Preface

All living matter, from the conventional basic unit of life, the cell, to a higher-order integrated manifestation of cells, an organism, exists an open dynamical system requiring capabilities for extracting energy from respective interstitial, host, or ambient environments, for converting that same energy to biologically useful forms, and for employing biologically useful energy to drive energetically expensive life processes. In a most general sense, the scope of the scientific discipline now called *bioenergetics* extends to all of biophysics and biochemistry as they concern the study and description of energy transformations that occur during thousands of organic chemical reactions in living soft matter. As one should expect, the definition and scope of bioenergetics have changed with time. Landmark transitions, such as the discoveries of photosynthesis, of glycolysis and oxidative phosphorylation, of adenosine triphosphate (ATP) and creatine phosphate and their roles in working muscle, of cytochromes and the respiratory chain, and of membrane-dependent electron transport and chemiosmotic coupling, accompany technological and conceptual innovations. Over the past thirty-or-so years, traditions in study at the level of membrane-bound energy-transducing catalysts have switched to an emphasis on the deeper molecular nature of bioenergetics, including the gene expression, biosynthesis, and membrane assembly of catalysts, the production and neutralization of harmful reactive oxygen species known as free radicals, the quantum efficiency of energy-harvesting protein complexes, and the effect these and other events have on the state of cells and organisms. This transition from the science of membrane physiology to molecular biology comes with advancing instrumentation and methods which allow researchers to probe the biological function and impact of macromolecules and substrate of smaller physical scales. As readers of this threesectioned collected volume will find, however, these trends in bioenergetics theory and research often complement, rather than replace, more established interests in membrane physiology and will lead to progress in such endeavors as preventing mitochondrial diseases, improving physical performance, and slowing aging.

Even in the midst of conceptual and technical revolutions, bioenergeticists typically take for granted that their discipline broadly entails studying the transformation of biological fuels by cells. Yet, despite many textbooks and peer-review articles published in scientific journals devoted to the subject of bioenergetics, no fixed origin for this field of study is objectively identifiable. A few words here placing contemporary scientific trends within the context of past and anticipated achievements might be therefore instructive to readers. Popular experts on bioenergetics assign its beginnings as far back as the mid-18th century (e.g., Ernster, 1984) and as recently as the mid-20th century (e.g., Nicholls, 1982). Discrepancies between authorities on this matter chiefly result from how one defines bioenergetics and from what historic scientific milestones one measures as being crucial to the field's development. Modernists have several convincing reasons for affixing the initial date of bioenergetics to circa 1950, such as mounting evidence at that time indicating mechanisms of respiratory chain catalysis and ATP synthesis were located in the inner mitochondrial membrane of animals, in the thylakoid membrane of plant chloroplasts, and in the chromatophore or plasma membrane of photosynthetic bacteria. However, this perspective ignores the enormous significance of roughly 200 years of preceding research. Ernster (1984), utilizing a general characterization of bioenergetics as the biological process of acquiring energy from oxidative reactions, cites the independent experimental discoveries of oxygen by Joseph Priestly, Antoine Lavoisier, and Carl Scheele during the 1770s as the birth of bioenergetics. Each of these pioneering figures in chemistry tested the properties of their newly found gas through its influence on living organisms. Priestly, for example, proposed a functional relationship between oxygen and blood, verified vertebrates consume purified oxygen with improvements in health, and showed green plants produce oxygen. While Lavoisier, dispelling George Stahl's phlogiston theory of combustible materials, demonstrated respiring guinea pigs emit heat. Also instrumental in Ernster's scholarly dating of bioenergetics was Scheele's subsequent isolation of organic compounds, such as citric acid, lactic acid, and glycerol, from living tissue: Jan Ingenhousz, Jean Senebier, and Nicolas-Théodore de Saussure's initial observations of photosynthesis and cellular respiration by green plants: and Julius von Mayer's formulation of the First Law of Thermodynamics, which relates energy conservation through concepts of a system's internal energy, heat exchange, and work.

Preface XI

materials. Soon after, Jöns Berselius' hypothesis that organisms synthesize their own organic compounds via catalysts instead of vital forces took hold among some leading authorities. Nevertheless, vitalism continued to find its way into the description of life processes. For instance, Pasteur writing about his discovery of the importance of oxygen availability for sugar fermentation by yeast, to be later known as the Pasteur effect, argued for the exclusive dependency of intact cell structure, a variant of cell theory postulated by Matthias Schleiden, Theodor Schwann, and their predecessors, and "ferments", a set of biocatalysts represented as vital forces. Adherence to vitalism ironically retarded progress in studying energy transfer in living matter because it demanded that physicochemical processes mediating bioenergetics only reside in live media. Such an axiom enabled the false conclusion that more easily replicable and less resource-intensive test-tube chemistry techniques were unsuitable for investigating the

The last vestiges of vitalism stubbornly disappeared by the early 20th century largely because of Eduard Büchner's Nobel-prize-winning research. Büchner's demonstration that the Pasteur effect was reproducible from a cell-free extract of pressed brewer's yeast reinforced the opinion of Justus von Liebig that the bioproducts, if not the composition and operation, of metabolic pathways were accessible to bench science. A rapid succession of central findings ensued during the first part of the 1900s (cf. Ernster, 1984; Racker, 1980), such as the observation that inorganic phosphate and soluble cofactors or coenzymes, including a key pyridine substance first named cozymase by discoverers Arthur Harden and William Young (and later renamed nicotinamide adenine dinucleotide (NAD)), were needed for cellular energy metabolism. Further identification of enzymatic reactions and chemical intermediates of glycolysis, the catabolic modification of monosaccharide sugars to pyruvate fated for oxidation in the citric acid cycle, also served as important stages in the development of bioenergetics. Prime examples include the finding by Otto Warburg that cozymase helps oxidize glyceraldehyde-3-phosphate and that this process is associated with ATP synthesis, Carl Neuberg's discovery of carboxylase, an enzyme that catalyzes the decarboxylation of pyruvate, and the work of Gustav Embden, Nobel laureate Otto Meyerhof, and Jakub Parnas which explicated the cycle responsible for lactic acid generation from glucose during muscle contraction. Using preparations of working muscle, Karl Lohmann, Yellapragada Subbarow, and Cyrus Fiske also made giant contributions when they isolated and bioassayed creatine phosphate and ATP, showing ATP phosphorylates creatine after cleavage of creatine phosphate. Around the same period, David Keilin united the disparate views debated by Nobel laureates Otto Warburg and Heinrich Wieland on the role played by oxygen, hydrogen, iron-possessing enzymes, and insoluble cytostructures in respiratory activity. Keilin rediscovered the heme proteins or cytochromes, previously reported by Charles MacMunn in the 1880s, in the flight muscles of insects and perceptively conjectured their involvement as electron carriers between biological fuels and molecular oxygen. Later studies on mammalian heart muscle performed with his colleague E.F. Hartree inspired the eventual description of cellular respiration as a

chemistry of life.

