Citrates Cycle: Function, Role & Diseases

The citrate cycle is a cycle of biochemical reactions that serves to break down organic matter. The process is embedded in the overall metabolism and takes over about half of the energy production in it. If the citrate cycle is impaired, mitochondriopathy may be present.

What is the citrate cycle?

In living organisms whose cells have a nucleus, the citrate cycle occurs in the mitochondrial matrix of the cells. The citrate cycle is a metabolic degradation pathway and as such plays an important role in cellular metabolism. It is also called the citric acid cycle and corresponds to a cycle of biochemical reactions. The center of the citrate cycle is oxidation, in which substances are degraded by the release of electrons. In the citric acid cycle, organic substances are broken down in this way to provide intermediate products for biosynthesis. In organisms whose cells have a nucleus, the citrate cycle takes place in the mitochondrial matrix of the cells. In all other organisms, it is localized in the cytoplasm. When the citrate cycle takes place in reverse order, it is called reductive citrate cycle. Such a reductive citrate cycle is present, for example, in the assimilation of carbon in the body of various bacteria. The citrate cycle owes its name to citrate, which is known as the anion of citric acid. Hans A. Krebs was the first to describe the citrate cycle, so the cycle is also called the Krebs cycle.

Function and task

The citrate cycle provides intermediates for the human organism to build organic components. It also provides energy to humans directly and indirectly in biochemical form. The degradation pathways of protein, fat and carbohydrate metabolism meet in the citrate cycle in the form of activated acetic acid. During the breakdown of sugars, fats and amino acids, acetyl-CoA is formed as an intermediate product. This acetyl-CoA is degraded to CO2 and H2O in the citric acid cycle. The first step is a condensation. Thus, a C-2 molecule of acetyl-CoA is condensed together with a C-4 molecule to form citrate, i.e. a C-6 molecule. This C-6 citrate is now degraded. The degradation takes place under a twofold CO2 cleavage and gives rise to the C-4 compound succinate. This is followed by oxidation over two steps. The C-4 compound thus becomes oxaloacetate and a new cycle can begin. After each cycle there is an acetyl residue, i.e. one more C-2 molecule. Two CO2 molecules each leave the cycle. One C-4 molecule each is consumed in the process, forming one C-6 molecule. Only when the cycle is complete can it be formed back again. Once the cycle has been fully completed, this results in the oxidation of acetate to water and carbon dioxide. The individual steps of the reactions take place through hydration, dehydration, dehydrogenation and decarboxylation. Considering all the branches of the citrate cycle, it can be said that the cycle is interconnected with the entire metabolism. Thus, the cycle also serves to prepare anabolic metabolic pathways. Energy is provided only by the four dehydrations of alpha-ketoglutarate, isocitrate, malate and succinate. This provision of energy is due to the oxidation that HCO2 undergoes as part of the respiratory chain. In the respiratory chain, this energy is required as part of oxidative phosphorylation to produce ATP from adenosine diphosphate. Thus, oxidation in the citrate cycle is tightly coupled to the receipt of energy in the respiratory chain. About half of all reactions for energy production in metabolism therefore occur through the citrate cycle.

Diseases and disorders

Malformations and damage to mitochondria are also known as mitochondriopathies. In such malformations, the citrate cycle cannot take place to the usual extent. Energy is thus no longer adequately provided in the form of ATP. Patients therefore feel weak, tired and fatigued. Mitochondrial pathologies can either be inherited or acquired through environmental influences. There is often a correlation between the two forms. For example, the inherited form often remains asymptomatic until environmental influences initiate the onset. The insufficient energy supply of the cells is now considered a possible cause of various neurodegenerative diseases.Cancer and cardiovascular diseases are now also associated with disturbed cell metabolism in the sense of mitochondrial dysfunction. Depending on which processes in the mitochondria are disturbed, there is talk of different mitochondrial pathologies. If, for example, pyruvate degradation is disturbed, the burning of glucose can no longer take place adequately and the end product of glucose combustion, i.e. glycolysis, cannot migrate into the citrate cycle. Most often, this phenomenon is preceded by a mutation in the X-linked semidominant inheritance. However, mitochondrial pathologies with other effects on the citrate cycle may also be present. Acetyl-CoA is further processed in the cycle from glycolysis. This is the penultimate step of carbohydrate combustion, which occurs before the respiratory chain. If this process is disturbed, a deficiency of ketoglutarate dehydrogenase, for example, can be responsible, i.e. an enzyme deficiency. A deficiency of fumarase can also be a possible cause. Mitochondrial pathologies manifest themselves in a lactic acid overload, which in turn is due to pyruvate congestion upstream of the citrate cycle. Symptoms are usually muscular and neurological complaints. Mitochondrial pathologies differ with the number of mutated mitochondria, but usually progress rapidly. Currently, no causative treatment pathways are available as therapeutic measures, only symptomatic treatments.