The Cori cycle (also known as the lactic acid cycle), named after its discoverers, Carl Ferdinand Cori and Gerty Cori, [1] is a metabolic pathway in which lactate, produced by anaerobic glycolysis in muscles, is transported to the liver and converted to glucose, which then returns to the muscles and is cyclically metabolized back to lactate. [2]
Muscular activity requires ATP, which is provided by the breakdown of glycogen in the skeletal muscles. The breakdown of glycogen, known as glycogenolysis, releases glucose in the form of glucose 1-phosphate (G1P). The G1P is converted to G6P by phosphoglucomutase. G6P is readily fed into glycolysis, (or can go into the pentose phosphate pathway if G6P concentration is high) a process that provides ATP to the muscle cells as an energy source. During muscular activity, the store of ATP needs to be constantly replenished. When the supply of oxygen is sufficient, this energy comes from feeding pyruvate, one product of glycolysis, into the citric acid cycle, which ultimately generates ATP through oxygen-dependent oxidative phosphorylation.
When oxygen supply is insufficient, typically during intense muscular activity, energy must be released through anaerobic metabolism. Lactic acid fermentation converts pyruvate to lactate by lactate dehydrogenase. Most importantly, fermentation regenerates NAD+, maintaining its concentration so additional glycolysis reactions can occur. The fermentation step oxidizes the NADH produced by glycolysis back to NAD+, transferring two electrons from NADH to reduce pyruvate into lactate. (Refer to the main articles on glycolysis and fermentation for the details.)
Instead of accumulating inside the muscle cells, lactate produced by anaerobic fermentation is taken up by the liver. This initiates the other half of the Cori cycle. In the liver, gluconeogenesis occurs. From an intuitive perspective, gluconeogenesis reverses both glycolysis and fermentation by converting lactate first into pyruvate, and finally back to glucose. The glucose is then supplied to the muscles through the bloodstream; it is ready to be fed into further glycolysis reactions. If muscle activity has stopped, the glucose is used to replenish the supplies of glycogen through glycogenesis. [3]
Overall, the glycolysis steps of the cycle produce 2 ATP molecules at a cost of 6 ATP molecules consumed in the gluconeogenesis steps. Each iteration of the cycle must be maintained by a net consumption of 4 ATP molecules. As a result, the cycle cannot be sustained indefinitely. The intensive consumption of ATP molecules in the Cori cycle shifts the metabolic burden from the muscles to the liver.
The cycle's importance is based on preventing lactic acidosis during anaerobic conditions in the muscle. However, normally, before this happens, the lactic acid is moved out of the muscles and into the liver. [3]
Additionally, this cycle is important in ATP production, an energy source, during muscle exertion. The end of muscle exertion allows the Cori cycle to function more effectively. This repays the oxygen debt so both the electron transport chain and citric acid cycle can produce energy at optimum effectiveness. [3]
The Cori cycle is a much more important source of substrate for gluconeogenesis than food. [4] [5] The contribution of Cori cycle lactate to overall glucose production increases with fasting duration before plateauing. [6] Specifically, after 12, 20, and 40 hours of fasting by human volunteers, gluconeogenesis accounts for 41%, 71%, and 92% of glucose production, but the contribution of Cori cycle lactate to gluconeogenesis is 18%, 35%, and 36%, respectively. [6] The remaining glucose production comes from protein breakdown, [6] muscle glycogen, [6] and glycerol from lipolysis. [7]
The drug metformin can cause lactic acidosis in patients with kidney failure because metformin inhibits the hepatic gluconeogenesis of the Cori cycle, particularly the mitochondrial respiratory chain complex 1. [8] The buildup of lactate and its substrates for lactate production, pyruvate and alanine, lead to excess lactate. [9] Normally, the excess acid that is the result of the inhibition of the mitochondrial chain complex would be cleared by the kidneys, but in patients with kidney failure, the kidneys cannot handle the excess acid. A common misconception posits that lactate is the agent responsible for the acidosis, but lactate is a conjugate base, being mostly ionised at physiologic pH, and serves as a marker of associated acid production rather than being its cause. [10] [11]
The citric acid cycle—also known as the Krebs cycle, Szent-Györgyi-Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions to release the energy stored in nutrients through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The chemical energy released is available under the form of ATP. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.
Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.
Pyruvic acid (IUPAC name: 2-oxopropanoic acid, also called acetoic acid) (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Cellular respiration is the process by which biological fuels are oxidized in the presence of an inorganic electron acceptor, such as oxygen, to drive the bulk production of adenosine triphosphate (ATP), which contains energy. Cellular respiration may be described as a set of metabolic reactions and processes that take place in the cells of organisms to convert chemical energy from nutrients into ATP, and then release waste products.
