Energetics, epigenetics, mitochondrial genetics

Abstract

The epigenome has been hypothesized to provide the interface between the environment and the nuclear DNA (nDNA) genes. Key factors in the environment are the availability of calories and demands on the organism's energetic capacity. Energy is funneled through glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), the cellular bioenergetic systems. Since there are thousands of bioenergetic genes dispersed across the chromosomes and mitochondrial DNA (mtDNA), both cis and trans regulation of the nDNA genes is required. The bioenergetic systems convert environmental calories into ATP, acetyl-Coenzyme A (acetyl-CoA), s-adenosyl-methionine (SAM), and reduced NAD(+). When calories are abundant, ATP and acetyl-CoA phosphorylate and acetylate chromatin, opening the nDNA for transcription and replication. When calories are limiting, chromatin phosphorylation and acetylation are lost and gene expression is suppressed. DNA methylation via SAM can also be modulated by mitochondrial function. Phosphorylation and acetylation are also pivotal to regulating cellular signal transduction pathways. Therefore, bioenergetics provides the interface between the environment and the epigenome. Consistent with this conclusion, the clinical phenotypes of bioenergetic diseases are strikingly similar to those observed in epigenetic diseases (Angelman, Rett, Fragile X Syndromes, the laminopathies, cancer, etc.), and an increasing number of epigenetic diseases are being associated with mitochondrial dysfunction. This bioenergetic-epigenomic hypothesis has broad implications for the etiology, pathophysiology, and treatment of a wide range of common diseases.

Figure 1. Energetic Regulation of the Epigenome

Mitochondrial energetics links the epigenome to calorie availability through high energy intermediates and redox reactions. The mitochondrion is at the top of the figure, the nucleus in the middle, and the cytosol in at the bottom. Calories as reducing equivalents enter the cell and mitochondria at the upper left resulting in generation of acetyl-CoA, reduction of NAD⁺, and ATP. Energy then flows from top to bottom. ATP drives the phosphorylation of nuclear and cytosolic signal transduction proteins, acetyl-CoA acetylates chromatin and signal transduction proteins, and NAD⁺ acts through the Sirtuins to deacetylate proteins. Abbreviations: AcCoA = acetyl-CoA, NAD⁺ = nicotinamide adenine dinucleotide (oxidized) & NADH (reduced), mtPTP = mitochondrial permeability transition pore, GPx1 = glutathione peroxidase 1, mCAT = mitochondrially-targeted catalase, PARP = poly ADP ribose polymerase. Other abbreviations are described in the text.