Energy Transfer and Cellular Oxidation

Cellular metabolism and survival depend on the continuous synthesis and degradation of adenosine triphosphate (ATP), the major source of energy for biological work. Work is performed in biological systems for contraction of skeletal, cardiac, and smooth muscle (e.g., exercise, digestion, glandular secretion, and thermoregulation) and for nerve impulse transmission (Box 2-1). These processes require a continuous supply of ATP, which is made available primarily by aerobic (oxygen-requiring) processes. In the event that oxygen delivery is inadequate, nonaerobic (anaerobic, or non–oxygen-requiring) energy-transferring processes can also supply ATP. Supplying energy anaerobically, however, is more costly metabolically; that is, it is not efficient, is limited, and cannot be sustained because of the disruptive effects of lactate (a cellular byproduct of anaerobic metabolism) on physiological processes. Metabolic acidosis is a consequence of lactate accumulation. In patients who are critically ill, the presence of metabolic acidosis secondary to anaerobic metabolism can be life threatening. Prolonged anaerobic metabolism is lethal in two respects. First, the patient is increasingly dependent on anaerobic metabolism because of inadequate DO₂ to peripheral tissues; second, acidosis interferes with normal cellular processes and homeostasis, which require an optimal pH of 7.40.

The ATP molecule consists of an adenine and a ribose molecule with three phosphates attached. The splitting of the terminal phosphate bond or the two terminal phosphate bonds generates a considerable amount of energy. This energy is used to power various chemical reactions associated with metabolism. These metabolic processes take place in specialized organelles in the cells called mitochondria. The primary pathways that are responsible for the formation of ATP are the Krebs cycle and the electron transfer chain.

The Krebs cycle and the electron transfer chain are the biochemical pathways in the mitochondria of the cell responsible for harnessing oxygen for aerobic metabolism and ensuring a continuous supply of oxygen for this process. Initially, glucose is phosphorylated to produce two molecules of ATP (glycolysis). Glucose is oxidized to produce two molecules of pyruvic acid, yielding a net gain of two molecules of ATP per molecule of glucose. The two pyruvate molecules enter the Krebs cycle, where they are oxidized to CO₂ and water. This process yields 30 ATP molecules. Hydrogen ions released in the process are transferred to the electron transfer chain, yielding 4 ATP molecules for cellular metabolism. Electrons are removed from hydrogen and funneled down the electron transport chain by specialized electron carrier molecules, cytochromes 1 to 5. Only the last of these cytochromes, cytochrome oxidase, can reduce molecular oxygen to water. This process is driven by a gradient of high-to-low potential energy. This energy, transferred as electrons, is passed from H₂ to O₂ and is trapped and conserved as high-energy phosphate bonds. Oxygen is involved in these metabolic pathways only at the end of the electron transfer chain, where oxygen is the final electron acceptor and combines with H₂ to form H₂O. More than 90% of ATP synthesis takes place through the electron transfer chain by means of the oxidative reactions associated with oxidative phosphorylation. An individual’s peak aerobic capacity is determined by the availability of oxygen at the end of the electron transport chain.

For each molecule of glucose that is metabolized, 36 molecules of ATP are produced: 4 molecules by substrate phosphorylation (anaerobic) and 32 by oxidative phosphorylation (aerobic). The low ATP yield from anaerobic metabolism explains why anaerobic metabolism can serve only as a short-term energy source.

The complex, enzymatically controlled chemical reactions of metabolism are designed to form and conserve energy through the Krebs cycle and the electron transfer chain and then use this energy for biological work.9,10 Carbohydrates, fats, and proteins ingested from foodstuffs in the diet are oxidized to provide the energy for phosphorylation of adenosine diphosphate (ADP) (i.e., the formation of ATP by combining ADP with phosphate). These substances are broken down, and they access the Krebs cycle at the pyruvic acid or acetyl coenzyme A (CoA) levels (Fig. 2-3). Some amino acids can enter the Krebs cycle directly.

The Krebs cycle degrades acetyl CoA to carbon dioxide (CO₂) and hydrogen (H₂) atoms. The primary purpose of this cycle is to generate hydrogen ions for the electron transfer chain by two principal electron acceptors, nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD). Many acids catalyze the numerous reactions of the Krebs cycle.

Cellular oxidation, or respiration, refers to the function of the electron transfer chain to release energy in small amounts and to conserve energy in the formation of high-energy bonds. It is this process that ensures a continual energy supply to meet the needs of metabolism (Fig. 2-4).

Three major systems of energy transfer exist to supply energy during all-out exercise over varying durations.¹⁰ Although these systems are discrete, they overlap. Cellular ATP and creatine phosphate (CP) are immediate energy sources for the first 10 seconds of exercise. From 30 to 60 seconds, glycolysis provides a short-term energy source. The ATP-CP system and the glycolytic system are anaerobic processes. As exercise persists for several minutes, the long-term aerobic system predominates. Thus, for sustained physical activity and exercise, energy is provided primarily by aerobic metabolism. For this process, oxygen is provided by the oxygen transport pathway. Carbon compounds that enter the body in the form of carbohydrate, fat, and protein undergo oxidative metabolism in the form of aerobic glycolysis in the mitochondria in the cytoplasm of cells.

Muscle Contraction and Metabolism

The basic mechanism for muscle contraction is excitation contraction coupling.11,12 Action potentials mediated centrally or through the spinal cord depolarize the muscle cell membrane (the sarcolemma) and stimulate the release of calcium from the lateral sacs of the sarcoplasmic reticulum. The sarcoplasmic reticulum is an extensive network of invaginations and tubular channels encasing the muscle fibers (myofibrils). The calcium floods over the myofilaments of the myofibrils within the sarcomere. Myofilaments consist of thin actin fiber and thick myosin fiber protein, which interdigitate with each other, giving the typical striated appearance to skeletal muscle (Fig. 2-5

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