Undoubtedly, these and other early contributions by skillful and conscientious scientists provided the foundation for our contemporary notions and understandings of bioenergetics. They established that oxygen was among the essential nutritional requirements for organisms to grow and fend-off infection and, perhaps more importantly, that cellular life derived energy and other substrate for life-sustaining work from their environments. But bioenergetics, as a discipline and a definition, started to take on its current identity only after the persistent ideology of vitalism, a belief that life was reducible to a natural or vital force, largely ceased to plague the natural sciences (cf. Ernster, 1984; Racker, 1980). In a cruder technological era, when determination of biomechanisms underlying many of life's processes often evaded physicochemical scrutiny, even clever scientists, such as Louis Pasteur, resorted to imprecise and invalid depictions of biological processes and substrates as vital forces. The early 19th century research of Friedrich Wöhler on synthesizing urea helped usher in the realization that organic substances were not alone the products of living organisms, but could be created by laboratory chemists using inorganic starting materials. Soon after, Jöns Berselius' hypothesis that organisms synthesize their own organic compounds via catalysts instead of vital forces took hold among some leading authorities. Nevertheless, vitalism continued to find its way into the description of life processes. For instance, Pasteur writing about his discovery of the importance of oxygen availability for sugar fermentation by yeast, to be later known as the Pasteur effect, argued for the exclusive dependency of intact cell structure, a variant of cell theory postulated by Matthias Schleiden, Theodor Schwann, and their predecessors, and "ferments", a set of biocatalysts represented as vital forces. Adherence to vitalism ironically retarded progress in studying energy transfer in living matter because it demanded that physicochemical processes mediating bioenergetics only reside in live media. Such an axiom enabled the false conclusion that more easily replicable and less resource-intensive test-tube chemistry techniques were unsuitable for investigating the chemistry of life.

X Preface

internal energy, heat exchange, and work.

contemporary scientific trends within the context of past and anticipated achievements might be therefore instructive to readers. Popular experts on bioenergetics assign its beginnings as far back as the mid-18th century (e.g., Ernster, 1984) and as recently as the mid-20th century (e.g., Nicholls, 1982). Discrepancies between authorities on this matter chiefly result from how one defines bioenergetics and from what historic scientific milestones one measures as being crucial to the field's development. Modernists have several convincing reasons for affixing the initial date of bioenergetics to circa 1950, such as mounting evidence at that time indicating mechanisms of respiratory chain catalysis and ATP synthesis were located in the inner mitochondrial membrane of animals, in the thylakoid membrane of plant chloroplasts, and in the chromatophore or plasma membrane of photosynthetic bacteria. However, this perspective ignores the enormous significance of roughly 200 years of preceding research. Ernster (1984), utilizing a general characterization of bioenergetics as the biological process of acquiring energy from oxidative reactions, cites the independent experimental discoveries of oxygen by Joseph Priestly, Antoine Lavoisier, and Carl Scheele during the 1770s as the birth of bioenergetics. Each of these pioneering figures in chemistry tested the properties of their newly found gas through its influence on living organisms. Priestly, for example, proposed a functional relationship between oxygen and blood, verified vertebrates consume purified oxygen with improvements in health, and showed green plants produce oxygen. While Lavoisier, dispelling George Stahl's phlogiston theory of combustible materials, demonstrated respiring guinea pigs emit heat. Also instrumental in Ernster's scholarly dating of bioenergetics was Scheele's subsequent isolation of organic compounds, such as citric acid, lactic acid, and glycerol, from living tissue: Jan Ingenhousz, Jean Senebier, and Nicolas-Théodore de Saussure's initial observations of photosynthesis and cellular respiration by green plants: and Julius von Mayer's formulation of the First Law of Thermodynamics, which relates energy conservation through concepts of a system's

Undoubtedly, these and other early contributions by skillful and conscientious scientists provided the foundation for our contemporary notions and understandings of bioenergetics. They established that oxygen was among the essential nutritional requirements for organisms to grow and fend-off infection and, perhaps more importantly, that cellular life derived energy and other substrate for life-sustaining work from their environments. But bioenergetics, as a discipline and a definition, started to take on its current identity only after the persistent ideology of vitalism, a belief that life was reducible to a natural or vital force, largely ceased to plague the natural sciences (cf. Ernster, 1984; Racker, 1980). In a cruder technological era, when determination of biomechanisms underlying many of life's processes often evaded physicochemical scrutiny, even clever scientists, such as Louis Pasteur, resorted to imprecise and invalid depictions of biological processes and substrates as vital forces. The early 19th century research of Friedrich Wöhler on synthesizing urea helped usher in the realization that organic substances were not alone the products of living organisms, but could be created by laboratory chemists using inorganic starting

