Bioenergetics, the origins of complexity, and the ascent of man

Organized Research Unit for Molecular and Mitochondrial Medicine and Genetics and Departments of Ecology and Evolutionary Biology, Biological Chemistry, and Pediatrics, University of California, Irvine, CA 92697-3940, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2010; 107 Suppl 2(Suppl 2):8947-53. DOI: 10.1073/pnas.0914635107
Source: PubMed


Complex structures are generated and maintained through energy flux. Structures embody information, and biological information is stored in nucleic acids. The progressive increase in biological complexity over geologic time is thus the consequence of the information-generating power of energy flow plus the information-accumulating capacity of DNA, winnowed by natural selection. Consequently, the most important component of the biological environment is energy flow: the availability of calories and their use for growth, survival, and reproduction. Animals can exploit and adapt to available energy resources at three levels. They can evolve different anatomical forms through nuclear DNA (nDNA) mutations permitting exploitation of alternative energy reservoirs, resulting in new species. They can evolve modified bioenergetic physiologies within a species, primarily through the high mutation rate of mitochondrial DNA (mtDNA)-encoded bioenergetic genes, permitting adjustment to regional energetic environments. They can alter the epigenomic regulation of the thousands of dispersed bioenergetic genes via mitochondrially generated high-energy intermediates permitting individual accommodation to short-term environmental energetic fluctuations. Because medicine pertains to a single species, Homo sapiens, functional human variation often involves sequence changes in bioenergetic genes, most commonly mtDNA mutations, plus changes in the expression of bioenergetic genes mediated by the epigenome. Consequently, common nDNA polymorphisms in anatomical genes may represent only a fraction of the genetic variation associated with the common "complex" diseases, and the ascent of man has been the product of 3.5 billion years of information generation by energy flow, accumulated and preserved in DNA and edited by natural selection.

