Did You Know That Red Blood Cells, Like Yeast That Produce Alcohol, Are Fermenters?

By William Aird

Did you know that red blood cells, like yeast that produce alcohol, are fermenters? In the presence of oxygen, other cells in the body break down glucose into carbon dioxide and water, and in the process generate some 36 molecules of adenosine triphosphate (ATP) for powering cellular activities, such as metabolic reactions, transport across membranes and mechanical work. Most of this energy is derived from the Krebs cycle and the electron transport chain, which operate within the confines of the mitochondria. When cells are deprived of oxygen (for example, ischemic muscle) or when they lack mitochondria (namely the mammalian erythrocyte), glucose is converted to lactate in a process called fermentation.¹ Fermentation is an alternative non-oxygen-requiring pathway for generating ATP, though the yield of high energy phosphates is much less compared with aerobic respiration. This is an example of an evolutionary trade-off whereby the loss of mitochondria in the ancestral mammalian red cell provided a brilliant solution for transporting oxygen without consuming it, but at the cost of reduced ATP generation. To overcome this limitation, the red cell is an avid “eater” – it has the highest specific rate of glucose utilization of any cell in the body, approximately 10 g of glucose/kg of tissue/day, compared with ~2.5 g of glucose/kg of tissue/day for the whole body.² The RBC uses most of this ATP to maintain electrochemical and ion gradients across its plasma membrane (these and other energy requiring functions are listed below). The lactic acid that is formed by red cells is released into the circulation, where it is taken up by liver hepatocytes. Hepatocytes then convert the lactate back to glucose, completing a cycle (glucose-lactate-glucose) that is referred to as the Cori cycle. The liver-derived glucose is then released for consumption by other tissues. When viewed from this perspective, the red cells help to feed the rest of the body!

Energy needs of red cell (learn more here):

Maintenance of glycolysis
Maintenance of the electrolyte gradient between plasma and red cell cytoplasm through the activity of adenosine triphosphate (ATP)-driven membrane pumps
Synthesis of glutathione and other metabolites
Purine and pyrimidine metabolism
Maintenance of hemoglobin’s iron in its functional, reduced, ferrous state
Protection of metabolic enzymes, hemoglobin, and membrane proteins from oxidative denaturation
Preservation of membrane phospholipid asymmetry

Term	Definition	Comments
Fermentation	Extraction of energy from carbohydrates in the absence of oxygen; end products include alcohol (yeast) and lactic acid (skeletal muscle, red cells). Produces 2 ATP molecules per molecule of glucose (from glycolysis, or conversion of glucose to pyruvate).	Occurs in some bacteria and yeast, in animal muscle during periods of intense exercise and in mammalian red cells.
Aerobic cellular respiration	During cellular respiration, a glucose molecule is gradually broken down into carbon dioxide and water in series of reactions that consume oxygen and generate energy in the form of high energy phosphates (ATP)P. About 36 ATPs are formed during aerobic respiration.	Requires the presence of oxygen and mitochondria. Red cells cannot respire because they do not have mitochondria.
Glycolysis	In glycolysis, glucose undergoes a series of chemical transformations, leading in the end to two molecules of pyruvate. Produces 2 ATP molecules per molecule of glucose.	Glycolysis itself does not require the presence of oxygen. It occurs as the first steps of glucose metabolism in both fermentation and aerobic respiration. The pyruvate generated by glycolysis either enters the Krebs cycle (aerobic respiration) or is converted to lactate or alcohol (fermentation).

In the presence of oxygen (O₂), all mammalian cells with the exception of red blood cells generate energy through aerobic respiration. By contrast, mammalian red cells, which lack mitochondria (in addition to other cellular organelles), as well as some yeast and bacteria, generate their energy needs through fermentation. Fermentation is a non-oxygen-utilizing strategy for generating energy in the form of ATP. In both aerobic respiration and fermentation, glucose is metabolized to pyruvate in a process called *glycolysis*. In cells with oxygen and mitochondria, pyruvate enters the Krebs cycle and is metabolized to water and carbon dioxide, releasing many molecules of ATP in the process. In fermenting cells, the pyruvate made in glycolysis does not continue through oxidation and the citric acid cycle. Instead, pyruvate is metabolized to lactate (or lactic acid) or, in the case of yeast and bacteria, to alcohol. The whole process of fermentation results in the net release of 2 molecules of ATP, a tiny fraction of what is generated in aerobically respiring cells. Note: the schematic shows glucose conversion to end products in 2 steps; there are, in fact, many intermediate steps that are not shown. Many of these steps are catalyzed by key enzymes, whose deficiency (typically hereditary) results in reduced ATP generation and impaired RBC function.

Because they cannot oxidize fats, red cells use glucose and glycolysis as their sole source of energy. Glycolysis – which leads to the generation of pyruvate – is not unique to fermenters. It kicks off glucose metabolism in all cells, whether under aerobic or anaerobic conditions (the lack of mitochondria in red cells being the functional equivalent of anaerobic). The availability of NAD⁺ is essential for glycolysis to proceed. In cells undergoing aerobic respiration, this NAD+ is replenished in the Krebs cycle. In fermenters, NAD+ is replenished from glycolysis-derived NADPH by the conversion of pyruvate to lactate. This reaction is mediated by the enzyme, lactate dehydrogenase (LDH), which is familiar to all hematologists as a marker of hemolysis. Red cell lactate is released into the blood, taken up by hepatocytes and converted to glucose. The glucose-lactate-glucose loop is called the *Cori cycle*.

Overall, about 90% of glucose is metabolized via glycolysis, yielding lactate, which is excreted into blood. The remaining 10% is metabolized by the hexose monophosphate shunt (also known as the pentose phosphate pathway, PPP), which generates NADPH using the rate limiting enzyme, G6PD, and the Luebering-Rapoport shunt (LRS), which generates 2,3-DPG, used to modulate the oxygen dissociation curve.

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