Cellular Function
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Mitochondria, such as RBCs, must rely totally on glycolysis for ATP production.
Citric Acid Cycle For most cells, glycolysis is only a prelude to the third stage of catabolism, which takes place in the mitochondria and results in the complete oxidation of glucose to its final end products: CO2 and H2O. The third stage begins with the citric acid cycle (also called the Krebs cycle or the tricarboxylic acid cycle) and ends with the production of ATP by oxidative phosphorylation. The purpose of the citric acid cycle is to break, by oxidation, the C–C and C–H bonds of the compounds produced in the second stage of catabolism. Pyruvate and fatty acids enter the mitochondrial matrix, where they are converted to acetyl CoA (Fig. 3.15). The pyruvate dehydrogenase complex cleaves pyruvate to form one CO2, one NADH, and one acetyl CoA molecule. Fatty acids are cleaved by a process called β oxidation to form one NADH and one reduced flavin adenine dinucleotide (FADH2, another type of electron carrier). No CO2 is produced by β oxidation of fatty acids. Patients who have difficulty excreting CO2 because of respiratory disease are sometimes given a high-fat, low-carbohydrate diet to take advantage of the lower CO2 production that accompanies fat metabolism.
In the first reaction of the citric acid cycle, the two-carbon acetyl group is transferred from coenzyme A to a four-carbon oxaloacetate molecule. This results in the formation of the six-carbon molecule citrate for which the cycle is named. In a series of enzymatic oxidations, carbon atoms are cleaved off in the form of CO2 (Fig. 3.16); this CO2 is free to diffuse from the cell and be excreted by the lungs as a waste product. Two carbon atoms are removed to form two CO2 molecules for each complete turn of the cycle. The extra oxygen molecules needed to create CO2 are provided by the surrounding H2O; therefore the citric acid cycle does not require molecular oxygen from respiration. However, the cycle will cease to function in the absence of oxygen because the carrier molecules, NADH and FADH2, cannot unload their electrons onto the electron transport chain (which does require oxygen) and thus are unavailable to accept electrons from the citric acid cycle.
Although the citric acid cycle directly produces only one ATP molecule (in the form of guanosine triphosphate [GTP]) per cycle, it captures a great deal of energy in the form of activated hydride ions (H−). These high-energy ions combine with larger carrier molecules, which transport them to the electron transport chain in the mitochondrial membrane. Two important carrier molecules are nicotinamide adenine dinucleotide (NAD+), which becomes NADH when reduced by H−, and flavin adenine dinucleotide (FAD), which becomes FADH2 when reduced by H−. The energy carried by these molecules is ultimately used to produce ATP through a process called oxidative phosphorylation. One glucose molecule provides for two turns of the cycle and produces a net of two GTP, four CO2, two FADH2 and six NADH.
Oxidative Phosphorylation Oxidative phosphorylation follows the processes of glycolysis and the citric acid cycle and results in the formation of ATP by the reaction of adenosine diphosphate (ADP) and inorganic phosphate (Pi): ADP + Pi → ATP. The energy to drive this unfavorable reaction is provided by the high-energy hydride ions (H−) derived from the citric acid cycle. This energy is not used to form ATP directly; a series of energy transfers through reduction-oxidation (redox) reactions is required. In eukaryotic cells, this series of energy transfers occurs along the electron transport chain on the inner mitochondrial membrane. The transport chain consists of three major enzyme complexes and two mobile electron carriers that shuttle electrons between the protein complexes
energy per mole of ATP is liberated when one of the phosphate bonds is hydrolyzed (broken with the aid of water) in a chemical reaction. A variety of enzymes in the cell are able to capture the energy released from ATP hydrolysis and use it to break or make other chemical bonds. In this way, ATP serves as the “energy currency” of the cell. A specific amount of ATP is “spent” to “buy” a specific amount of work. Most cells contain only a small amount of ATP, sufficient to maintain cellular activities for just a few minutes. Because ATP cannot cross the plasma membrane, each cell must continuously synthesize its own ATP to meet its energy needs; ATP cannot be “borrowed” from other cells or “banked” in any significant quantity within a cell. It must be synthesized continually from the breakdown of glycogen and fat to meet the cell’s energy needs.
An average adult has enough glycogen stores (primarily in liver and muscle) to supply about 1 day’s needs, but enough fat to last for a month or more. After a meal, the excess glucose entering the cells is used to replenish glycogen stores or to synthesize fats for later use. Fat is stored primarily in adipose tissue and is released into the bloodstream for other cells to use when needed. When cellular glucose levels fall, glycogen and fats are broken down to provide glucose and fatty acyl molecules, respectively, which are ultimately metabolized to provide ATP. During starvation, body proteins can also be used for energy production by a process called gluconeogenesis.
Cellular metabolism is the biochemical process whereby foodstuffs are used to provide cellular energy and biomolecules. Cellular metabolism includes two separate and opposite phases: anabolism and catabolism. Anabolism refers to energy-using metabolic processes or pathways that result in the synthesis of complex molecules such as fats. Catabolism refers to the energy-releasing breakdown of nutrient sources such as glucose to provide ATP to the cell. Both of these processes require a long, complex series of enzymatic steps. The catabolic processes of cellular energy production are briefly discussed in the following sections. (See Chapter 42 for a detailed discussion of metabolism.)