The last vestiges of vitalism stubbornly disappeared by the early 20th century largely because of Eduard Büchner's Nobel-prize-winning research. Büchner's demonstration that the Pasteur effect was reproducible from a cell-free extract of pressed brewer's yeast reinforced the opinion of Justus von Liebig that the bioproducts, if not the composition and operation, of metabolic pathways were accessible to bench science. A rapid succession of central findings ensued during the first part of the 1900s (cf. Ernster, 1984; Racker, 1980), such as the observation that inorganic phosphate and soluble cofactors or coenzymes, including a key pyridine substance first named cozymase by discoverers Arthur Harden and William Young (and later renamed nicotinamide adenine dinucleotide (NAD)), were needed for cellular energy metabolism. Further identification of enzymatic reactions and chemical intermediates of glycolysis, the catabolic modification of monosaccharide sugars to pyruvate fated for oxidation in the citric acid cycle, also served as important stages in the development of bioenergetics. Prime examples include the finding by Otto Warburg that cozymase helps oxidize glyceraldehyde-3-phosphate and that this process is associated with ATP synthesis, Carl Neuberg's discovery of carboxylase, an enzyme that catalyzes the decarboxylation of pyruvate, and the work of Gustav Embden, Nobel laureate Otto Meyerhof, and Jakub Parnas which explicated the cycle responsible for lactic acid generation from glucose during muscle contraction. Using preparations of working muscle, Karl Lohmann, Yellapragada Subbarow, and Cyrus Fiske also made giant contributions when they isolated and bioassayed creatine phosphate and ATP, showing ATP phosphorylates creatine after cleavage of creatine phosphate. Around the same period, David Keilin united the disparate views debated by Nobel laureates Otto Warburg and Heinrich Wieland on the role played by oxygen, hydrogen, iron-possessing enzymes, and insoluble cytostructures in respiratory activity. Keilin rediscovered the heme proteins or cytochromes, previously reported by Charles MacMunn in the 1880s, in the flight muscles of insects and perceptively conjectured their involvement as electron carriers between biological fuels and molecular oxygen. Later studies on mammalian heart muscle performed with his colleague E.F. Hartree inspired the eventual description of cellular respiration as a chain of electron-transporting redox catalysts that begins with NADH dehydrogenase and ends with cytochrome *a*3. Kreilin's advancements in understanding aerobic respiration were followed by Nobel laureates Albert Szent-Györgi and Hans Krebs' elaboration of the amphibolic citric acid cycle, which creates usable energy from the catabolism of carbohydrates, fats, and proteins.

Preface XIII

better resolution and reconstitution protocols, allowed studies into respiratory chain kinetics and metabolic states in intact and subparticulate mitochondrial preparations. With such methodology, Chance and coworkers, for instance, demonstrated sites of respiratory chain phosphorylation, the concentration of electron-transport catalysts, the reversibility of oxidative phosphorylation, and the energy-linked uptake of divalent cations. Additional work carried out in the laboratory of Nobel laureate Paul Boyer exposed partial reactions involving the association of H2O and ATP to inorganic phosphate. Boyer subsequently speculated that the mechanism for ATP synthesis primarily required energy for phosphate binding and ATP release. Three identical circularly arranged catalytic sites of a single enzyme were thought to perform sequential changes in binding driven by rotation of an internal catalytic subunit. Confirmation of membrane-associated ATPases, electron transport complexes, and the involvement of ubiquinone, nonheme iron proteins, and metalloflavoproteins as redox carriers in the respiratory chain helped to refine these concepts. For example, Efraim Racker and his colleagues Anima Datta, Maynard Pullmand, and Harvey Penefsky identified and purified an important enzyme, called Factor 1 or F1, needed to create the proton gradient for ATP synthesis. Racker's research team showed Factor 1 was part of the ATP synthase Complex V, a peripheral membrane protein required for oxidative phosphorylation. By 1960, cumulative findings involving the nature of membranedependent energy transport and synthesis in animal tissues led to Mitchell's groundbreaking chemiosmotic hypothesis of oxidative phosphorylation, where a mitochondrial transmembrane proton gradient enables energy transfer between electron transport and ATP synthesis. A few years latter, Mitchell generalized his model to photosynthesis. Another decade would pass until critics of the chemiosmotic hypothesis relented to mounting experimental findings against earlier arguments in

favor of energy transfer by individual respiratory-chain catalysts.

Meanwhile, trends in photosynthesis and origins of life research commensurate with developments in the study of mitochondrial physiology encouraged a more comprehensive view of cell metabolism across phylogeny and presumptive protolife (cf. Ernster & Schatz, 1981; Fuller, 1999; Jagendorf, 1998; San Pietro, 2008; Orgel, 2004). From the 1930s to the 1970s, researchers, including Cornelis Van Niel, Robert Emerson, Robin Hill, Daniel Arnon, Anthony San Pietro, Horst Witt, André Jagendorf, Mordhay Avron, Achim Trebst, and Nobel laureates Melvin Calvin, Johann Deisenhoffer, Robert Huber, and Rudolph Marcus, made substantial progress toward elaborating the roles of, among other substrate, chloroplasts, chromatophores, photosystems, and photopigments in the light harvesting and energy conversion of photosynthesis. 19th century scientists knew chloroplasts as the site of carbon dioxide assimilation and sugar and starch formation in plants. Studying photosynthetic microbes, Van Niel and Emerson made respective significant contributions in the photochemistry of bacteria, algae, and diatoms, such as identifying H as the reducing agent of CO2 in anoxygenic photosynthesis and identifying two separate photosystems, described decades later by Louis Duysens as PSI and PSII, containing photopigments of different spectral absorption. Employing artificial reducing agents, including iron oxalate and

But not until the 1940s and 1950s, as acknowledged by Peter Mitchell in his Nobel lecture, was much of Keilin's ideas on aerobic respiration largely brought to completion. Nobelist Fritz Lipmann a decade following the discovery of ATP suggested ATP was the main molecule for cellular energy transport, with hydrolysis at one of two phosphodiester bonds liberating stored energy for biological work at distant cell sites. Lipmann also developed the idea that respiration occurred through phosphorylation of an oxidized electron donor. In part, this model found support from thiol ester mechanisms of glycolytic phosphylation and from results of V.A. Belitser and E.T. Tsybakova that confirmed at least two ATP molecules arise from each atom of oxygen consumed. The growing belief of many researchers was that if respiration drives ATP synthesis, then phosphorylation must be coupled to a series of mostly exergonic reactions that culminate in the reduction of O2 to H2O. Morris Friedkin and Albert Lehninger took a big step toward proving this hypothesis in the late 1940s when they confirmed respiration was a chain of events involving phosphorylation. Several years afterwards, experiments performed by Nobelist Albert Claude and collaborators B.H. Hogeboom and R.D. Hotchkiss and by Eugene Kennedy and Lehninger revealed that mitochondria are the sites of cellular respiration and of oxidative phosphorylation, the citric acid cycle, and fatty acid oxidation. Together, these and additional ultrastructural findings brought about through improved use of tissue-fractionation and microscopy techniques, anaerobiosis, and respiratory inhibitors and uncouplers paved the path for redefining and localizing what Keilin termed a "colloidal surface" for animal cell respiration to the folded inner mitochondrial membrane (cf. Ernster & Schatz, 1981; Slater, 1981).

