORC1 regulation of nutrient metabolism; mTORC1 is also modulated by AMP kinase, which is activated by reductions in high-energy phosphates. Virtually every signal transduction pathway is modulated by ATP-mediated phosphorylation, so almost all cellular

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