Article

Colloquium paper: 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: 9.81). 05/2010; 107 Suppl 2:8947-53. DOI: 10.1073/pnas.0914635107
Source: PubMed

ABSTRACT 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.

2 Bookmarks
 · 
78 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    02/2015; 141. DOI:10.1016/j.redox.2015.02.001
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria are highly efficient energy-transforming organelles that convert energy stored in nutrients into ATP. The production of ATP by mitochondria is dependent on oxidation of nutrients and coupling of exergonic electron transfer reactions to the genesis of transmembrane electrochemical potential of protons. Electrons can also prematurely "spin-off" from prosthetic groups in Krebs cycle enzymes and respiratory complexes and univalently reduce di-oxygen to generate reactive oxygen species (ROS) superoxide (O2•(-)) and hydrogen peroxide (H2O2), important signaling molecules that can be toxic at high concentrations. Production of ATP and ROS are intimately linked by the respiratory chain and the genesis of one or the other inherently depends on the metabolic state of mitochondria. Various control mechanisms converge on mitochondria to adjust ATP and ROS output in response to changing cellular demands. One control mechanism that has gained a high amount of attention recently is S-glutathionylation, a redox sensitive covalent modification that involves formation of a disulfide bridge between glutathione and an available protein cysteine thiol. A number of S-glutathionylation targets have been identified in mitochondria. It has also been established that S-glutathionylation reactions in mitochondria are mediated by the thiol oxidoreductase glutaredoxin-2 (Grx2). In the following review, emerging knowledge on S-glutathionylation reactions and its importance in modulating mitochondrial ATP and ROS production will be discussed. Major focus will be placed on Complex I of the respiratory chain since (1) it is a target for reversible S-glutathionylation by Grx2 and (2) deregulation of Complex I S-glutathionylation is associated with development of various disease states particularly heart disease. Other mitochondrial enzymes and how their S-glutathionylation profile is affected in different disease states will also be discussed.
    Frontiers in Cell and Developmental Biology 11/2014; 2:68. DOI:10.3389/fcell.2014.00068
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with hypothyroidism can present a series of so-called residual symptoms which are said to be without physical pathology. These symptoms, however, affect negatively the well-being state of these patients. Currently there are no explanations for this situation. Based on previous investigations done with thyroid disease patients we have carried out a clinical examination which is centered on musculoskeletal features together with a simple evaluation of psychological stressors (scaled 1–3). Laboratory diagnosis was focused on serum magnesium. This report includes the data from 166 women including 58 euthyroid controls (six males) and 108 patients with hypothyroidism (eight males). The most common complaints seen in our patients included fatigue, being easily tired, concentration deficit, ankle instability, and gait insecurity, giving way of the ankle, muscle cramps in the shanks, visual disturbances, irritability, and vertigo sensation. Besides this symptomatology a great majority of the patients (89.5%) presented musculoskeletal alterations. The main finding was that of lateral tension which entails an eccentric muscle action of the affected lower extremity. Lateral tension was always accompanied by (forward) rotation of the hemi-pelvis of the affected side. Idiopathic moving toes were found to be independent of lateral tension. Stress scores in patients were higher in patients than in the control group. Serum magnesium levels were significantly lower in patients (0.87 ± 0.1 mmol/l vs. 0.92 ± 0.07 mmol/l, p = 0.041) and showed a trend toward an inverse correlation to the intensity of lateral tension as well as to the stress score. Patients having magnesium levels below 0.9 mmol/l received 3× 1.4 mmol daily of elemental magnesium in the form of 400 mg of magnesium citrate. In cases presenting stress scores of 2 or 3 a relaxation treatment procedure was included in the treatment. This treatment was extended to the use of acupuncture on points of the Triple Burner meridian. Treatment success was observed in 90% of cases, i.e. residual symptoms were no longer present and patients reported an improved feeling of well-being. We hypothesize that magnesium deficit is facilitated by the presence of physical and psychological stressors. This condition has the potential to negatively influence the function of Complex V of oxidative phosphorylation which relies on magnesium-ATP. Reproductive processes, which have high energetic requirements in women, could thus be affected. The disappearance of the so-called psychosomatic symptoms after our therapeutic scheme brings a new light into this field of medicine and it stresses the importance of holistic handling. Understanding of body–mind interactions is explained by discussing thermodynamics, noesis, Salutogenesis and Resilience, and shamanism.
    03/2014; DOI:10.1016/j.woman.2014.02.001

Preview

Download
3 Downloads
Available from