Obligatory Heat Production

Obligatory heat production is the heat released during anabolic and catabolic reactions responsible for all cellular processes, primarily through the utilization and resynthesis of ATP molecules. At rest, the majority of the energy expended by a cell is being used to drive various molecular transport mechanisms, many of which are responsible for maintaining essential electrochemical gradients across membranes. For example, it has been estimated that the Na⁺,K⁺-ATPase pump reaction, which couples ATP hydrolysis to transport of K⁺ into cells and movement of Na⁺ out of cells, accounts for 20% to 40% of whole-body resting energy expenditure (McBride and Kelly, 1990). In highly metabolically active cell types, such as hepatocytes (liver cells), proton (H⁺) pumping across the mitochondrial membrane may represent up to 30% of the energy used by the cell. At rest, other processes that contribute substantially to energy needs include reactions responsible for macromolecular synthesis and degradation (e.g., protein and phospholipid turnover) and substrate cycling (discussed later in this chapter).

Regulatory Heat Production

Regulatory heat production is important for homeothermic organisms (i.e., those that maintain a constant body temperature). Regulatory heat production is needed to maintain a constant body temperature in the face of fluctuating environmental temperature. Shivering, which is triggered in response to cold exposure, can involve a substantial increase in skeletal muscle contraction, which results in a significant increase in ATP turnover and subsequently increased heat production. Heat generated through uncoupling mechanisms (discussed in a subsequent section of this chapter) can also contribute significantly to regulatory heat production. Conversely, exposure to increased environmental temperature stimulates sweat production, which helps cool the body through the heat loss associated with evaporation (see Chapter 35). The processes of modulating heat production and loss confer tremendous flexibility to many species so that they may survive in many different environmental conditions.

Postprandial Heat Production and Exercise Thermogenesis

Excess heat production also occurs during the postprandial period by the reactions referred to as the thermic effect of food (TEF). During physical activity, large amounts of heat can be produced as a consequence of muscle contraction and related processes. This heat production is referred to as the energy expenditure for physical activity (EEPA). The heat production associated with food intake or physical activity can also contribute to maintenance of body temperature in a cold environment.

Oxidation of Fuel Molecules

Energy for the synthesis of ATP within cells comes mainly from the oxidation of energy-yielding molecules, which include predominantly carbohydrate and fat but also protein and alcohol (Flatt, 1985). The complete metabolic oxidation of fuel molecules to CO₂ and H₂O occurs with a similar stoichiometry to that for combustion of the fuels in a flame, but the processes involved are quite different. As summarized in Figure 21-3, catabolism of fuel molecules involves the oxidation of the fuel molecules coupled to the reduction of other molecules such as NAD(P) and FAD. Some ATP equivalents are formed by substrate-level phosphorylation (e.g., in two steps of glycolysis and in the citric acid cycle). CO₂ is formed primarily from oxidation of acetyl-CoA by the citric acid cycle with H₂O as the source of the additional oxygen needed to convert the acetyl moiety to CO₂. However, most ATP production and almost all molecular O₂ consumption occur at the level of oxidative phosphorylation in the mitochondria. The electrons carried by the reduced NADH and FADH₂ generated in the citric acid cycle as well as by glycolysis and β-oxidation are transferred to the mitochondrial electron transport chain, which fuels phosphorylation of ADP to yield ATP. Molecular O₂ is the terminal electron (and proton) acceptor in electron transport; O₂ is reduced to produce H₂O. In macronutrient oxidation, the release of CO₂ generally occurs at earlier stages in nutrient catabolism and thus prior to O₂ consumption and H₂O production.

The ATP yield per gram of glucose, fatty acid, or amino acid differs in proportion to the oxidation state of the different molecules. For example, carbohydrates are partially oxidized compounds, already have one oxygen atom (hydroxyl substituent) for every carbon atom, and thus yield fewer reducing equivalents per carbon atom during their catabolism. In contrast, almost every carbon atom in a fat molecule is saturated with hydrogen; therefore fat yields more reducing equivalents per carbon atom during its catabolism. Amino acids have an intermediate oxidation state in between that of fat and carbohydrate. However, because of the need to excrete the nitrogen as urea, the actual energy yield per carbon atom is similar for carbohydrates and amino acids. The following equations for the complete oxidation (requiring input of O₂) of representative macromolecules (e.g., glucose, palmitic acid, and alanine) to CO₂ and H₂O (and urea, in the case of alanine) illustrate the basis for the relationships among energy expenditure, O₂ consumption, CO₂ release, the respiratory quotient (RQ), and type of macronutrient oxidized as fuel.

