Isocitric

Increased urinary isocitrate levels when:

→ Diet

• High carbohydrate intake

• Citrate intake

→ Endocrine

• Parathyroid extract or hyperparathyroidism

→ Inborn errors of metabolism

• These disorders are usually diagnosed in infancy.

→ Toxic exposures

• Lead or other toxic metals

  • Lead can leach out of bones during and after andropause or menopause.

  • Lead solder was not banned in housing construction until about 1990.

Elevated levels of isocitrate may occur when there are nutritional enzyme inhibitions of the breakdown pathways, inherited low-activity enzymes are present, if there are high levels of precursors (cis-aconitate), or if there are higher levels of its downstream products (alpha- ketoglutarate). The interconversion of citrate and isocitrate (via cis-aconitate) is necessary and allows the Citric Acid Cycle (CAC) to function in either direction. Some parts of the cycle may reverse their flow during low oxygen conditions, if there is a shortage of NAD+, or due to dietary intakes. Dicarboxylic acids (cis-aconitate, isocitrate, succinate, malate, suberate, and adipate) may be excreted in high amounts due to increased mobilization of fatty acids, beta-oxidation defects, increased gut permeability or fasting.

→ Consider supporting the breakdown of isocitrate with vitamin B3, magnesium, and manganese (if deficient).

Iron deficiencies and overload at the systemic or cellular levels can negatively impact the aconitase enzyme and overall mitochondrial health and function. Due diligence with iron assessment is recommended when levels of these organic acids are abnormal. Glutathione may also be an important means of modulating aconitase activity during oxidative stress. Various toxins may influence mitochondrial enzymes and contribute to mitochondrial dysfunction, such as fluoride, aluminum, mercury, arsenic, and tin.

Decreased urinary isocitrate levels if:

→ Oxidative stress

Low levels of isocitrate may occur if there are low levels of precursors (cis-aconitate), if there are nutritional enzyme inhibitions, or if a low-activity enzyme variant is inherited. Low levels of isocitrate may occur with chronic fatigue syndrome. The interconversion of citrate and isocitrate (via aconitase) is necessary and allows the Citric Acid Cycle (CAC) to function in either direction. Aconitase is the Citric Acid Cycle (CAC) enzyme most sensitive to oxidative stress. Some parts of the cycle may reverse their flow during low oxygen conditions, if there is a shortage of NAD+, or due to dietary intakes.

→ Mitochondrial aconitase requires iron-sulfur cluster cofactors. The synthesis of iron-sulfur clusters can be supported with B2, B3, B6, zinc, and glutathione (antioxidants). Dysregulation of iron-sulfur cluster synthesis is associated with Friedreich’s ataxia, sideroblastic anemia, myopathy, and other inherited mitochondrial disorders. Iron deficiency or anemia may inhibit the synthesis of iron-sulfur clusters.

→ Chronic fatigue may increase levels of pyruvate and decrease citrate, cis-aconitate, isocitrate, and malate.

A two-carbon group from Acetyl-CoA is transferred to oxaloacetate to form citric acid. Citric acid is then converted to isocitric acid through a cis-aconitic intermediate using the enzyme aconitase. Aconitase is an iron-sulfate protein that controls iron homeostasis.