To the extent you're familiar with the word "fermentation," you may be inclined to associate it with the process of creating alcoholic beverages. While this indeed takes advantage of one type of fermentation (formally and non-mysteriously called alcoholic fermentation), a second type, lactic acid fermentation, is actually more vital and is almost certainly occurring to some extent in your own body as you read this.
Fermentation refers to any mechanism by which a cell can use glucose to release energy in the form of adenosine triphosphate (ATP) in the absence of oxygen – that is, under anaerobic conditions. Under all conditions – for example, with or without oxygen, and in both eukaryotic (plant and animal) and prokaryotic (bacterial) cells – the metabolism of a molecule of glucose, called glycolysis, proceeds through a number of steps to produce two molecules of pyruvate. What then happens depends on what organism is involved and whether oxygen is present.
Setting the Table for Fermentation: Glycolysis
In all organisms, glucose (C6H12O6) is used as an energy source and is converted in a series of nine distinct chemical reactions to pyruvate. Glucose itself comes from the breakdown of all manner of foodstuffs, including carbohydrates, proteins and fats. These reactions all take place in the cell cytoplasm, independent of special cellular machinery. The process begins with an investment of energy: Two phosphate groups, each of them taken from a molecule of ATP, are attached to the glucose molecule, leaving two adenosine diphosphate (ADP) molecules behind. The result is a molecule resembling the fruit sugar fructose, but with the two phosphate groups attached. This compound splits into a pair of of three-carbon molecules, dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G-3-P), which have the same chemical formula but different arrangements of their constituent atoms; the DHAP is then converted into G-3-P anyway.
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The two G-3-P molecules then enter what is often termed the energy-producing stage of glycolysis. G-3-P (and remember, there are two of these) gives up a proton, or hydrogen atom, to a molecule of NAD+ (nicotinamide adenine dinucleotide, an important energy carrier in many cellular reactions) to produce NADH, while the NAD donates a phosphate to G-3-P to convert it to bisphosphoglycerate (BPG), a compound with two phosphates. Each of these is given off to ADP to form two ATP as pyruvate is finally generated. Recall, however, that everything that happens after the splitting of the six-carbon sugar into two three-carbon sugars is duplicated, so this means that the net result of glycolysis is four ATP, two NADH and two pyruvate molecules.
It is important to note that glycolysis is considered anaerobic because oxygen is not required for the process to occur. It is easy to confuse this with "only if no oxygen is present." In the same way you can coast down a hill in a car even with a full tank of gas, and thus engage in "gasless driving," glycolysis unfolds the same way whether oxygen is present in generous amounts, smaller amounts or not at all.
Where and When Does Lactic Acid Fermentation Occur?
Once glycolysis has reached the pyruvate step, the fate of the pyruvate molecules depends on the specific environment. In eukaryotes, if sufficient oxygen is present, almost all of the pyruvate is shuttled into aerobic respiration. The first step of this two-step process is the Krebs cycle, also called the citric acid cycle or tricarboxylic acid cycle; the second step is the electron transport chain. These take place in the mitochondria of cells, organelles that are often likened to tiny power plants. Some prokaryotes can engage in aerobic metabolism despite not having any mitochondria or other organelles (the "facultative aerobes"), but for the most part they can meet their energy needs through anaerobic metabolic pathways alone, and many bacteria are actually poisoned by oxygen (the "obligate anaerobes").
When sufficient oxygen is not present, in prokaryotes and most eukaryotes, pyruvate enters the lactic acid fermentation pathway. The exception to this is the single-celled eukaryote yeast, a fungus that metabolizes pyruvate to ethanol (the two-carbon alcohol found in alcoholic beverages). In alcoholic fermentation, a carbon dioxide molecule is removed from pyruvate to create acetaldehyde, and a hydrogen atom is then attached to acetaldehyde to generate ethanol.
Lactic Acid Fermentation
Glycolysis could in theory proceed indefinitely to supply energy to the parent organism, since each glucose results in a net energy gain. After all, glucose could be more or less continually fed into the scheme if the organism simply eats enough, and ATP is essentially a renewable resource. The limiting factor here is the availability of NAD+, and this is where lactic acid fermentation comes in.
An enzyme called lactate dehydrogenase (LDH) converts pyruvate to lactate by adding a proton (H+) to the pyruvate, and in the process, some of the NADH from glycolysis is converted back to NAD+. This provides a NAD+ molecule that can be returned "upstream" to participate in, and thus help maintain, glycolysis. In reality, this is not entirely restorative in terms of an organism's metabolic needs. Using humans as an example, even a person sitting at rest could not come close to meeting her metabolic needs via glycolysis alone. This is probably evident in the fact that when people stop breathing, they cannot sustain life for very long for lack of oxygen. As a result, glycolysis combined with fermentation is really just a stopgap measure, a way to draw on the equivalent of a small, auxiliary fuel tank when the engine needs extra fuel. This concept forms the entire basis of colloquial expressions in the exercise world: "Feel the burn," "hit the wall" and others.
