methyltransferases using SAM can also modulate the affinity of proteins for DNA.
ATP is generated by both glycolysis and OXPHOS when caloric reducing equivalents are prevalent. Mammalian cell acetyl-CoA is generated primarily in the mitochondrion during pryruvate or fatty acid oxidation. Within the mitochondrion, the acetyl-CoA is converted to citrate by condensation with oxaloacetate (OAA) via citrate synthetase. Citrate can be exported into the cytosol, where it is cleaved back to acetyl-CoA and OAA by ATP-citrate lyase (Wallace and Fan, 2010). Mitochondrial acetyl-CoA can also be exported out of the mitochondrion as acetylcarnitine by the carnitine/acylcarnitine acetyltranslocase. In the cytosol, acetylcarnitine reverts back into acetyl-CoA for use in histone acetylation (Madiraju et al., 2009).
SAM is produced in the cytosol by the reaction L-methionine + ATP. ATP is generated by the mitochondrion and glycolysis, whereas the methyl groups to convert homocystine to methionine come from the mitochondrion. Therefore, all of the primary substrates for chromatin modification are produced by the bioenergetic pathways, which in turn are fueled by the availability of calories in the environment (Wallace and Fan, 2010).
Evidence that the epigenome regulates bioenergetics comes from the facts that pathogenic mtDNA mutations result in symptoms similar to those attributed to the epigenomic disease and that several epigenomic diseases have been associated with mitochondrial dysfunction. Epigenomic diseases affect imprinting, methylation, and chromatin organization (Feinberg, 2007). The epigenome can regulate dispersed bioenergetic genes in either the cis configuration for adjacent genes or in the trans configuration for dispersed genes. Current knowledge about chromatin organization suggests that the cis regulation occurs with chromatin loop domains and that trans regulation occurs by diffusible trans-acting factors or by bringing together dispersed genes into transcriptional islands, in part through shared enhancer sequences (Wallace and Fan, 2010).
Imprinting diseases generally involve cis-acting epigenetic defects. In Angelman and Prader-Willi syndromes, the perturbation of cell function involves genetic inactivation of the active allele on chromosome 15q11–13 in the context of an inactive imprinted allele on the opposite chromosome. The pathophysiology of Angelman syndrome appears to be mitochondrial, as analysis of an Angelman murine model has revealed that the hippocampal neurons have a reduced synaptic vesicle density and shrunken mitochondria and the brain has a partial defect in OXPHOS complexes II + III (Wallace and Fan, 2010).
The pathophysiology of Beckwith-Wiedemann syndrome and Wilm’s tumor may also involve bioenergetic dysfunction. Both of these diseases are associated with loss of imprinting (LOI) on chromosome 11q15.5