Throughout the mid-20th century, concerted efforts of innumerable scientists were aimed at uncovering the details of respiratory-chain constituents, operation, and localization. Much of the research of this era, such as that conducted by Fritz Lipmann, Albert Lehninger, Paul Boyer, David Green, Efraim Racker, Bill Slater, Henry Lardy, and Britton Chance, supported the concept of respiration as the processes of electron transport and ATP synthesis coupled to energy-rich nonphosphorylated intermediates (cf. Ernster, 1984; Ernster & Schatz, 1981; Racker, 1980). This "chemical" model, first proffered by Slater in 1953, diverged from Lipmann's earlier suggested mechanism. Slater's conceptualization benefited from publication of new evidence, some of which were reported from Lipmann's group, implicating thiol esters and coenzyme A in phosphorylations linked to α-ketoglutarate and pyruvate oxidation. Later research would show this model of individual catalysts, each thought directly capable of ATP synthesis, was an over-simplification. Furthermore, the introduction of sensitive experimental methods for analysis of mitochondrial electron transport, such as combined use of dual-wavelength spectrophotometry and oxygen electrodes and better resolution and reconstitution protocols, allowed studies into respiratory chain kinetics and metabolic states in intact and subparticulate mitochondrial preparations. With such methodology, Chance and coworkers, for instance, demonstrated sites of respiratory chain phosphorylation, the concentration of electron-transport catalysts, the reversibility of oxidative phosphorylation, and the energy-linked uptake of divalent cations. Additional work carried out in the laboratory of Nobel laureate Paul Boyer exposed partial reactions involving the association of H2O and ATP to inorganic phosphate. Boyer subsequently speculated that the mechanism for ATP synthesis primarily required energy for phosphate binding and ATP release. Three identical circularly arranged catalytic sites of a single enzyme were thought to perform sequential changes in binding driven by rotation of an internal catalytic subunit. Confirmation of membrane-associated ATPases, electron transport complexes, and the involvement of ubiquinone, nonheme iron proteins, and metalloflavoproteins as redox carriers in the respiratory chain helped to refine these concepts. For example, Efraim Racker and his colleagues Anima Datta, Maynard Pullmand, and Harvey Penefsky identified and purified an important enzyme, called Factor 1 or F1, needed to create the proton gradient for ATP synthesis. Racker's research team showed Factor 1 was part of the ATP synthase Complex V, a peripheral membrane protein required for oxidative phosphorylation. By 1960, cumulative findings involving the nature of membranedependent energy transport and synthesis in animal tissues led to Mitchell's groundbreaking chemiosmotic hypothesis of oxidative phosphorylation, where a mitochondrial transmembrane proton gradient enables energy transfer between electron transport and ATP synthesis. A few years latter, Mitchell generalized his model to photosynthesis. Another decade would pass until critics of the chemiosmotic hypothesis relented to mounting experimental findings against earlier arguments in favor of energy transfer by individual respiratory-chain catalysts.

XII Preface

chain of electron-transporting redox catalysts that begins with NADH dehydrogenase and ends with cytochrome *a*3. Kreilin's advancements in understanding aerobic respiration were followed by Nobel laureates Albert Szent-Györgi and Hans Krebs' elaboration of the amphibolic citric acid cycle, which creates usable energy from the

But not until the 1940s and 1950s, as acknowledged by Peter Mitchell in his Nobel lecture, was much of Keilin's ideas on aerobic respiration largely brought to completion. Nobelist Fritz Lipmann a decade following the discovery of ATP suggested ATP was the main molecule for cellular energy transport, with hydrolysis at one of two phosphodiester bonds liberating stored energy for biological work at distant cell sites. Lipmann also developed the idea that respiration occurred through phosphorylation of an oxidized electron donor. In part, this model found support from thiol ester mechanisms of glycolytic phosphylation and from results of V.A. Belitser and E.T. Tsybakova that confirmed at least two ATP molecules arise from each atom of oxygen consumed. The growing belief of many researchers was that if respiration drives ATP synthesis, then phosphorylation must be coupled to a series of mostly exergonic reactions that culminate in the reduction of O2 to H2O. Morris Friedkin and Albert Lehninger took a big step toward proving this hypothesis in the late 1940s when they confirmed respiration was a chain of events involving phosphorylation. Several years afterwards, experiments performed by Nobelist Albert Claude and collaborators B.H. Hogeboom and R.D. Hotchkiss and by Eugene Kennedy and Lehninger revealed that mitochondria are the sites of cellular respiration and of oxidative phosphorylation, the citric acid cycle, and fatty acid oxidation. Together, these and additional ultrastructural findings brought about through improved use of tissue-fractionation and microscopy techniques, anaerobiosis, and respiratory inhibitors and uncouplers paved the path for redefining and localizing what Keilin termed a "colloidal surface" for animal cell respiration to the folded inner

mitochondrial membrane (cf. Ernster & Schatz, 1981; Slater, 1981).

Throughout the mid-20th century, concerted efforts of innumerable scientists were aimed at uncovering the details of respiratory-chain constituents, operation, and localization. Much of the research of this era, such as that conducted by Fritz Lipmann, Albert Lehninger, Paul Boyer, David Green, Efraim Racker, Bill Slater, Henry Lardy, and Britton Chance, supported the concept of respiration as the processes of electron transport and ATP synthesis coupled to energy-rich nonphosphorylated intermediates (cf. Ernster, 1984; Ernster & Schatz, 1981; Racker, 1980). This "chemical" model, first proffered by Slater in 1953, diverged from Lipmann's earlier suggested mechanism. Slater's conceptualization benefited from publication of new evidence, some of which were reported from Lipmann's group, implicating thiol esters and coenzyme A in phosphorylations linked to α-ketoglutarate and pyruvate oxidation. Later research would show this model of individual catalysts, each thought directly capable of ATP synthesis, was an over-simplification. Furthermore, the introduction of sensitive experimental methods for analysis of mitochondrial electron transport, such as combined use of dual-wavelength spectrophotometry and oxygen electrodes and

catabolism of carbohydrates, fats, and proteins.

