Uncoupling proton diffusion from ATP production

For the chemiosmotic mechanism to work, the diffusion of H+ and the formation of ATP must be tightly coupled; that is, the protons must pass only through the ATP synthase channel in order to move into the mitochondrial matrix. If a second type of H+ diffusion channel (not ATP synthase) is inserted into the mitochondrial membrane, the energy of the H+ gradient is released as heat, rather than being coupled to the synthesis of ATP. Such uncoupling molecules are deliberately used by some organisms to generate heat instead of ATP. For example, the natural uncoupling protein thermogenin plays an important role in regulating the temperature of some mammals, especially newborn human infants who lack the hair to keep warm and of hibernating animals.

Fermentation: ATP from Glucose, without O₂

Recall that fermentation is the breakdown of the pyruvate produced by glycolysis in the absence of O₂. Because fermentation results in the incomplete oxidation of glucose, it releases much less energy than cellular respiration. Why would such an inefficient process exist? Suppose the supply of oxygen to a respiring cell is reduced (an anaerobic condition). As a consequence, oxygen is no longer available to pick up electrons at the end of the respiratory chain. As we can deduce from Figure , the first consequence of an insufficient supply of O2 is that the cell cannot reoxidize cytochrome c, so all of that compound is soon in the reduced form. When this happens, QH₂ cannot be oxidized back to Q, and soon all the Q is in the reduced form. So it goes, until the entire respiratory chain is reduced. Under these circumstances, no NAD+ and no FAD are regenerated from their reduced forms. Therefore, the oxidative steps in glycolysis, pyruvate oxidation, and the citric acid cycle also stop. If the cell has no other way to obtain energy from its food, it will die. Under anaerobic conditions, many (but not all) cells can produce a small amount of ATP by glycolysis, provided that fermentation metabolizes and regenerates the NAD+ necessary to keep glycolysis running. Fermentation, like glycolysis, occurs in the cytoplasm. It has two defining characteristics:

_ Fermentation uses NADH + H+ formed by glycolysis to reduce pyruvate or one of its metabolites, and consequently NAD+ is regenerated. NAD+ is required for reaction 6 of glycolysis, so once the cell has replenished its NAD+ supply in this way, it can carry more glucose through glycolysis.

_ Fermentation enables glycolysis to produce a small but sustained amount of ATP. The reactions of fermentation do not themselves produce any ATP. Only as much ATP is produced as can be obtained from substrate-level phosphorylation—not the much greater yield of ATP obtained by cellular respiration using chemiosmosis.

When cells capable of fermentation become anaerobic, the rate of glycolysis speeds up tenfold or even more. Thus a substantial rate of ATP production is maintained, although efficiency in terms of ATP molecules per glucose molecule is greatly reduced compared with cellular respiration under aerobic conditions. Some organisms are confined to totally anaerobic environments and use only fermentation. Usually, there are two metabolic reasons for this. First, these organisms lack the molecular machinery for oxidative phosphorylation, and second, they lack enzymes to detoxify the toxic by-products of O2, such as hydrogen peroxide (H₂O₂). An example of such an obligate anaerobe is Clostridium botulinum, the bacterium that thrives in sealed containers of foods and releases the potentially deadly botulinum toxin. Other bacteria, such as Mycobacterium tuberculosis, which causes tuberculosis, cannot carry out fermentation and must grow in aerobic environments. Still others, such as Escherichia coli, which grows in the human large intestine, can perform either respiration or fermentation, but prefer the former in an aerobic environment. And several bacteria carry on cellular respiration—not fermentation— without using oxygen gas as an electron acceptor. Instead, to oxidize their cytochromes, these bacteria reduce nitrate ions (NO₃ ^–) to nitrite ions (NO₂^–).

Some fermenting cells produce lactic acid and some produce alcohol

Different types of fermentation are carried out by different bacteria and eukaryotic body cells. These different fermentation processes are distinguished by the final product produced. For example, in lactic acid fermentation, pyruvate is reduced to lactate. Lactic acid fermentation takes place in many microorganisms as well as in our muscle cells. Unlike muscle cells, nerve cells (neurons) are incapable of fermentation because they lack the enzyme that reduces pyruvate to lactate. For that reason, without adequate oxygen the human nervous system (including the brain) is rapidly destroyed; it is the first part of the body to die. Certain yeasts and some plant cells carry on a process called alcoholic fermentationunder anaerobic conditions (Figure ). This process requires two enzymes to metabolize pyruvate. First, carbon dioxide is removed from pyruvate, leaving the compound acetaldehyde. Second, the acetaldehyde is reduced by NADH + H+, producing NAD+ and ethyl alcohol (ethanol). This is how beer and wine are made.

Contrasting Energy Yields

The total net energy yield from glycolysis using fermentation is two molecules of ATP per molecule of glucose oxidized. In contrast, the maximum yield that can be obtained from a molecule of glucose through glycolysis followed by cellular respiration is much greater —about 36 molecules of ATP.

Why is so much more ATP produced by cellular respiration? As we have repeatedly stated, glycolysis is only a partial oxidation of glucose, as is fermentation. Much more energy remains in the end products of fermentation, such as lactic acid and ethanol, than in the end product of cellular respiration, CO₂. In cellular respiration, carriers (mostly NAD+) are reduced in pyruvate oxidation and the citric acid cycle, then oxidized by the respiratory chain, with the accompanying production of ATP (three for each NADH + H+ and two for each FADH₂) by the chemiosmotic mechanism. In an aerobic environment, an organism capable of this type of metabolism will be at an advantage (in terms of energy availability per glucose molecule) over one limited to fermentation. The total gross yield of ATP from one molecule of glucose processed through glycolysis and cellular respiration is 38. However, we may subtract two from that gross — for a net yield of 36 ATP — because in some animal cells the inner mitochondrial membrane is impermeable to NADH and a “toll” of one ATP must be paid for each NADH produced in glycolysis that is shuttled into the mitochondrial matrix.