Adenosine monophosphate deaminase deficiency type 1 or AMPD1, is a human metabolic disorder in which the body consistently lacks the enzyme AMP deaminase, in sufficient quantities. This may result in exercise intolerance, muscle pain and muscle cramping. The disease was formerly known as myoadenylate deaminase deficiency (MADD).
Anaerobic glycolysis is the transformation of glucose to lactate when limited amounts of oxygen (O2) are available. Anaerobic glycolysis is an effective means of energy production only during short, intense exercise, providing energy for a period ranging from 10 seconds to 2 minutes. This is much faster than aerobic metabolism. The anaerobic glycolysis (lactic acid) system is dominant from about 10–30 seconds during a maximal effort. It replenishes very quickly over this period and produces 2 ATP molecules per glucose molecule, or about 5% of glucose's energy potential (38 ATP molecules). The speed at which ATP is produced is about 100 times that of oxidative phosphorylation.
Anabolism is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-down aspect. Anabolism is usually synonymous with biosynthesis.
Digestion is the breakdown of carbohydrates to yield an energy-rich compound called ATP. The production of ATP is achieved through the oxidation of glucose molecules. In oxidation, the electrons are stripped from a glucose molecule to reduce NAD+ and FAD. NAD+ and FAD possess a high energy potential to drive the production of ATP in the electron transport chain. ATP production occurs in the mitochondria of the cell. There are two methods of producing ATP: aerobic and anaerobic. In aerobic respiration, oxygen is required. Using oxygen increases ATP production from 4 ATP molecules to about 30 ATP molecules. In anaerobic respiration, oxygen is not required. When oxygen is absent, the generation of ATP continues through fermentation. There are two types of fermentation: alcohol fermentation and lactic acid fermentation.
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is an ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.
Lactic acidosis is a medical condition characterized by a build-up of lactate in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates due to a problem with the body's oxidative metabolism.
Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.
In oncology, the Warburg effect is the observation that most cancer cells release energy predominantly not through the 'usual' citric acid cycle and oxidative phosphorylation in the mitochondria as observed in normal cells, but through a less efficient process of 'aerobic glycolysis' consisting of a high level of glucose uptake and glycolysis followed by lactic acid fermentation taking place in the cytosol, not the mitochondria, even in the presence of abundant oxygen. This observation was first published by Otto Heinrich Warburg, who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme". The precise mechanism and therapeutic implications of the Warburg effect, however, remain unclear.
The Cahill cycle, also known as the alanine cycle or glucose-alanine cycle, is the series of reactions in which amino groups and carbons from muscle are transported to the liver. It is quite similar to the Cori cycle in the cycling of nutrients between skeletal muscle and the liver. When muscles degrade amino acids for energy needs, the resulting nitrogen is transaminated to pyruvate to form alanine. This is performed by the enzyme alanine transaminase (ALT), which converts L-glutamate and pyruvate into α-ketoglutarate and L-alanine. The resulting L-alanine is shuttled to the liver where the nitrogen enters the urea cycle and the pyruvate is used to make glucose.
The Pasteur effect describes how available oxygen inhibits ethanol fermentation, driving yeast to switch toward aerobic respiration for increased generation of the energy carrier adenosine triphosphate (ATP). More generally, in the medical literature, the Pasteur effect refers to how the cellular presence of oxygen causes in cells a decrease in the rate of glycolysis and also a suppression of lactate accumulation. The effect occurs in animal tissues, as well as in microorganisms belonging to the fungal kingdom.
Bioenergetic systems are metabolic processes that relate to the flow of energy in living organisms. Those processes convert energy into adenosine triphosphate (ATP), which is the form suitable for muscular activity. There are two main forms of synthesis of ATP: aerobic, which uses oxygen from the bloodstream, and anaerobic, which does not. Bioenergetics is the field of biology that studies bioenergetic systems.
Cellular waste products are formed as a by-product of cellular respiration, a series of processes and reactions that generate energy for the cell, in the form of ATP. One example of cellular respiration creating cellular waste products are aerobic respiration and anaerobic respiration.
Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvate to lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one molecule to another.
Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.
The lactate shuttle hypothesis describes the movement of lactate intracellularly and intercellularly. The hypothesis is based on the observation that lactate is formed and utilized continuously in diverse cells under both anaerobic and aerobic conditions. Further, lactate produced at sites with high rates of glycolysis and glycogenolysis can be shuttled to adjacent or remote sites including heart or skeletal muscles where the lactate can be used as a gluconeogenic precursor or substrate for oxidation. The hypothesis was proposed by professor George Brooks of the University of California at Berkeley.
Pseudohypoxia refers to a condition that mimics hypoxia, by having sufficient oxygen yet impaired mitochondrial respiration due to a deficiency of necessary co-enzymes, such as NAD+ and TPP. The increased cytosolic ratio of free NADH/NAD+ in cells (more NADH than NAD+) can be caused by diabetic hyperglycemia and by excessive alcohol consumption. Low levels of TPP results from thiamine deficiency.