Matt Pratt-Hyatt
Chief Science Officer, KBMO

Energy production pathways

Our bodies use a lot of energy day to day. Our cells produce this energy through an extremely complicated set of reactions. The mitochondria in the cells produce adenosine triphosphate (ATP) and lactate, to both store and release energy for many processes in the body.

There are three main pathways that the body uses to produce energy. The first process is called the Krebs Cycle (also called the TCA Cycle, or Citric Acid Cycle).

The second process is the Lactic Acid Cycle, which produces lactate as fuel when the demand for oxygen and ATP exceeds the cellular supply, such as when we are exercising, dealing with an infection, or have undergone toxic exposure (1).

Third, is Fatty Acid oxidation (FAO), which is a metabolic process that provides energy in times of starvation and metabolic stress (2).

The Metabolic Insights Panel (MIP) has markers to monitor how well each of these processes are working, and in combination with other groups of markers gives insight into underlying causes of dysfunction in your patient.

1. The Krebs Cycle

The Krebs cycle has 8 stages:

1. Citrate synthesis
2. Isomerization of citrate
3. Oxidative decarboxylation of isocitrate
4. Oxidative decarboxylation of alpha-ketoglutarate
5. Cleavage of succinyl coenzyme A
6. Oxidation of succinate
7. Hydration of fumarate
8. Oxidation of malate  (3, 4).

Some of the metabolites of these processes are not excreted in large amounts in urine and therefore do not make good markers. However, there are still over half a dozen markers that can give us insight into what is happening at a cellular level.

There are many things that can speed up and slow down the Krebs cycle.  Figure 1 (5), gives some examples of these:

(5)

Some of the most important markers in this group include:

Citric Acid – Low levels could indicate calcium stone disease. Low values could be caused by kidney disease, excessive muscle activity, hypoparathyroidism, or the use of ACE inhibitors

High levels could indicate a high carbohydrate diet, estrogen therapy, or excess vitamin D (6).

Succinate – Succinate is converted to Fumarate by the enzyme succinate-4-dehydrogenase. This enzyme can be inhibited by pesticides and other environmental toxins, leading to a buildup of succinate in the body (7).

Low levels of succinate could be caused by poor dietary intake or poor absorption of branched-chain amino acids. One other possible cause is a deficiency of B12 leading to a decrease in the precursor succinyl-CoA (8), or from autoimmune disease (9).

2. The Lactic Acid Cycle

Although not as efficient as the Krebs Cycle, the Lactic Acid Cycle still accounts for a large percentage of the body’s total energy production.

In this process glucose is converted to pyruvate through a series of catalytic reactions. These reactions are dependent on lactate dehydrogenase (LDH) (10).

The Lactic Acid Cycle has three main functions:

1. Energy regulation
2. Redox buffer
3. Regulation of fatty acid metabolism (11).

Some of the important markers for this section are:

L-Lactate – High lactate can occur when the body produces energy through anaerobic respiration. This often happens when tissues are deprived of oxygen. This can occur from excessive exercise but can also occur from toxins such as mycotoxins (12).

Pyruvate – High pyruvate could mean that the pathway to form Acetyl-Co-A is inhibited. This could be caused by mutations, or a deficiency in cofactors such as vitamins B1, B2, B3, and B7. Magnesium deficiency could also pay a role in high levels of pyruvic acid.  Patients that are consuming a high amount of carbohydrates could also have high amounts of pyruvate in their urine.

Low Levels of pyruvate could indicate that the patient is ingesting a low carbohydrate diet (13).

3. Fatty Acid Oxidation

Fatty acid oxidation (FAO) is performed in cells through the mitochondria and the peroxisome.  Acetyl-CoA is generated through FAO and is then a substrate for ketone body synthesis. NADH and FADH2 are also formed through FAO, and are used in phosphorylation to generate ATP (2).

This important part of energy regulation is monitored by multiple markers. Here are some of the most important:

Adipate – Very large amounts could indicate underlying metabolic disease. Elevations could lead to seizures (14).

Suberate – Elevated levels could indicate ketosis undergoing in the body (15).

Acetoacetic – Elevations in urine indicate the body is using fat for energy, which could be the result of a ketogenic diet. Symptoms associated with high levels include increased thirst, increased urination, fatigue, fruity-smelling breath, and confusion (16).

Want to Learn More?

If you’re interested in learning more about how organic acids can provide insights into metabolism and mitochondrial function in your patients, please contact us here.

The KBMO Diagnostics Metabolics Insights Profile (MIP) provides a full metabolic snapshot for your patients, including markers that can reveal issues such as nutritional deficiencies, microbial overgrowth, toxic exposure, oxalates, mitochondrial impairment, neurotransmitter imbalances and much more.

References:

1. A. R. Harmer et al., Sprint training increases muscle oxidative metabolism during high-intensity exercise in patients with type 1 diabetes. Diabetes Care 31, 2097-2102 (2008).
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11. X. Li et al., Lactate metabolism in human health and disease. Signal Transduct Target Ther 7, 305 (2022).
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14. D. A. Hasbini, M. A. Mikati, Z. M. Habbal, Isolated adipic aciduria. Pediatr Neurol 24, 77-78 (2001).
15. J. E. Pettersen, E. Jellum, L. Eldjarn, The occurrence of adipic and suberic acid in urine from ketotic patients. Clin Chim Acta 38, 17-24 (1972).
16. E. A. Nyenwe, A. E. Kitabchi, The evolution of diabetic ketoacidosis: An update of its etiology, pathogenesis and management. Metabolism 65, 507-521 (2016).