Pyruvic Acid

Pyruvic acid, also known as pyruvate, is a pivotal organic acid in cellular metabolism and energy production. 

It is produced during glycolysis, where glucose is converted into pyruvate and ATP by the enzyme pyruvate kinase. 

Pyruvate serves as a key intersection in several metabolic pathways, being converted into acetyl-CoA for the citric acid cycle, back into carbohydrates via gluconeogenesis, or into fatty acids and amino acids. 

It also plays a crucial role in anaerobic respiration, where it is converted into lactate to regenerate NAD+ for continued glycolysis.

What is Pyruvic Acid?

Pyruvic acid, also known as pyruvate, is an organic acid that is important in several biochemical pathways, particularly in energy production and cellular metabolism.

It is formed during the final step of glycolysis, along with ATP, by the enzyme pyruvate kinase, which is a magnesium-dependent enzyme. [7.] 

 As the end product of glycolysis and the starting substrate for the tricarboxylic acid cycle, pyruvic acid serves as an important indicator of cellular metabolic status.

It is a simple alpha-keto acid composed of a carboxyl group and a ketone group, making it a highly reactive molecule.

As with many enzymes in the glycolytic pathway, 

Role in Cellular Metabolism [9., 16.] 

Pyruvic acid, produced from glucose in the final step of glycolysis, can be converted back to carbohydrates through gluconeogenesis or to fatty acids via a reaction with acetyl-CoA.  [16.] 

It is also a precursor for the amino acid alanine and can be converted into ethanol or lactic acid through fermentation. [16.] 

In the presence of oxygen (aerobic respiration), pyruvic acid supplies energy to cells via the citric acid cycle (Krebs cycle). Pyruvic acid is converted to acetyl CoA by pyruvate dehydrogenase, which requires vitamins B1, B2, B3, B5, and lipoic acid. 

When oxygen is absent, it ferments to produce lactate or lactic acid, allowing for the regeneration of NAD+ and the continuation of glycolysis. [16.] 

Pyruvic acid is a central metabolite, linking several key pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis, and fatty acid synthesis.

Pyruvic acid plays an indirect role in beta-oxidation by providing acetyl-CoA through its conversion in the citric acid cycle, which is essential for the entry of fatty acids into the beta-oxidation pathway. [9.] 

Causes of Elevated Levels of Pyruvic Acid

Elevated levels of pyruvic acid in biological fluids such as blood or urine can be indicative of various metabolic disorders or conditions. Some potential causes include:

Genetic Mutations

Certain genetic mutations can cause altered enzyme function in relationship to glycolysis and/or the Krebs cycle. These conditions are often severe and can cause very high levels of metabolites such as pyruvic acid. 

For example, pyruvate metabolism disorders are genetic conditions that impair the body's ability to process pyruvate, leading to a buildup of lactic acid and various neurological issues. [15.] 

Key disorders include Pyruvate Dehydrogenase Deficiency, which can cause symptoms like weak muscles, seizures, and intellectual disability, and Pyruvate Carboxylase Deficiency, often fatal and marked by developmental delays and lactic acidosis. 

Diagnosis involves enzyme activity tests or genetic testing. Some disorders may be managed through dietary changes and vitamin supplements, although treatments are often limited.

Mitochondrial Dysfunction 

Impaired mitochondrial function can lead to a buildup of pyruvic acid due to disruptions in the TCA cycle and oxidative phosphorylation. 

Mitochondrial dysfunction is characterized by defects in ATP generation through oxidative phosphorylation (OXPHOS), often due to mtDNA mutations, imbalances in calcium homeostasis, and defects in mitochondrial dynamics and mitophagy. 

These dysfunctions lead to reduced ATP production, increased reactive oxygen species (ROS), and impaired muscle function, in skeletal muscle. [3.] 

Mitochondrial dysfunction can also manifest in neurological issues, cardiac arrhythmias, metabolic disorders such as diabetes, and hearing or vision problems. [14.] 

Diabetes

In type 2 diabetes, altered glucose metabolism and impaired glycolysis can result in changes in pyruvic acid levels.

Chronically high glucose levels have been shown to be a mitochondrial toxin in pancreatic beta cells, participating in the pathogenesis of diabetes and in the presence of elevated pyruvic acid levels, due to increased glycolysis. [8.] 

Over time, decreased levels of pyruvic acid can be seen due to complex shifts in glucose metabolism that occur in this disease process. [12.]

Cancer

Cancer cells often exhibit metabolic reprogramming, including increased glycolysis and lactate production (the Warburg effect), which can affect pyruvic acid levels.

One study examined pyruvic acid levels in saliva and serum among healthy individuals and oral cancer patients: it found that cancer cells exhibit increased glycolysis, leading to elevated pyruvic acid levels in saliva and serum. [1.] 

The Warburg Effect: Altered Cell Metabolism Seen in Cancer Cells [18.] 

The Warburg effect describes how cancer cells prefer aerobic glycolysis over mitochondrial oxidative phosphorylation, producing lactate even in the presence of oxygen. 

This metabolic shift is less efficient for ATP production but supports rapid cell proliferation by facilitating the uptake and incorporation of nutrients into biomass needed for cell growth. 

