The TCA Cycle and Oxidative Phosphorylation

Meisenberg G, Simmons WH (1998) The oxidation of glucose. Glycolysis, the TCA cycle, and oxidative phosphorylation. In Meisenberg G, Simmons WH (eds) Principles of medical biochemistry. Mosby, St. Louis, MO, pp 297-331... 

Fig. 8.1 Glucose metabolism in coupled neuron and astrocyte system. ATP is produced via oxidative energy metabolism (glycolysis, TCA cycle and oxidative phosphorylation) in neurons and in astrocytes. Na+ entry during electrical activity initiates increased oxidative energy metabolism within neurons. The activation of neuronal Na+-K+ ATPase in the plasma membrane leads to reduced levels of ATP, which rapidly activates glycolysis. This process requires an elevated glucose level, which is transported via the neuronal glucose transporter (GT). The generated ATP can restore the Na+/K+ balance via Na+-K+ ATPase. The rapid increase of glycolysis results in increased NADH/NAD+ and increased cytoplasmic pyruvate. In astrocytes,...

The electron transport chain gets its substrates from the NADH and FADH2 supplied by the TCA cycle. Since the TCA cycle and electron transport are both mitochondrial, the NADH generated by the TCA cycle can feed directly into oxidative phosphorylation. NADH that is generated outside the mitochondria (for example, in aerobic glycolysis) is not transported directly into the mitochondria and oxidized—that would be too easy. 

Where two enzymes compete for the same substrate, we expect to see some form of metabolic control and in this case the concentrations of NADH and acetyl-CoA are the key controlling factors (Figure 6.44). When glucose is not available as a fuel, metabolism switches to 3- oxidation of fatty acids, which generates more than sufficient quantities of both NADH and acetyl-CoA to drive the TCA cycle and to maintain oxidative phosphorylation. Pyruvate dehydrogenase activity is suppressed and pyruvate carboxylase is stimulated by ATP, NADH and acetyl-CoA (strictly speaking by low mitochondrial ratios of ADP/ATP, NAD+/NADH and coenzyme A/acetyl-CoA), so... 

Once in the mitochondrial matrix, acyl-CoA (e.g. palmitoyl-CoA), is degraded by 13-oxidation generating acetyl-CoA for the TCA cycle and reduced coenzymes which supply hydrogen atoms and electrons for oxidative phosphorylation. 

In this chapter, discussion focuses on the TCA cycle and its central role in the aerobic catabolism of carbohydrates. Chapter 14 explains how the free energy present in the reduced coenzymes that are generated by glycolysis and the TCA cycle is conserved as ATP during the companion process of electron transport and oxidative phosphorylation. 

The components of respiratory metabolism include glycolysis, the tricarboxylic acid (TCA) cycle, the electron-transport chain, and the oxidative phosphorylation of ADP to ATP. Glycolysis converts glucose to pyruvate the TCA cycle fully oxidizes the pyruvate (by means of acetyl-CoA) to C02 by transferring electrons stepwise to... 

The ANLSH challenged the classic view [2, 3]. It postulates compartmentaliza-tion of brain lactate metabolism between neurons and astrocytes the activity-induced uptake of glucose takes place predominantly in astrocytes, which metabolize glucose anaerobically. Lactate produced from anaerobic glycolysis in astrocytes is then released from astrocytes and provides the primary metabolic fuel for neurons. The increased lactate in the neurons is converted to pyruvate via lactate dehydrogenase (LDH), which enters the TCA cycle, and increases ATP production in the neurons via oxidative phosphorylation (Fig. 8.1). This view is highly discussed, pro [4, 5]) and contra [1, 6]. 

Lactate indicates insufficient oxidative phosphorylation by the TCA cycle. In this case, the pyruvate which is produced by glycolysis can not be transferred to the TCA cycle and is converted into lactate. 

In the third stage, ATP is producedfrom the complete oxidation of the acetyl unit of acetyl CoA. The third stage consists of the citric acid cycle and oxidative phosphorylation, which are the final common pathways in the oxidation offuel molecules. Acetyl CoA brings acetyl units into the citric acid cycle [also called the tricarboxylic acid (TCA) cycle or Krebs cycle], where they are completely oxidized to CO2. Four pairs of electrons are transferred (three to NAD+ and one to FAD) for each acetyl group that is oxidized. Then, a proton gradient is generated as electrons flow from the reduced forms of these carriers to O2, and this gradient is used to synthesize ATP. 

Mitochondria contain most of the enzymes for the pathways of fuel oxidation and oxidative phosphorylation and thus generate most of the ATP required by mammalian cells. Each mitochondrion is surrounded by two membranes, an outer membrane and an inner membrane, separating the mitochondrial matrix from the cytosol (Fig. 10.18). The inner membrane forms invaginations known as cristae containing the electron transport chain and ATP synthase. Most of the enzymes for the TCA cycle and other pathways for oxidation are located in the mitochondrial matrix, the compartment enclosed by the inner mitochondrial membrane. (The TCA cycle and electron transport chain are described in more detail in Chapters 20 and 21.)... 

Two major messengers feed information on the rate of ATP utilization back to the TCA cycle (a) the phosphorylation state of ATP, as reflected in ATP and ADP levels, and (b) the reduction state of NAD, as reflected in the ratio of NADH/NAD. Within the cell, even within the mitochondrion, the total adenine nucleotide pool (AMP, ADP, plus ATP) and the total NAD pool (NAD plus NADH) are relatively constant. Thus, an increased rate of ATP utilization results in a small decrease of ATP concentration and an increase of ADP. Likewise, increased NADH oxidation to NAD by the electron transport chain increases the rate of pathways producing NADH. Under normal physiological conditions, the TCA cycle and other... 

Energy from fuel oxidation is converted to the high-energy phosphate bonds of adenosine triphosphate (ATP) by the process of oxidative phosphorylation. Most of the energy from oxidation of fuels in the TCA cycle and other pathways is conserved in the form of the reduced electron-accepting coenzymes, NADH and FAD(2H). The electron transport chain oxidizes NADH and FAD(2H), and donates the electrons to O2, which is reduced to H2O (Fig. 21.1). Energy from reduction 0/O2 is used for phosphorylation of adenosine diphosphate (ADP) to ATP by ATP synthase (FgFjATPase). The net yield of oxidative phosphorylation is approximately 2.5 moles of ATP per mole of NADH oxidized, or 1.5 moles of ATP per mole of FAD(2H) oxidized. 

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