Lactate and Exercise
If lactic acid – a substance you have almost certainly heard of, again in the context of exercise – sounds like something that might be found in milk (you may have seen product names like Lactaid in the local dairy cooler), this is no accident. Lactate was first isolated in stale milk way back in 1780. (Lactate is the name of the form of lactic acid that has donated a proton, as all acids by definition do. This "-ate" and "-ic acid" naming convention for acids spans all of chemistry.) When you are running or lifting weights or participating in high-intensity types of exercise – anything that makes you breathe uncomfortably hard, actually – aerobic metabolism, which relies on oxygen, is no longer sufficient to keep up with the demands of your working muscles.
Under these conditions, the body goes into "oxygen debt," which is something of a misnomer since the real issue is a cellular apparatus that produces "only" 36 or 38 ATP per molecule of glucose supplied. If the intensity of exercise is sustained, the body attempts to keep pace by kicking LDH into high gear and generating as much NAD+ as possible via the conversion of pyruvate to lactate. At this point the aerobic component of the system is clearly maxed out, and the anaerobic component is struggling in the same way someone frantically bailing out a boat notices that the water level continues to creep up despite his efforts.
The lactate that is produced in fermentation soon has a proton attached to it, generating lactic acid. This acid continues to build up in the muscles as work is maintained, until finally all pathways to generating ATP simply cannot keep pace. At this stage, muscular work must slow down or cease altogether. A runner who is in a mile race but starts somewhat too fast for her fitness level may find herself three laps into the four-lap contest already in crippling oxygen debt. In order to simply finish, she must drastically slow down, and her muscles are so taxed that her running form, or style, is likely to visibly suffer. If you have ever watched a runner in a long sprint race, such as the 400 meters (which takes world-class athletes about 45 to 50 seconds to finish) slow severely in the final portion of the race, you have probably noticed that he or she almost appears to be swimming. This, loosely speaking, is attributable to muscle failure: Absent fuel sources of any kind, the fibers in the athlete's muscles simply cannot contract completely or with precision, and the consequence is a runner who suddenly looks as if he is carrying an invisible piano or other large object on his back.
Lactic Acid and "The Burn": A Myth?
Scientists for a long time have known that lactic acid builds up rapidly in muscles that are on the verge of failing. Similarly, it is well-established that the kind of physical exercise that leads to this type of rapid muscle failure produces a unique and characteristic burning sensation in the affected muscles. (It is not hard to induce this; drop to the floor and try to do 50 uninterrupted push-ups, and it is virtually certain that the muscles in your chest and shoulders will soon experience "the burn.") It was therefore natural enough to assume, absent contrary evidence, that lactic acid itself was the cause of the burn, and that lactic acid itself was something of a toxin – a necessary evil along the way to making much-needed NAD+. This belief has been propagated thoroughly throughout the exercise community; go to a track meet or 5K road race, and you are likely to hear runners complain of being sore from the previous day's workout thanks to too much lactic acid in their legs.
More recent research has called this paradigm into question. Lactate (here, this term and "lactic acid" are used interchangeably for simplicity's sake) has been found to be anything but a wasteful molecule that is not the cause of muscle failure or burning. It apparently serves as both a signaling molecule between cells and tissues and a well-disguised source of fuel in its own right.
The traditional rationale offered for how lactate allegedly causes muscle failure is low pH (high acidity) in the working muscles. The body's normal pH hovers close to neutral between acidic and basic, but lactic acid shedding its protons to become lactate floods muscles with hydrogen ions, rendering them unable to function per se. This idea, however, has been strongly challenged since the 1980s. In the view of the scientists advancing a different theory, very little of the H+ that builds up in working muscles actually comes from lactic acid. This idea has sprung mainly from a close study of the glycolysis reactions "upstream" from pyruvate, affecting both pyruvate and lactate levels. Also, more lactic acid is transported out of muscle cells during exercise than was previously believed, thus limiting its ability to dump H+ into the muscles. Some of this lactate can be taken up by the liver and used to make glucose by following the steps of glycolysis in reverse. Summarizing how much confusion still exists as of 2018 around this issue, some scientists have even suggested using lactate as a fuel supplement for exercise, thus turning long-held ideas completely upside-down.