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Energy and Metabolism Raul K. Suarez*1 ABSTRACT Although firmly grounded in metabolic biochemistry, the study of energy metabolism has gone well beyond this discipline and become integrative and comparative as well as ecological and evolutionary in scope. At the cellular level, ATP is hydrolyzed by energy-expending processes and resynthesized by pathways in bioenergetics. A significant development in the study of bioenergetics is the realization that fluxes through pathways as well as metabolic rates in cells, tissues, organs, and whole organisms are “system properties.” Therefore, studies of energy metabolism have become, increasingly, experiments in systems biology. A significant challenge continues to be the integration of phenomena over multiple levels of organization. Body mass and temperature are said to account for most of the variation in metabolic rates found in nature. A mechanistic foundation for the understanding of these patterns is outlined. It is emphasized that evolution, leading to adaptation to diverse lifestyles and environments, has resulted in a tremendous amount of deviation from popularly accepted scaling “rules.” This is especially so in the deep sea which constitutes most of the biosphere. C 2012 American Physiological Society. Compr Physiol 2:2527- 2540, 2012. Introduction The study of the biology of energy expenditure has become part of the research agenda of comparative physiology (112). Cells expend energy mainly in the synthesis of large The most noble aim of the biochemist, molecules, active transport across membranes, and the per- often discussed when inebriate, seldom when sober, formance of mechanical work. These are made possible by is to relate the in vitro to the in vivo group transfer and hydrolysis reactions involving ATP. Under Chantler (20). steady-state conditions, ATP concentrations remain relatively stable because rates of synthesis are matched to rates of hy- Energy metabolism has been the subject of much research drolysis. As cells change the rates at which they engage in for over a century. The intricate details of the reactions in- biosynthesis, active transport, or mechanical work, regulatory volved as well as the structures and properties of the enzymes mechanisms ensure that rates of ATP synthesis are dynami- that catalyze them now fill multiple chapters in undergradu- cally matched to rates of ATP hydrolysis. ATP turnover is the ate textbooks. So much is known about the subject that it is central process of cellular energy metabolism (2). often regarded by nonspecialists as a static collection of facts. Given the complex, multicellular nature of animals, purely However, new discoveries and advances in the understand- biochemical, reductionist approaches to the study of bioener- ing of biochemical processes underlying energy metabolism getics provide a very incomplete picture of the process. The continue to be made. While many biochemists continue to metabolism of an organ consisting of multiple cell and tissue focus primarily on questions concerning mechanisms, oth- types, supplied with metabolic fuels and O2 by a circulatory ers have joined with physiologists, expanding the scope of system and displaying a rate of physiological function that is investigations to address functional significance. Thus, the regulated according to the needs of the whole animal cannot study of energy metabolism in animals has evolved to be- be explained solely on the basis of biochemical phenomena come much broader, more integrative and, therefore, physio- occurring within individual cells. It is the animal, consisting logical. Studies of energy metabolism address a wide range of multiple (metabolizing) organs, that displays a whole-body of questions concerning how the enzymes and pathways of metabolic rate that changes with the animal’s behavior and re- bioenergetics operate in vivo, how metabolism is integrated sponds to changes in its environment (Fig. 1). Thus, to address over multiple levels of biological organization and regulated a wide range of questions, metabolic rates are measured at over time courses ranging from seconds to years. Evolution- rest, or as time-averaged values in the field, as values elevated ary processes have made animals structurally and function- ally diverse as well as adapted to a wide range of environ- *Correspondence to [email protected] mental conditions. Therefore, in addition to asking whether 1Department of Ecology, Evolution and Marine Biology, University of metabolic rates adapt physiologically within the lifetimes of California, Santa Barbara, California individual animals, researchers ask whether adaptation occurs Published online, October 2012 (comprehensivephysiology.com) across generations, whether evolution gives rise