Meanwhile, trends in photosynthesis and origins of life research commensurate with developments in the study of mitochondrial physiology encouraged a more comprehensive view of cell metabolism across phylogeny and presumptive protolife (cf. Ernster & Schatz, 1981; Fuller, 1999; Jagendorf, 1998; San Pietro, 2008; Orgel, 2004). From the 1930s to the 1970s, researchers, including Cornelis Van Niel, Robert Emerson, Robin Hill, Daniel Arnon, Anthony San Pietro, Horst Witt, André Jagendorf, Mordhay Avron, Achim Trebst, and Nobel laureates Melvin Calvin, Johann Deisenhoffer, Robert Huber, and Rudolph Marcus, made substantial progress toward elaborating the roles of, among other substrate, chloroplasts, chromatophores, photosystems, and photopigments in the light harvesting and energy conversion of photosynthesis. 19th century scientists knew chloroplasts as the site of carbon dioxide assimilation and sugar and starch formation in plants. Studying photosynthetic microbes, Van Niel and Emerson made respective significant contributions in the photochemistry of bacteria, algae, and diatoms, such as identifying H as the reducing agent of CO2 in anoxygenic photosynthesis and identifying two separate photosystems, described decades later by Louis Duysens as PSI and PSII, containing photopigments of different spectral absorption. Employing artificial reducing agents, including iron oxalate and ferricyanide, Hill first showed chloroplasts evolve oxygen, an intermediate-mediated photo-ionization process now known as the Hill reaction. Martin Kamen and Samuel Rueben using algal preparations next revealed that O2 liberation during the Hill reaction originates from H2O. In contrast to energy-capturing and -storing light reactions, Calvin, Andrew Benson, and James Bassham explained the pathway for CO2 fixation and carbohydrate generation via dark reactions, oftentimes referred to as the Calvin or Calvin-Benson cycle. Without fully characterizing the photosynthetic apparati and pathways of photoautotrophs, similarities to mitochondrial bioenergetics were emerging for light-dependent ATP synthesis and photophosphorylation. In the 1950s, Arnon, Frenkel, Jagendorf, Marcus and others began to build upon Van Niel's demonstration that photosyntheis is a redox reaction. These scientists ascertained the sites and kinetics of light and dark reactions. Among the first findings were the localization of light-induced electron-transport-coupled ATP synthesis and photophosphorylation to plant thylakoid membranes and bacterial plasma membranes. Exciting achievements in distinguishing the subunits, cofactors, and catalytic sequence of photosynthesis shortly followed for light-harvesting complexes and reaction centers (cf. Barber, 2004; Fuller, 1999). In addition, a surprising happening in this period of science directed the field of bioenergetics in a new bearing marked by 100-year-old synthetic chemistry. Stanley Miller's 1953 report of amino acid synthesis in an electric discharge commenced the search for prebiotic chemistry capable of sustaining the emergence and evolution of life. Miller's findings, reminiscent of the contentious exchanges between organic and inorganic chemists over the validity of vitalism, require atmospheric conditions now considered unlikely for early Earth. However, his research stimulated discussion and study into the advent of cellular life from putative antecedent evolutionary states, endeavors that continue today.

Preface XV

energetics evolved from primitive bacteria-like symbiots incorporated into hosts. Prior to being expressed as cellular organelles, these symbiots likely adapted to unstable host environments, where specialized energy-transformation and –transport

Interests in the study of membrane bioenergetics transitioned to study of molecular bioenergetics during the closing decades of the last millennium. This paradigm shift primarily resulted from development and wide availability of new experimental and computational technologies useful for examination of the static and dynamic structure of molecules as well as their biological functions. In the late 1950s and early 1960s, Xray crystallography, liquid scintillation, zone-sedimentation-velocity and equilibriumgradient centrifugation, polyacrylamide gel electrophoresis, and high-performance liquid chromatography were cutting-edge methods for extracting information about the structure of tissue-isolated proteins. People, such as Racker, Chance, Lehninger, and J.B. Chappell, exploited these tools to discover, for example, ionophores, anion translocators, coupling factors, and proton pumps involved in mitochondrial energetics. Similar results were obtained from those researching photosynthesis (cf. Barber, 2004; Fuller, 1999). While these and derivative methods still play an important role in biochemistry research, intervening years of improving technologies gave rise to, among other advances, restriction cleavage mapping, Southern blotting, gene cloning, site-directed mutagenesis, DNA and protein sequencing, DNA amplification, *in situ* hybridization labeling, scanning and tunneling microscopy, and nuclear magnetic resonance. The bioenergeticist's toolbox brims with powerful techniques to competently practice his/her trade and to satisfy his/her curiosities. Now researchers may track phosphotransfer networks, such as chains of sequential rapidly equilibrating reactions catalyzed by creatine kinase and adenylate kinase, for distant intracellular delivery of ATP and removal of ATPase byproducts in living cells (cf. Dzeja & Terzic, 2003). Or, one may evaluate the transcriptional responses of photorespiratory genes (cf. Foyer et al., 2009). Even physicians exploit new technologies involving dietary restrictions, antioxidants, and combinations of uncoupling agents and electron-transport inhibitors to effectively treat energetically ravenous neoplasms, degenerative diseases, and apoptotic tissue damage and aging due to mitochondrial free radical production (cf. Adam-Vizi & Chinopoulos, 2006; Demetrius et al., 2010; Wallace, 2005; Wallace & Starkov, 2000). Yet, despite modern technological innovations, a surprising lack of knowledge pervades the discipline of bioenergetics, ranging from the exact structure and conformational changes of mitochondrial ion channels (O'Rourke, 2007) to how mutations and epigenetic control over bioenergetics genes directly and reciprocally affect the evolution of life forms,

mechanisms were advantageous for progressively increasing mutualism.

their social groups, and inhabited ecological niches (cf. Wallace, 2010).