Cancer cells achieve this by activating specific signaling pathways that promote nutrient uptake and metabolic processes beneficial for proliferation. 

Liver Diseases [5.] 

Pyruvic acid levels can be significantly elevated in the blood and spinal fluid of patients with severe liver diseases, such as viral hepatitis and portal cirrhosis, and even more so during hepatic coma. 

This elevation correlates with the severity of hepatic failure. 

The rise in pyruvic acid is not due to hypoxia but is likely related to the impaired ability of the liver to metabolize pyruvic acid effectively, leading to its accumulation in the blood.

Severe Pulmonary Disease [10.] 

In severe pulmonary disease such as chronic obstructive pulmonary disease (COPD), pyruvic acid levels increase primarily due to enhanced glycolysis and altered glucose metabolism. 

The disease leads to higher rates of glucose production and glycolysis, resulting in increased pyruvate formation. 

Additionally, the oxidative capacity of muscles may be impaired, leading to insufficient conversion of pyruvate into acetyl-CoA in the citric acid cycle. Instead, more pyruvate accumulates, contributing to elevated levels of pyruvic acid in the blood. 

Furthermore, the increased energy demands and metabolic alterations in COPD exacerbate this effect.

Nutrient Deficiencies

Deficiencies in required cofactors including vitamins B1, B2, B3, B5, lipoic acid, and/or magnesium may manifest with elevated pyruvic acid levels. [4., 7., 13.] 

What Are Organic Acids?  [2., 6.]

Organic acids are organic compounds with acidic properties.  They include a variety of functional groups like carboxyl, phenol, enol, and thiol, with carboxylic acids having the strongest acidity.

Organic acids are considered weak acids, with those containing phenol, enol, alcohol, or thiol groups being even weaker.  

Their structures vary in terms of carbon chain types—aromatic, aliphatic, alicyclic, heterocyclic—saturation, substitutions, and the number of functional groups. 

These acids play critical roles in metabolic and catabolic pathways, notably in the tricarboxylic acid cycle inside mitochondria, which is central to energy production in eukaryotes.  They are also pivotal in determining the sensory properties of fruits and vegetables.

Organic Acid Testing in Functional Medicine

In functional medicine, organic acid testing is utilized to evaluate a patient's metabolic function through a simple urine test. This testing can identify metabolic imbalances that may affect a patient’s mood, energy, and overall health. 

Testing provides insights into nutrient deficiencies, dietary habits, toxic exposures, and gut microbiome activity. 

The results assist practitioners in customizing treatment plans to address specific metabolic dysfunctions and improve health outcomes. 

Additionally, it helps in assessing the impact of microbial metabolism and the efficiency of the Krebs Cycle, aiding in personalized healthcare.

Laboratory Testing for Pyruvic Acid

Test Information, Sampling Methods and Preparation

Laboratory testing for organic acids including pyruvic acid is typically done in urine, although it can also be tested in blood.  Testing may be ordered to diagnose an inborn metabolic disorder, or to assess metabolic function and gastrointestinal health in a functional medicine setting.  

Urine samples may be collected in a clinical setting; they can also be collected at home.  Some labs recommend or require a first morning void sample, to provide a concentrated sample.  

Interpretation of Pyruvic Acid Testing

Optimal Levels of Pyruvic Acid

Interpretation of organic acid test results requires a comprehensive assessment of various organic acids, and possibly other vitamins, minerals, and biomarkers, for a full picture of mitochondrial health and function. 

Generally, falling within reference ranges for organic acids is recommended, although for many of these organic acids, a level towards the lower end of the reference range is considered optimal.  

It is essential to consult with the laboratory company used for their recommended reference range for pyruvic acid.  

One company reports the following optimal range for pyruvic acid:  7-32 mmol/mol creatinine [17.]

Clinical Significance of Elevated Pyruvic Acid

High pyruvic acid levels may indicate an inherent or acquired mitochondrial dysfunction. Inherent mitochondrial dysfunctions are often due to genetic alterations and may be associated with serious health consequences.

Acquired mitochondrial dysfunction may be due to metabolic issues such as diabetes or conditions associated with decreased oxygenation, as in serious pulmonary disease. 

Serious liver disease, cancer, congestive heart failure and nutrient cofactor deficiencies such as thiamine deficiency may also play a role in elevated pyruvic acid levels. [19.]

Clinical Significance of Decreased Pyruvic Acid

Low levels of pyruvic acid may be seen in very low carbohydrate intake, or some nutrient cofactor deficiencies such as magnesium. [7.] 

Low pyruvic acid levels may also be seen in excessive insulin supplementation, as insulin has been shown to lower pyruvic acid levels in diabetes. [11.]

Interpreting Organic Acid Test Results

Interpretation of organic acid test results requires a comprehensive assessment of various organic acids, and possibly other vitamins, minerals, and biomarkers, for a full picture of mitochondrial health and function. 

Reputable resources are available to learn more about mitochondrial health assessment, including the following:

Class: How to Use Metabolomics Testing to Identify and Correct Mitochondrial Dysfunction

Article: Mitochondria - What They Are, Why We Should Care, and How to Support Them Using Functional Medicine Strategies

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