ReviewEnergetics, epigenetics, mitochondrial genetics
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.
Section snippets
Mitochondrial bioenergetics
Complex structures can only be maintained by the continual flux of energy. Life, therefore, is the interaction between structure, energy, and information, with information required for both structure and energetics (Wallace, 2007).
THe energetic evolution of the epigenome
Prior to the advent of free oxygen in the biosphere, substrate-level phosphorylation was the primary mechanism for generating ATP in non-photosynthetic organisms. After the generation of free oxygen by photosystem II the redox range of biology was greatly expanded and OXPHOS became the most efficient system for generating ATP from the reducing equivalents present in organic molecules (Lane, 2002, Lane, 2005, Wallace, 2007).
Mitochondrial genetic disease
The elucidation of a broad spectrum of mtDNA and nDNA mitochondrial gene mutation diseases has revealed that mitochondrial dysfunction can result in the entire range of clinical phenotypes associated with metabolic and degenerative diseases as well as cancer and aging (Wallace et al., 2007). Mitochondrial diseases have been shown to affect the highly oxidative tissues including the brain, heart, muscle, kidney, and endocrine systems; as well as the metabolic systems resulting in diabetes,
Mitochondrial explanations for epigenetic diseases
Therefore, mitochondrial gene defects can result in virtually all of the symptoms associated with the common “complex” diseases, confirming the importance of mitochondrial bioenergetics in health. Since mitochondrial metabolism also regulates the substrates for epigenomic regulation, it follows that changes in mitochondrial metabolism may also perturb the epigenomic state. Furthermore, in cells and animals in which the epigenomic elements NRs, PGC-1α and β, and the Sirtuins are inactivated,
Perspective
The similarity in symptoms between mitochondrial and epigenomic diseases suggests that they have a common pathophysiology. Is so, alterations in mitochondrial function will have important effects on the epigenome and alterations in the epigenome will have significant effects on mitochondrial function (Borrelli et al., 2008).
The epigenome has been hypothesized to provide the interface between the environment and the regulation of nDNA gene expression (Feinberg, 2007, Feinberg, 2008). The most
Acknowledgments
The authors would like to thank Ms. Marie T. Lott for her assistance in assembling this document. The work has been supported by NIH Grants NS21328, AG24373, DK73691, AG13154, AG16573, a CIRM Comprehensive Grant RC1-00353-1, a Doris Duke Clinical Interfaces Award 2005, and an Autism Speaks High Impact Grant awarded to DCW and a CIRM Predoctoral Fellowship awarded to WF.
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