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Review
. 2009:74:383-93.
doi: 10.1101/sqb.2009.74.031. Epub 2009 Dec 2.

Mitochondria, bioenergetics, and the epigenome in eukaryotic and human evolution

D C Wallace  1
Affiliations
Review

Mitochondria, bioenergetics, and the epigenome in eukaryotic and human evolution

D C Wallace. Cold Spring Harb Symp Quant Biol. 2009.

Abstract

Studies on the origin of species have focused largely on anatomy, yet animal populations are generally limited by energy. Animals can adapt to available energy resources at three levels: (1) evolution of different anatomical forms between groups of animals through nuclear DNA (nDNA) mutations, permitting exploitation of alternative energy reservoirs and resulting in new species with novel niches, (2) evolution of different physiologies within intraspecific populations through mutations in mitochondrial DNA (mtDNA) and nDNA bioenergetic genes, permitting adjustment to energetic variation within a species' niche, and (3) epigenomic regulation of dispersed bioenergetic genes within an individual via mitochondrially generated high-energy intermediates, permitting individual adjustment to environmental fluctuations. Because medicine focuses on changes within our species, clinically relevant variation is more likely to involve changes in bioenergetics than anatomy. This may explain why mitochondrial diseases and epigenomic diseases frequently have similar phenotypes and why epigenomic diseases are being found to involve mitochondrial dysfunction. Therefore, common complex diseases may be the result of changes in any of a large number of mtDNA and nDNA bioenergetic genes or to altered epigenomic regulation of these bioenergetic genes. All of these changes result in similar bioenergetic failure and consequently related phenotypes.