Glucose:

C6H12O6+6O2→6CO2+6H2O+673kcalpermole(or3.8kcal/g)

RQforglucose=6CO2/6O2=1

Palmitic acid:

C16H32O2+23O2→16CO2+16H2O+2,380kcalpermole(or9.3kcal/g)

RQforpalmiticacid=16CO2/23O2=0.7

Alanine:

2(C3H7O2N)+6O2→5CO2+5H2O+CH4ON2+312kcalpermole(or3.5kcal/g)

RQforalanine=5CO2/6O2=0.83

Although these reactions, with the exception of urea formation, appear similar to those used to describe the combustion of organic compounds in a flame, it is important to remember that the processes of O₂ consumption and CO₂ and H₂O production do not occur simultaneously in the body as they do when these compounds are oxidized by burning. In the body, metabolism (or oxidation) of fuel molecules occurs in small and separate steps. The initial processes involve the production of CO₂ and the transfer of reducing equivalents to flavin and pyridine nucleotides. In the later steps, the reducing equivalents are transferred to the electron transport chain, which ultimately transfers the electrons and H⁺ to O₂, resulting in O₂ consumption and H₂O production as well as conservation of some of the energy in the chemical bonds of ATP.

Phosphorylation of ADP to ATP

The synthesis of ATP during oxidative phosphorylation is linked to the release of electrons carried by the flavin and pyridine nucleotides to proteins of the electron transport chain. Hydrogen ions are pumped out of the mitochondrial matrix across the inner mitochondrial membrane at three sites along the electron transport chain to create an electrochemical gradient. This proton gradient is subsequently dissipated as protons are allowed back through the membrane by ATP synthase, which couples this process to ATP synthesis, as shown in Figure 21-4. Sufficient free energy may be collected at three sites along the electron transport chain (complexes I, III, and IV) to allow phosphorylation of ADP, yielding ATP. A maximum of three molecules of ATP can be generated from each molecule of NADH that is oxidized via donation of its pair of electrons to the electron transport chain. FADH₂ donates its electrons at a later step in the electron transport chain, allowing a maximum of only two molecules of ATP to be generated from each FADH₂ molecule.

Terminal Electron Acceptor: O₂ Consumption

Molecular oxygen serves as the terminal electron acceptor at the end of the electron transport chain. Transfer of 4 electrons plus 4 protons (H⁺) to 1 molecule of O₂ results in formation of 2 molecules of H₂O. Because most fuel oxidation results in the transfer of electrons from reduced pyridine and flavin coenzymes to the mitochondrial electron transport chain, the energy yield or heat produced by oxidation of fuel molecules can be closely estimated by measuring oxygen consumption.

P/O Ratio

A frequently used index of the efficiency of oxidative phosphorylation is the P/O ratio. The P/O ratio is defined as the number of ATP molecules produced per pair of electrons traveling through the electron transport chain (or per oxygen atom that is reduced). Depending on where electrons enter the chain, the maximal P/O ratio will change (Murphy and Brand, 1987). At maximal biological efficiency, the complete oxidation of NADH yields 3 ATP molecules, and so the maximal P/O ratio for this process is 3. For the complete oxidation of FADH₂, the maximal P/O ratio is 2. Few direct attempts to determine the P/O ratio in intact cells have been made because of the difficulties encountered in determining the rapid turnover of ATP molecules involved in the maintenance of a cell’s metabolic activities without disturbing the cell’s internal milieu. Nevertheless, the physiological P/O ratio is almost certainly somewhat less than the maximal values of 3 and 2 (probably closer to 2.5 and 1.5) that are commonly used as a basis for calculating the “ATP equivalents” produced by oxidation of NADH and FADH₂, respectively, by the electron transport chain.

Generation of Oxygen Free Radicals

Molecular oxygen is an excellent electron acceptor, but the reduction of O₂ can produce potentially harmful intermediates. Although the transfer of 4 electrons and 4 H⁺ to O₂ to produce 2 H₂O is harmless, the transfer of one electron to O₂ forms superoxide (O₂^•–) and the transfer of 2 electrons forms peroxide (O₂^•2–). These anionic species each have one unpaired valence shell electron and thus are free radicals. These reactive oxygen species and their reaction products are harmful to cells. Complexes I and III of the electron transport chain have been described as the main producers of reactive oxygen species in the mitochondria; this happens because a small percentage of the electrons passing through the electron transport chain are prematurely leaked and react with O₂, resulting in its incomplete reduction. Several antioxidant systems in the body, such as superoxide dismutase and catalase, are involved in protection against these harmful reactive oxygen species (ROS).

O2+e−→O2•−(superoxide)

O2+2e−→O2•2−(peroxide)