Succinyl CoA becomes succinic acid using succinyl CoA synthetase. This reaction produces NADH which directly provides electrons for the electron transport chain or respiratory chain. Succinic acid requires the enzyme succinate dehydrogenase to become fumarate. This enzyme is ironbased and requires vitamin B2 to support flavin adenine dinucleotide (FAD) as a redox coenzyme. Succinate dehydrogenase plays a critical role in mitochondrial metabolism. Impairment of this enzyme’s activity has been linked to a variety of diseases such as cancer and neurodegenerative diseases.
References:
- Tretter L, Adam-Vizi V. Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2335-2345.
- Rutter J, Winge DR, Schiffman JD. Succinate dehydrogenase - Assembly, regulation and role in human disease. Mitochondrion. 2010;10(4):393-401.
- Van Vranken JG, Na U, Winge DR, Rutter J. Protein-mediated assembly of succinate dehydrogenase and its cofactors. Crit Rev Biochem Molec Biol. 2015;50(2):168-180.
- Connors J, Dawe N, Van Limbergen J. The Role of Succinate in the Regulation of Intestinal Inflammation. Nutrients. 2018;11(1):25.
- Wentzel JF, Lewies A, Bronkhorst AJ, Van Dyk E, Du Plessis LH, Pretorius PJ. Exposure to high levels of fumarate and succinate leads to apoptotic cytotoxicity and altered global DNA methylation profiles in vitro. Biochimie. 2017;135:28-34.
- Harris RA, Joshi M, Jeoung NH, Obayashi M. Overview of the Molecular and Biochemical Basis of Branched-Chain Amino Acid Catabolism. J Nutr. 2005;135(6):1527S-1530S.
Low levels of succinic acid can be seen with poor dietary intake or absorption of branched-chain amino acids. Branched-chain amino acids are catabolized to acetyl-CoA or succinyl-CoA to feed the Citric Acid Cycle. Additionally, vitamin B12 deficiency can induce a defect in the conversion of methylmalonyl-CoA to succinyl-CoA at the distal end of the valine and isoleucine pathways which can then decrease succinyl-CoA.
The succinate precursor succinyl-CoA can be synthesized in the liver from dietary fats via the omega-oxidation pathway, or from dietary proteins. Inhibition of the omega-oxidation pathway may result in low succinate levels.
→ Consider supporting succinate synthesis from alpha-ketoglutarate with vitamins B1, B2, calcium, and lipoic acid.
→ The succinate precursor succinyl-CoA may also be derived from branch-chain amino acids or fatty acids. Support this pathway in patients on “keto”, high protein, or low carbohydrate diets. Consider supporting alternate pathways with vitamins B1, B2, B3, B6, B12, biotin, r-lipoic acid, iron (if deficient), magnesium, and molybdenum. If the liver omega-oxidation pathway is inhibited (B3 or zinc deficiency) then levels of adipate, suberate, ethylmalonate, and methylsuccinate may be low.
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Elevated levels of succinate 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 (succinyl-CoA, alpha-ketoglutarate), or if there are higher levels of its downstream products (fumarate).
High levels of succinate may also occur if there is complex II electron transport chain (ETC) inhibition. A loss of gastrointestinal barrier function (leaky gut) can increase circulating levels of bacterial proteins (lipopolysaccharides), which may also inhibit these enzymes.
Chronically increased succinate levels may increase oxidative stress and dysregulate the immune system. 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 adipate and suberate), increased gut permeability or fasting.
→ Consider supporting the conversion of succinate into fumarate with vitamins B2, B3, copper, iron, zinc, CoQ10, resveratrol, and antioxidants. Melatonin may help upregulate enzyme activity.
→ Adult-onset complex II ETC inherited defects are rare and may present with cardiac problems or muscle weakness, incoordination, and possibly seizures.
Complex II (succinate dehydrogenase)
Elevated lactate
Some will also have elevated succinate, fumarate
Consider supporting ETC function with additional vitamins B2, B3, B5, B12, E, selenium, taurine and melatonin.
→ Obesity or diabetes can decrease alpha-ketoglutarate but increase succinate.
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2-Hydroxybutyric acid, 2-Hydroxyhippuric acid, 2-Hydroxyisocaproic acid, 2-Hydroxyisovaleric acid, 2-Hydroxyphenylacetic acid, 2-Oxo-4-methiolbutyric acid, 2-Oxoglutaric acid, 2-Oxoisocaproic acid, 2-Oxoisovaleric, 3-Hydroxy-3-methylglutaric, 3-Hydroxybutyric acid, 3-Hydroxyglutaric acid, 3-Indoleacetic acid (IAA), 3-Methyl-2-oxovaleric acid, 3-Methylglutaconic, 3-Methylglutaric acid, 3-Oxoglutaric acid, 4-Cresol, 4-Hydroxybenzoic acid, 4-Hydroxybutyric acid, 4-Hydroxyhippuric acid, 4-Hydroxyphenylacetic acid, 4-Hydroxyphenyllactic acid, 5-Hydroxyindoleacetic acid (5-HIAA), 5-Hydroxymethyl-furoic acid, Acetoacetic acid, Aconitic acid, Adipic acid, Arabinose, Ascorbic acid (Vitamin C), Carboxycitric acid, Citramalic acid, Citric acid, Creatinine, DHPPA (dihydroxyphenylpropionic acid), Dihydroxyphenylacetic acid (DOPAC), Ethylmalonic acid, Fumaric acid, Furan-2,5-dicarboxylic acid, Furancarbonylglycine, GABA, Glutaric acid (Vitamin B2), Glyceric acid, Glycolic acid, Hippuric acid, Homogentisic acid, Homovanillic acid (HVA), HPHPA (3-(3-hydroxyphenyl)-3-hydroxypropionic acid), HVA/DOPAC, HVA/DOPAC Ratio, Kynurenic acid, Lactic acid, Malic acid, Malonic acid, Mandelic acid, Methylcitric acid (Vitamin H), Methylmalonic acid (Vitamin B12), Methylsuccinic acid, N-Acetylaspartic acid, N-Acetylcysteine acid, Orotic acid, Oxalic acid, Pantothenic acid (Vitamin B5), Phenyllactic acid, Phenylpyruvic acid, Phosphoric acid, Pyridoxic acid (Vitamin B6), Pyroglutamic acid, Pyruvic acid, Quinolinic acid, Quinolinic acid/5-HIAA, Sebacic acid, Suberic acid, Succinic acid, Tartaric acid, Thymine, Tricarballyic acid, Uracil