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Figures

Figure 1
Figure 1
Three hypothesized levels of animal eukaryotic cell adaptation to varying energy resources. The original eukaryotic symbiosis brought together the glycolytic nucleus-cytosol with the oxidative mitochondrion. Most of the mitochondrial genome was then transferred to the nDNA, such that the current animal cell nucleus encodes the genes for determining cellular and organismal structure plus the genes for glycolysis and most of the genes for oxidative metabolism, all inherited according to the laws of Mendel. Maternally inherited mtDNA retains the core genes for generating, maintaining, and using the mitochondrial inner membrane potential, ΔP, which links the calories metabolized with cellular energy metabolism. The epigenome evolved to coordinate nDNA gene expression in relation to the availability of environmental calories. This is mediated by the modification of proteins and DNA elements of the epigenome via intracellular levels of the high-energy intermediates: ATP, acetyl-CoA, SAM, plus the redox status of the cell. When calories are abundant, the bioenergetic intermediates increase, chromatin is modified and decondensed, gene expression increases, and growth and reproduction are stimulated. When calories are limited, the reverse is true. Between species and higher taxa, mutations in the nDNA developmental genes change anatomy and permit the exploitation of different energy reservoirs. This creates species and defines niches. Within a species, mutations in the mtDNA change the cellular physiology to permit adaptation of regional populations to consistent regional differences in energy resources. Frequent fluctuations in energy resources of a species are addressed by changes in the epigenome that modulate the coordinate expression of cis- and trans-distributed nDNA bioenergetic genes. De novo mutations in nDNA bioenergetic genes, mutations and polymorphisms in mtDNA bioenergetic genes, and mutational or environmentally induced alterations in the epigenomic regulation of bioenergetic genes can all perturb bioenergetic homeostasis and contribute to the pathophysiology of common diseases, cancer, and aging.
Figure 2
Figure 2
Bioenergetic interface with the environment explains the importance of mtDNA and epigenomic variation of intraspecific animal adaptation. Energy availability and demand are the central factors in an animal’s environment, the energy environment. Primary sources of available energy for omnivores, such as humans, are dietary calories generally obtained as carbohydrates and fats. Demands for calories include physical activity, thermal stress, hypoxia, oxidative stress, infection, body maintenance, and reproduction. Available calories are processed through cellular and mitochondrial bioenergetic pathways. The bioenergetic system is assembled from both mtDNA and nDNA genes. The mtDNA encodes core genes of OXPHOS. It has a very high mutation rate, resulting in the continual generation of functional variants, thus providing the genetic variation to permit animals to adapt to regional variation in the energetic environment. The nDNA encodes all of the genes for glycolysis, most of the genes for mitochondrial biogenesis and energy production, and all of the genes for the energetic- and redox-regulated signal transduction systems. These nDNA genes have a low mutation rate, within the time range for speciation. However, expression of the ~2000 nDNA-encoded energy genes is regulated by the production of high-energy intermediates by glycolysis and OXPHOS including ATP, acetyl-CoA, and SAM. These cellular bioenergetic substrates then drive the modification of the chromatin by phosphorylation, acetylation, and methylation, thus coordinating gene expression in relation to short-term fluctuations in the individual’s energetic environment.
Figure 3
Figure 3
Classes of human mitochondrial gene mutations in the origin of metabolic and degenerative diseases, cancer, and aging. The “mitochondrial genome” encompasses ~1500 nDNA genes dispersed across the chromosomes plus 37 critical energetic genes within mtDNA. Genetic variation in any of these mitochondrial genes may perturb the mitochondrial OXPHOS. An array of common environmental agents and pharmacological agents can also modulate mitochondrial bioenergetics and/or biogenesis. Inhibition of OXPHOS can increase mitochondrial ROS production, which will damage mtDNA, gradually erode the cellular capacity to generate energy, and create the clock central to aging and adult cancers. OXPHOS dysfunction will have the greatest effect on tissues having the highest energy demand (brain, heart, skeletal muscle, kidney, endocrine system) to cause degenerative diseases. Altered mitochondrial energy production will also perturb caloric sensing and use, resulting in common metabolic diseases such as diabetes and obesity. Finally, altered mitochondrial ROS production and redox biology will precipitate inflammatory disease and change mitochondrial coupling efficiency to affect thermal modulation and sensitivity to radiation-induced cellular toxicity.
Figure 4
Figure 4
Mitochondrial bioenergetic coupling with the epigenome. The flow of reducing equivalents (calories) through glycolysis and mitochondrial oxidation regulates levels of cellular ATP and acetyl-CoA. High-calorie intake increases ATP and acetyl-CoA levels, thereby increasing histone phosphorylation and acetylation. This opens the chromatin to stimulate transcription, growth, and replication. Acetylation also regulates major signal transduction pathways, including the insulin signaling pathway. Forkhead box class O (FOXO) transcription factors that regulate expression of PGC-1α, the key transcription factor to regulate mitochondrial OXPHOS and biogenesis, can be acetylated and inactivated. During carbohydrate metabolism by glycolysis (Glyc), the cytosolic NADH/NAD+ ratio increases, thus limiting NAD+ availability for Sirt1-mediated FOXO and PGC-1α deacetylation. This inhibits FOXOs and PGC-1α, which down-regulate mitochondrial OXPHOS and biogenesis. Fatty acid and ketone body oxidation within the mitochondrion leaves the cytosolic NADH/NAD+ more oxidized, thereby stimulating Sirt1-mediated deacetylation and activation of FOXOs and PGC-1α, causing up-regulation of mitochondrial OXPHOS. Thus, the availability and nature of calories directly regulates the epigenome and modulates the bioenergetic pathways required for optimal caloric exploitation. (AcCoA) Acetyl-CoA, (AcAc) acetylaldehyde, (BOB) β-hydroxybutyrate, (OAA) oxaloacetate, (Pyr) pyruvate, (suc) succinate, (Suc-CoA) succinyl-CoA, (SSA) succinate semialdehyde, (GABA) γ-aminobutyric acid, (αKG) α-ketoglutarate, (G6P) glucose-6-phosphate, (HATs) histoacetyltransferases, (HDAC) histone deacetylase, (GSSG and GSH) oxidized and reduced glutathione.
Figure 5
Figure 5
Epigenomic disease association with mitochondrial dysfunction. (Left side) Diseases associated with loss of imprinting (LOI) potentially alter chromatin loop domain structure and cause aberrant cis interactions of bioenergetic genes. Chromatin domains affected by LOI can correlate with LOCHs (large organized chromatin K9 modifications blocks [Wen et al. 2009]) and LADs (lamina-associated domains [Guelen et al. 2008]). (Right side) Diseases associated with aberrations in the interaction of chromatin domains on different chromosomes or chromosomal domains resulting in aberrant trans interactions on bioenergetic genes. (Mito Δ) Extent of evidence for mitochondrial dysfunction associated with epigenetic disease. (IGF2) insulin-like growth factor 2 gene, (SNRPN) small nuclear ribonuclear polypeptide N, (ICR) imprinting control region, (UBE3A) ubiquitin-protein ligase E3A, (MeCP2) methyl C binding protein 2, (LMNA) lamin A gene, (MUT) mutant, (HDAC) histone deacetylase.
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