Certain of these problems in molecular bioenergetics will be undeniably solved by applying the computational framework imparted by quantum mechanics (and by perhaps more unifying extradimensional and holographic physics). At the edge between macroscopic and microscopic scales, classical Newtonian mechanics, which dominated the fundamental principles of bioenergetics almost since the field's

The possibility that polymerization and even template-directed synthesis of sugars, purines, pyrimidines, and nucleosides could arise in a prebiotic microenvironment caused debate between supporters of protein- and lipid-first hypotheses (cf. Fox, 1988). In a moderately reducing atmosphere or hydrothermal environment believed common to prebiotic Earth, nucleotide starting materials could have been produced by aqueous or solvent-less reactions, such as sugar synthesis from formose or synthesis of amino acids and proteins from CO2 reduction over ferrous sulfide. By the late 1960s, such conditions were independently proposed by Leslie Orgel, Francis Crick, and C. Woese to evolve naked protoreplicators made of macromolecular nucleotides, now typically labeled the RNA- and DNA-world hypotheses. Simple self-replicating molecules were largely thought to unreliably code, synthesize, select, and propagate metabolic enzymes without semipermeable shells. An appealing aspect on variations of this promising model for early metabolism defended by evolutionists Orgel, Sidney Fox, and others is that membrane-like shells initially served to encapsulate the contents of protocells then evolved to compartmentalize cell structures and functions to regulate cell energetics and other processes under ambient ecological pressure. That bioprocesses of comparatively sophisticated mitochondria and chloroplasts entail operation of membrane-associated components partly indicated eukaryotic cell energetics evolved from primitive bacteria-like symbiots incorporated into hosts. Prior to being expressed as cellular organelles, these symbiots likely adapted to unstable host environments, where specialized energy-transformation and –transport mechanisms were advantageous for progressively increasing mutualism.

XIV Preface

ferricyanide, Hill first showed chloroplasts evolve oxygen, an intermediate-mediated photo-ionization process now known as the Hill reaction. Martin Kamen and Samuel Rueben using algal preparations next revealed that O2 liberation during the Hill reaction originates from H2O. In contrast to energy-capturing and -storing light reactions, Calvin, Andrew Benson, and James Bassham explained the pathway for CO2 fixation and carbohydrate generation via dark reactions, oftentimes referred to as the Calvin or Calvin-Benson cycle. Without fully characterizing the photosynthetic apparati and pathways of photoautotrophs, similarities to mitochondrial bioenergetics were emerging for light-dependent ATP synthesis and photophosphorylation. In the 1950s, Arnon, Frenkel, Jagendorf, Marcus and others began to build upon Van Niel's demonstration that photosyntheis is a redox reaction. These scientists ascertained the sites and kinetics of light and dark reactions. Among the first findings were the localization of light-induced electron-transport-coupled ATP synthesis and photophosphorylation to plant thylakoid membranes and bacterial plasma membranes. Exciting achievements in distinguishing the subunits, cofactors, and catalytic sequence of photosynthesis shortly followed for light-harvesting complexes and reaction centers (cf. Barber, 2004; Fuller, 1999). In addition, a surprising happening in this period of science directed the field of bioenergetics in a new bearing marked by 100-year-old synthetic chemistry. Stanley Miller's 1953 report of amino acid synthesis in an electric discharge commenced the search for prebiotic chemistry capable of sustaining the emergence and evolution of life. Miller's findings, reminiscent of the contentious exchanges between organic and inorganic chemists over the validity of vitalism, require atmospheric conditions now considered unlikely for early Earth. However, his research stimulated discussion and study into the advent of cellular life

from putative antecedent evolutionary states, endeavors that continue today.

The possibility that polymerization and even template-directed synthesis of sugars, purines, pyrimidines, and nucleosides could arise in a prebiotic microenvironment caused debate between supporters of protein- and lipid-first hypotheses (cf. Fox, 1988). In a moderately reducing atmosphere or hydrothermal environment believed common to prebiotic Earth, nucleotide starting materials could have been produced by aqueous or solvent-less reactions, such as sugar synthesis from formose or synthesis of amino acids and proteins from CO2 reduction over ferrous sulfide. By the late 1960s, such conditions were independently proposed by Leslie Orgel, Francis Crick, and C. Woese to evolve naked protoreplicators made of macromolecular nucleotides, now typically labeled the RNA- and DNA-world hypotheses. Simple self-replicating molecules were largely thought to unreliably code, synthesize, select, and propagate metabolic enzymes without semipermeable shells. An appealing aspect on variations of this promising model for early metabolism defended by evolutionists Orgel, Sidney Fox, and others is that membrane-like shells initially served to encapsulate the contents of protocells then evolved to compartmentalize cell structures and functions to regulate cell energetics and other processes under ambient ecological pressure. That bioprocesses of comparatively sophisticated mitochondria and chloroplasts entail operation of membrane-associated components partly indicated eukaryotic cell Interests in the study of membrane bioenergetics transitioned to study of molecular bioenergetics during the closing decades of the last millennium. This paradigm shift primarily resulted from development and wide availability of new experimental and computational technologies useful for examination of the static and dynamic structure of molecules as well as their biological functions. In the late 1950s and early 1960s, Xray crystallography, liquid scintillation, zone-sedimentation-velocity and equilibriumgradient centrifugation, polyacrylamide gel electrophoresis, and high-performance liquid chromatography were cutting-edge methods for extracting information about the structure of tissue-isolated proteins. People, such as Racker, Chance, Lehninger, and J.B. Chappell, exploited these tools to discover, for example, ionophores, anion translocators, coupling factors, and proton pumps involved in mitochondrial energetics. Similar results were obtained from those researching photosynthesis (cf. Barber, 2004; Fuller, 1999). While these and derivative methods still play an important role in biochemistry research, intervening years of improving technologies gave rise to, among other advances, restriction cleavage mapping, Southern blotting, gene cloning, site-directed mutagenesis, DNA and protein sequencing, DNA amplification, *in situ* hybridization labeling, scanning and tunneling microscopy, and nuclear magnetic resonance. The bioenergeticist's toolbox brims with powerful techniques to competently practice his/her trade and to satisfy his/her curiosities. Now researchers may track phosphotransfer networks, such as chains of sequential rapidly equilibrating reactions catalyzed by creatine kinase and adenylate kinase, for distant intracellular delivery of ATP and removal of ATPase byproducts in living cells (cf. Dzeja & Terzic, 2003). Or, one may evaluate the transcriptional responses of photorespiratory genes (cf. Foyer et al., 2009). Even physicians exploit new technologies involving dietary restrictions, antioxidants, and combinations of uncoupling agents and electron-transport inhibitors to effectively treat energetically ravenous neoplasms, degenerative diseases, and apoptotic tissue damage and aging due to mitochondrial free radical production (cf. Adam-Vizi & Chinopoulos, 2006; Demetrius et al., 2010; Wallace, 2005; Wallace & Starkov, 2000). Yet, despite modern technological innovations, a surprising lack of knowledge pervades the discipline of bioenergetics, ranging from the exact structure and conformational changes of mitochondrial ion channels (O'Rourke, 2007) to how mutations and epigenetic control over bioenergetics genes directly and reciprocally affect the evolution of life forms, their social groups, and inhabited ecological niches (cf. Wallace, 2010).