to qualitative DOI: 10.1002/cphy.c110009 or quantitative variation in pathways, enzymes, and fluxes. Copyright C American Physiological Society Volume 2, October 2012 2527 Energy and Metabolism Comprehensive Physiology found in most, if not all, animal species. Biochemists have been profoundly impressed by what they consider to be the highly conserved nature of organisms at the molecular level, that is, the unity of life. Upon further investigation, compara- tive physiologists and biochemists came to realize that there is considerable diversity within this apparent unity (67). Cell types within an organism as well as homologous cells across species vary in terms of the kinds or amounts of enzymes that they express; such variation commonly leads to variation in the extent to which fuels and pathways are used for energy metabolism. In-depth coverage of adaptive variation in kinds of enzymes (e.g. in relation to temperature, hydrostatic pres- sure, and solute microenvironment) is beyond the scope of this article; excellent introductory accounts have been published and updated over the past decades (65 and 66). With respect to enzyme concentrations, there is a well-developed concep- tual framework (83, 84, 110) for the use of maximal enzyme activities, i.e., Vmax values, measured in vitro, as measures of the maximum capacities for flux through these pathways in vivo. In this context Figure 1 The transport of fuels and O2 to cells at various rates of energy expenditure [from Weibel (134), with permission]. The illustra- = × , tion emphasizes how, at basal metabolic rate (BMR), ATP hydrolysis Vmax [E] kcat by processes such as biosynthesis and ion transport mainly determine the rate of whole-body energy metabolism. Physical activity results in where [E] is enzyme concentration and k is catalytic effi- increasing contribution to ATP hydrolysis by muscle work such that, at cat maximum metabolic rate (MMR or V˙O2max), 90% or more of whole- ciency or turnover number. In general, the kcat values of or- body metabolic rate is due to the respiration of muscle mitochondria. thologous enzymes purified from animals with similar body It is proposed that, at BMR, energy expenditure dominates the control temperatures are remarkably similar (66, 67). Thus, interspe- of whole-body V˙O2 while, at MMR, processes involved in the delivery of fuels and/or O2 to cells contribute to the control of V˙O2max (34). cific or inter-tissue variation in Vmax is due to variation in [E]. It is possible to compare maximum capacities for flux, estimated using this approach, with physiological rates of flux during exercise, digestion, lactation, thermogenesis, osmoreg- in vivo. This approach has been used, for example, to deter- ulation or depressed during hibernation, anoxia, dessication, mine the main substrates and pathways used by the locomo- or estivation. The importance of a fundamental understanding tory muscles of many species of vertebrates and invertebrates of the mechanisms underlying temporal, mass-dependent, on- (27-29, 123, 149). togenetic, intrapopulation, or interspecific variation in rates of energy metabolism has become recognized across biological disciplines. However, the scope of the subject is so enor- Understanding metabolic regulation mous that an introduction to it is necessarily incomplete and Critical to the study of energy metabolism is a basic un- idiosyncratic. This one is intended for readers with a basic derstanding of metabolic biochemistry. The qualitative and background in physiology and biochemistry. It serves as a quantitative variation observed in bioenergetic pathways can gateway to some key concepts that have emerged, as well as be understood in light of these basic principles, but gain bio- the literature pertinent to them. logical meaning in the context of ecology and evolution. Enzyme-catalyzed reactions in multistep pathways dif- Biochemical Underpinnings fer in their thermodynamic and kinetic properties. In the glycolytic pathway, for example, certain reactions (glyco- Anything that is true of E. coli must be true for elephants, gen phosphorylase, hexokinase, and phosphofructokinase) are except more so held far from equilibrium in vivo; that is, the ratios of [prod- Jacques Monod (in a discussion in 1954). uct]/[substrate] of these reactions in vivo are much less than The complete combustion of carbon compounds to CO2 + their respective equilibrium constants, measured in vitro.As H2O leads to the production of heat. However, in biolog- a result, their Gibbs free energy changes, G, are large and ical systems, the operation of pathways for the oxidation negative, given of carbohydrates, fats, and amino acids leads to both heat production—Kleiber’s “Fire of Life” (73), as well as the step- G = Go − RT ln[product]/[substrate], wise, regulated