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.

Introduction

“The modern definition of epigenetics is information heritable during cell division other than the DNA sequence itself” (Feinberg, 2007). Hence, epigenetics is thought to provide a flexible interface between the organism and its environment. Until now, the DNA sequences of interest to biology and medicine have been in the chromosomal DNA, which is transmitted during meiotic and mitotic cell division according to the rules of Gregor Mendel. However, most common metabolic and degenerative diseases and multiple cancers are familial, but are not classically Mendelian in their transmission. Therefore, such “complex diseases” have been attributed to epigenetic changes in response to the environmental change (Feinberg, 2007, Feinberg, 2008).

However, deficiency in energy metabolism has also emerged as an alternative explanation for the etiology of complex diseases over the past 21 years. The primary limiting factor for growth and reproduction of all biological systems is energy and the first reports that mitochondrial DNA (mtDNA) mutations can cause disease (Goto et al., 1990, Holt et al., 1988, Holt et al., 1990, Shoffner et al., 1990, Wallace et al., 2007, Wallace et al., 1988a, Wallace et al., 1988b) have been followed by reports that a broad spectrum of metabolic and degenerative diseases can have a mitochondrial etiology (Wallace et al., 2007). Moreover, environmentally adaptive mtDNA variants have been associated with predisposition to virtually the entire range of common “complex” diseases (Wallace, 2008).

However, similar symptoms imply a common pathophysiology. Therefore, epigenetic and mitochondrial genetic diseases must be interrelated through their impinging on a common function.

To understand nuclear–mitochondrial interactions, we must consider the early stages in the endosymbiontic event that created the eukaryotic cell about 2 billion years ago (Lane, 2002, Lane, 2005, Wallace, 2007). In the beginning, the proto-nucleus–cytosol was limited by energy. This limitation was alleviated by its symbiosis with an oxidative α-protobacterion, the proto-mitochondrion. Therefore, growth and replication of the nucleus became limited by mitochondrial energy production and thus calorie availability. This necessitated the regulation of nuclear replication and gene expression by calorie availability mediated by mitochondrial energetics. This was achieved by coupling modulation of nDNA chromatin structure and function by modification via high energy intermediates: phosphorylation by ATP, acetylation by acetyl-Coenzyme A (Ac-CoA), deacetylation by nicotinamide adenine dinucleotide (NAD⁺), and methylation by s-adenosyl-methionine (SAM).

Conversely, the nucleus had to develop mechanisms for modulating mitochondrial growth and replication. This was additionally complicated by the successive transfer of genes from the proto-mitochondrial DNA to the nDNA, with the cytosolic translation products being directionally imported back into the mitochondrion (Wallace, 2007). This process proceeded over a billion years with the result that the nDNA-encoded genes of the mitochondrial genome are now dispersed throughout the chromosomes (Wallace, 2007). Therefore, new mechanisms had to evolve to permit the coordinate expression of the mitochondrial genes based on nuclear requirements for energy for growth and reproduction. As a result, this became one of the early driving forces for the evolution of inter-chromosomal coordinate transcriptional regulation.

Over the subsequent 1.2 billion years, the nucleus–cytosol became increasingly specialized in specifying structure while the mitochondrion became entirely dedicated to energy production. Ultimately, this subcellular specialization became sufficiently refined and efficient that it permitted the advent of multicellularity and thus plants and animals (Wallace, 2007). Still, all subsequent tissue development, species radiation, and environmental adaptation were rooted in the fundamental energetic–epigenetic cooperation.