Certain of these problems in molecular bioenergetics will be undeniably solved by applying the computational framework imparted by quantum mechanics (and by perhaps more unifying extradimensional and holographic physics). At the edge between macroscopic and microscopic scales, classical Newtonian mechanics, which dominated the fundamental principles of bioenergetics almost since the field's inception, begin to acquiesce to the trickiness of quantum phenomena. Hints of the power that quantum mechanics would give bioenergeticists to explain cell energetics appeared in the early 1960s, with, for instance, the perceptive forays of collaborators Britton Chance and Don DeVault into the effects of quantum tunneling on cytochrome oxidation rates. Present-day bienergeticists must also confront problems in both classical and quantum physicochemistry to gain a fuller appreciation of life processes. As a result, the discipline of bioenergetics is being infused by the start of a new revolution in science -- *quantum biology*. Leaders in this area of research, such as Koichiro Matsuno, Klaus Schulten, Peter Wolynes, Lloyd Demetrious, Johnjoe McFadden, and other individuals, have discovered quantum influences that govern energy transformation in different biological systems, including light capture and energy transduction by bacterial photosynthetic apparati (cf. Trevors & Masson, 2010), allometric scaling of metabolic rates across phylogeny (Demetrius, 2003, 2006; Demetrius & Tuszynski, 2010), regulation of oxidative phosphorylation and glycolysis in cancer cells (Demetrius et al., 2010), engine-like properties of the citric acid cycle under hydrothermal flow (Matsuno, 2006), adaptive mutation of lactose-fermenting bacteria (McFadden & Al-Khalili, 1999), and learned changes in the kinetics of autocatalytic Ca2+ reactions that tune behavioral output and metabolic expenditures in microbes and possibly plants and animals (Clark, 2010a-e, 2011a-c, 2012, in press a, b).

Preface XVII

**Kevin B. Clark** Portland, OR

USA

and policies. I further extend my gratitude to both the InTech Information Technology Department for clarifying technical issues caused by incompatible computer software and the Intech Production Department and countless unnamed in-house editorial staff

Adam-Vizi, V. & Chinopoulos, C. (2006). Bioenergetics and the formation of

Barber, J. (2004). Engine of life and big bang of evolution: A personal perspective.

Clark, K.B. (2010a). Origins of learned reciprocity in solitary ciliates searching grouped

Clark, K.B. (2010b). Bose-Einstein condensates form in heuristics learned by ciliates

Clark, K.B. (2010c). On classical and quantum error-correction in ciliate mate selection.

Clark, K.B. (2010d). Arrhenius-kinetics evidence for quantum tunneling in microbial

Clark, K.B. (2010e). Quantum 'social' intelligences expressed by microbes. *SciTopics*,

Clark, K.B. (2011b). The social insights and analyses of ciliates. *SciTopics*,

Clark, K.B. (2011c). Live soft-matter quantum computing. In: *Computer Search*

Clark, K.B. (2012). Social biases determine spatiotemporal sparseness of ciliate mating

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heuristics. *Communicative & Integrative Biology*, Vol. 5, No. 1, pp. 3-11, ISSN

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members for their efforts in launching this single edited collection.

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61122-527-3, Hauppauge, New York, USA

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obes.html.

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New York, USA

**References**

Although far from being exhaustive, the preceding historical survey illustrates that bioenergetics has become a very fertile and diverse research field in the span of a few centuries. Its accepted importance for chemistry and biology is underscored by the respectable number of Noble prizes awarded to scientists investigating aspects of bioenergetics (cf. Govindjee & Krogmann, 2002). I confidently expect this honored tradition to continue. As this century progresses, many significant unanswered questions of bygone and of incipient scientific generations will be tackled with fresh approaches toward bioenergetics and the life sciences. Indeed, a better understanding of bioenergetics at all levels of physical structure and function will become critical to resolving some of the most pressing concerns and ambitions of humanity, including, but not limited to, manned deep space travel, adaptation to increasingly extreme environments and habitat destruction, development of cures for cancer and metabolic pathologies, the search for extraterrestrial life, improving physical performance, creation of alternative green technologies, perfecting yield and health of aqua- and agricultural products, and management of parasitism and infectious disease. I hope the contents of this book on bioenergetics will help inspire contemporary and future scientists to meet and overcome the above and additional challenges.

Finally, I thank InTech for inviting me to edit this volume. I wish to acknowledge the indispensable contributions of many individuals in preparing *Bioenergetics*. Foremost among this group of people is the chapter authors. Without their labor, insights, and openness to editorial suggestion, our undertaking would have resulted in a poorer quality publication, if not downright failure. The work of Ms. Maja Jukic, Intech's Publishing Process Manager for *Bioenergetics*, was also exemplary in her diligence to accommodate author needs and for assisting me with InTech publishing procedures and policies. I further extend my gratitude to both the InTech Information Technology Department for clarifying technical issues caused by incompatible computer software and the Intech Production Department and countless unnamed in-house editorial staff members for their efforts in launching this single edited collection.