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    • "In aerobic cells, O 2 is utilized by many enzyme systems but is primarily the driving force behind aerobic ATP production. The use of O 2 in nutrient metabolism maximized energy conservation among aerobic eukaryotes prompting an increase in biological complexity culminating the evolution of humanity [8] [9]. In aerobic eukaryotes, production of ATP by oxidative phosphorylation occurs in mitochondria, double membrane organelles with prokaryotic origins that house the necessary enzymatic machinery required for O 2 -dependent production of ATP from carbon oxidation [10] [11]. "
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    ABSTRACT: Mitochondria fulfill a number of biological functions which inherently depend on ATP and O2(-•)/H2O2 production. Both ATP and O2(-•)/H2O2 are generated by electron transfer reactions. ATP is the product of oxidative phosphorylation whereas O2(-•) is generated by singlet electron reduction of di-oxygen (O2). O2(-•) is then rapidly dismutated by superoxide dismutase (SOD) producing H2O2. O2(-•)/H2O2 were once viewed as unfortunately by-products of aerobic respiration. This characterization is fitting considering over production of O2(-•)/H2O2 by mitochondria is associated with range of pathological conditions and aging. However, O2(-•)/H2O2 are only dangerous in large quantities. If produced in a controlled fashion and maintained at a low concentration, cells can benefit greatly from the redox properties of O2(-•)/H2O2. Indeed, low rates of O2(-•)/H2O2 production are required for intrinsic mitochondrial signaling (e.g. modulation of mitochondrial processes) and communication with the rest of the cell. O2(-•)/H2O2 levels are kept in check by anti-oxidant defense systems that sequester O2(-•)/H2O2 with extreme efficiency. Given the importance of O2(-•)/H2O2 in cellular function, it is imperative to consider how mitochondria produce O2(-•)/H2O2 and how O2(-•)/H2O2 genesis is regulated in conjunction with fluctuations in nutritional and redox states. Here, I discuss the fundamentals of electron transfer reactions in mitochondria and emerging knowledge on the 11 potential sources of mitochondrial O2(-•)/H2O2 in tandem with their significance in contributing to overall O2(-•)/H2O2 emission in health and disease. The potential for classifying these different sites in isopotential groups, which is essentially defined by the redox properties of electron donator involved in O2(-•)/H2O2 production, as originally suggested by Brand and colleagues is also surveyed in detail. In addition, redox signaling mechanisms that control O2(-•)/H2O2 genesis from these sites are discussed. Finally, the current methodologies utilized for measuring O2(-•)/H2O2 in isolated mitochondria, cell culture and in vivo are reviewed. Copyright © 2015 The Author. Published by Elsevier B.V. All rights reserved.
    Full-text · Article · Feb 2015
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    • "For example, mtDNA damage may be a major cause of abnormal reactive oxygen species (ROS) production in AD or may increase neuronal susceptibility to oxidative injury during aging. Human mtDNA is a maternally inherited 16,569ebase pair loopecontaining genes critical to mitochondrial energy production (Wallace, 2010), and bioenergetic defects resulting from acquired and inherited mtDNA mutations may be critical for both age-related dementia and associated neuropathological changes observed in AD (Brown and Wallace, 1994; Corral-Debrinski et al., 1994; Coskun et al., 2010; De Vivo, 1993; Graeber et al., 1998; Hutchin et al., 1997; Manczak et al., 2004; Tranah et al., 2012b; Wallace, 2001). Sequence variation within the 13 mtDNA-encoded oxidative phosphorylation (OXPHOS) genes may have an impact on superoxide production at OXPHOS Complexes I and III through respiratory chain impairment (Niemi et al., 2005), apoptosis (Li et al., 2003), and ATP generation efficiency (Tarnopolsky et al., 2004). "
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    ABSTRACT: Mitochondrial dysfunction occurs early in the course of several neurodegenerative diseases, and is potentially related to increased oxidative damage and amyloid-beta (Abeta) formation in Alzheimer's disease. The goals of this study were to assess mtDNA sequence associations with dementia risk, 10-year cognitive change, and markers of oxidative stress and Abeta among 1089 African-Americans in the population-based Health, Aging, and Body Composition Study. Participants were free of dementia at baseline, and incidence was determined in 187 (18%) cases over 10 to 12 follow-up years. Haplogroup L1 participants were at increased risk for developing dementia (odds ratio = 1.88, 95% confidence interval = 1.23-2.88, p = 0.004), lower plasma Abeta42 levels (p = 0.03), and greater 10-year decline on the Digit Symbol Substitution Test (p = 0.04) when compared with common haplogroup L3. The p.V193I, ND2 substitution was associated with significantly higher Abeta42 levels (p = 0.0012), and this association was present in haplogroup L3 (p = 0.018) but not L1 (p = 0.90) participants. All associations were independent of potential confounders, including APOEepsilon4 status and nuclear genetic ancestry. Identification of mtDNA sequence variation associated with dementia risk and cognitive decline may contribute to the development of new treatment targets and diagnostic tests that identify responders to interventions targeting mitochondria.
    Full-text · Article · Nov 2013 · Neurobiology of aging
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    • "One of these structures is nucleic acids, which can accumulate information. Each year, the flow of energy through the biosphere from sunlight on the Earth's surface or from geothermal vents on the ocean floor provides the energy to generate more nucleic acids, and the more nucleic acids the more information, the more information the greater the complexity [7]. Originally, energy flow created nucleic acids directly, though inefficiently [6,8]. "
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    ABSTRACT: Two major inconsistencies exist in the current neo-Darwinian evolutionary theory that random chromosomal mutations acted on by natural selection generate new species. First, natural selection does not require the evolution of ever increasing complexity, yet this is the hallmark of biology. Second, human chromosomal DNA sequence variation is predominantly either neutral or deleterious and is insufficient to provide the variation required for speciation or for predilection to common diseases. Complexity is explained by the continuous flow of energy through the biosphere that drives the accumulation of nucleic acids and information. Information then encodes complex forms. In animals, energy flow is primarily mediated by mitochondria whose maternally inherited mitochondrial DNA (mtDNA) codes for key genes for energy metabolism. In mammals, the mtDNA has a very high mutation rate, but the deleterious mutations are removed by an ovarian selection system. Hence, new mutations that subtly alter energy metabolism are continuously introduced into the species, permitting adaptation to regional differences in energy environments. Therefore, the most phenotypically significant gene variants arise in the mtDNA, are regional, and permit animals to occupy peripheral energy environments where rarer nuclear DNA (nDNA) variants can accumulate, leading to speciation. The neutralist-selectionist debate is then a consequence of mammals having two different evolutionary strategies: a fast mtDNA strategy for intra-specific radiation and a slow nDNA strategy for speciation. Furthermore, the missing genetic variation for common human diseases is primarily mtDNA variation plus regional nDNA variants, both of which have been missed by large, inter-population association studies.
    Full-text · Article · Jul 2013 · Philosophical Transactions of The Royal Society B Biological Sciences
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