In an automobile engine, hydrocarbon fuel is oxidatively and explosively converted in an essentially one-step process to mechanical work (i.e., driving a piston) plus the products CO₂ and H₂O. The process is relatively inefficient in that substantial amounts of the chemical energy stored in the fuel are wasted, as they are converted to unused heat, and substantial amounts of fuel are only partially oxidized and are released as carbonaceous, sometimes toxic, exhaust. In the competition to survive, organisms cannot afford to squander their sometimes limited energy sources on an equivalently inefficient process and have therefore evolved a more efficient mechanism for converting fuel into work. That mechanism, known as aerobic oxidation, provides the following advantages:

An important feature of ATP production from the breakdown of nutrient fuels into CO₂ and H₂O (see Figure 12-1, top) is a set of reactions, called respiration, involving a series of oxidation and reduction reactions called an electron-transport chain. The combination of these reactions with phosphorylation of ADP to form ATP is called oxidative phosphorylation and occurs in mitochondria in nearly all eukaryotic cells. When oxygen is available and is used as the final recipient of the electrons transported via the electron-transport chain, the respiratory process that converts nutrient energy into ATP is called aerobic oxidation or aerobic respiration. Aerobic oxidation is an especially efficient way to maximize the conversion of nutrient energy into ATP because O₂ is a relatively strong oxidant. If some molecule other than O₂—for example, the weaker oxidants sulfate (SO₄²⁻) or nitrate (NO³⁻)—is the final recipient of the electrons in the electron-transport chain, the process is called anaerobic respiration. Anaerobic respiration is typical of some prokaryotic microorganisms. Although there are exceptions, most known multicellular (metazoan) eukaryotic organisms use aerobic oxidation to generate most of their ATP.

In our discussion of aerobic oxidation, we will be tracing the fate of the two main cellular fuels: sugars (principally glucose) and fatty acids. Under certain conditions—for example, starvation conditions—amino acids also feed into these metabolic pathways. We first consider glucose oxidation, then turn to fatty acids.

The complete aerobic oxidation of one molecule of glucose yields 6 molecules of CO₂, and the energy released is coupled to the synthesis of as many as 30 molecules of ATP. The overall reaction is

C₆H₁₂O₆ + 6 O₂ + 30 P_i²⁻ + 30 ADP³⁻ + 30 H⁺ → 6 CO₂ + 30 ATP⁴⁻ + 36 H₂O

Glucose oxidation in eukaryotes takes place in four stages (see Figure 12-1, top):

Stage I: Glycolysis In the cytosol, one 6-carbon glucose molecule is converted by a series of reactions to two 3-carbon pyruvate molecules; a net of 2 ATPs are produced for each glucose molecule.

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Stage II: Citric Acid Cycle In the mitochondrion, pyruvate oxidation to CO₂ is coupled to the generation of the high-energy electron carriers NADH and FADH₂, which store the energy for later use. These two carriers can be considered the sources of high-energy electrons.

Stage III: Electron-Transport Chain High-energy electrons flow down their electric potential gradient from NADH and FADH₂ to O₂ via membrane proteins that convert the energy released into a proton-motive force (H⁺ gradient). The energy released from the electrons pumps protons across a membrane, thus generating the gradient.

Stage IV: ATP Synthesis The proton-motive force powers the synthesis of ATP as protons flow down their concentration and voltage gradients through the ATP-synthesizing enzyme ATP synthase, which is embedded in a mitochondrial membrane. For each original glucose molecule, an estimated 28 additional ATPs are produced by this mechanism of oxidative phosphorylation.

In this section, we discuss stage I: the biochemical pathways that break down glucose into pyruvate in the cytosol. We also discuss how these pathways are regulated, and we contrast the metabolism of glucose under anaerobic and aerobic conditions. The ultimate fate of pyruvate, once it enters mitochondria, is discussed in Section 12.3.