> **Kevin B. Clark** Portland, OR USA

#### **References**

XVI Preface

inception, begin to acquiesce to the trickiness of quantum phenomena. Hints of the power that quantum mechanics would give bioenergeticists to explain cell energetics appeared in the early 1960s, with, for instance, the perceptive forays of collaborators Britton Chance and Don DeVault into the effects of quantum tunneling on cytochrome oxidation rates. Present-day bienergeticists must also confront problems in both classical and quantum physicochemistry to gain a fuller appreciation of life processes. As a result, the discipline of bioenergetics is being infused by the start of a new revolution in science -- *quantum biology*. Leaders in this area of research, such as Koichiro Matsuno, Klaus Schulten, Peter Wolynes, Lloyd Demetrious, Johnjoe McFadden, and other individuals, have discovered quantum influences that govern energy transformation in different biological systems, including light capture and energy transduction by bacterial photosynthetic apparati (cf. Trevors & Masson, 2010), allometric scaling of metabolic rates across phylogeny (Demetrius, 2003, 2006; Demetrius & Tuszynski, 2010), regulation of oxidative phosphorylation and glycolysis in cancer cells (Demetrius et al., 2010), engine-like properties of the citric acid cycle under hydrothermal flow (Matsuno, 2006), adaptive mutation of lactose-fermenting bacteria (McFadden & Al-Khalili, 1999), and learned changes in the kinetics of autocatalytic Ca2+ reactions that tune behavioral output and metabolic expenditures in microbes and possibly plants and animals (Clark, 2010a-e, 2011a-c, 2012, in press a, b).

Although far from being exhaustive, the preceding historical survey illustrates that bioenergetics has become a very fertile and diverse research field in the span of a few centuries. Its accepted importance for chemistry and biology is underscored by the respectable number of Noble prizes awarded to scientists investigating aspects of bioenergetics (cf. Govindjee & Krogmann, 2002). I confidently expect this honored tradition to continue. As this century progresses, many significant unanswered questions of bygone and of incipient scientific generations will be tackled with fresh approaches toward bioenergetics and the life sciences. Indeed, a better understanding of bioenergetics at all levels of physical structure and function will become critical to resolving some of the most pressing concerns and ambitions of humanity, including, but not limited to, manned deep space travel, adaptation to increasingly extreme environments and habitat destruction, development of cures for cancer and metabolic pathologies, the search for extraterrestrial life, improving physical performance, creation of alternative green technologies, perfecting yield and health of aqua- and agricultural products, and management of parasitism and infectious disease. I hope the contents of this book on bioenergetics will help inspire contemporary and future

scientists to meet and overcome the above and additional challenges.

Finally, I thank InTech for inviting me to edit this volume. I wish to acknowledge the indispensable contributions of many individuals in preparing *Bioenergetics*. Foremost among this group of people is the chapter authors. Without their labor, insights, and openness to editorial suggestion, our undertaking would have resulted in a poorer quality publication, if not downright failure. The work of Ms. Maja Jukic, Intech's Publishing Process Manager for *Bioenergetics*, was also exemplary in her diligence to accommodate author needs and for assisting me with InTech publishing procedures


Clark, K.B. (in press b). The mating judgments of microbes. In: *Social Learning Theory*, K.B. Clark, (Ed.), Nova Science Publishers, Inc., Hauppauge, New York, USA

Preface XIX

Racker, E. (1980). From Pasteur to Mitchell: A hundred years of bioenergetics. *Federation Proceedings*, Vol. 39, No. 2, pp. 210-215, ISSN 0014-9446 San Pietro, A. (2008). Memories: From Protein synthesis to photosynthesis. *Photosynthesis Research*, Vol. 96, No. 3, pp. 185-199, ISSN 0166-8595 Slater, E.C. (1981). A short history of the biochemistry of mitochondria. In:

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**Part 1** 

**Reviews of Bioenergetics Applied** 

**to Life Span and Disease** 

**Part 1** 

**Reviews of Bioenergetics Applied to Life Span and Disease** 

*Brazil* 

**Antioxidant Action of Mobile** 

 Juliana C. Araújo-Chaves3, Felipe S. Pessoto2, Mayara K. Kisaki1 and Vivian W. R. Moraes1

> *1Universidade Federal do ABC 2Universidade Federal de São Paulo 3Universidade de Mogi das Cruzes*

 **Electron Carriers of the Respiratory Chain** 

Both oxidative photophosphorylation and oxidative phosphorylation are dependent on electron transport chains sharing similarities that are suggestive of evolution of a chemolithotrophy-based common ancestor (conversion hypothesis). Therefore, an early form of electron transport chain with oxidative phosphorylation that is known as prerespiration was able of donating electrons to terminal acceptors available in the primitive reducing biosphere. In the evolutionary pathway this apparatus was supplemented by a photocatalyst capable of a redox reaction. Therefore, oxygenic photosynthesis was a late event during evolution that was preceded by anoxygenic photosynthesis. The development of the manganese complex able to promote water oxidation was a key event in developing oxygenic photosynthesis (Xiong & Bauer, 2002; Bennnown, 1982; Castresanal et al., 1994). The development of oxygenic photosynthesis was one of the most important events in the biological evolution because it changed the redox balance on Earth and created conditions for the biological evolution to more complex life forms. Molecular data showing cytochrome oxidase in the common ancestor of Archaea and Bacteria and an existing cytochrome oxidase in nitrogen-fixing bacteria living in an environment where the level of oxygen was very low are indicia that aerobic metabolism could be present in an ancient organism, prior to the appearance of eubacterial oxygenic photosynthetic organisms. Although the hypothesis that aerobic metabolism arose several times in evolution after oxygenic photosynthesis is not sustained by the above mentioned data, the widespread use of molecular oxygen as final acceptor of electrons resulting from the oxidation of biological fuels was an evolutionary acquisition subsequent to the oxygen photosynthesis. The use of molecular oxygen as final acceptor of electrons removed from biological fuels resulted in a significant improvement of energy yield, a crucial event for the rise of complex heterotrophic organisms. According to the endosymbiotic theory, the respiratory chain present in prokaryotes was transferred to eukaryotes and resulted in cells bearing mitochondria. At the present step of the biological evolution, the aerobic oxidation of biological fuels occurs in the respiratory chain apparatus of the cell membrane of

**1. Introduction** 

**1.1 Evolutionary aspects** 

Iseli L. Nantes1, Tiago Rodrigues1, César H. Yokomizo2,
