3-Hydroxy Glutaric Acid

What is 3-hydroxy glutaric acid?

3-hydroxy glutaric acid¹ is a linear, five-carbon dicarboxylic acid that is formed as an intermediate in amino acid catabolism. As a metabolite in mammals, the regulation of 3-hydroxy glutaric acid is mediated by the enzyme glutaryl-CoA dehydrogenase (GCDH). GCDH is involved in the catabolism of lysine and tryptophan—amino acids sourced exclusively from food.

Although the mechanisms and signaling cascades involved with 3-hydroxy in mammals remain largely unknown, it serves as a critical biomarker for a rare genetic disorder called glutaric aciduria type 1 (GA1). Elevated levels of 3-hydroxy glutaric acid found in urine, blood, or cerebrospinal fluid (CSF) indicate GA1, and the symptoms are severe.

(Figure from Peters et al., 2019)

3-hydroxyglutaric acid and glutaric aciduria type 1

GA1 is a disorder that begins a few months after birth and is estimated to affect 1 in 100,000 newborns². The disorder disrupts amino acid degradation, a crucial process for survival, and is caused by mutations encoding GCDH. Decreases in GCDH initiate a corresponding increase in 3-hydroxyglutaric acid in biofluids like blood, urine, and CSF. Patients with GA1 have a 100-fold increase in 3-hydroxyglutaric acid levels in these biofluids, as well as elevated levels in the brain and liver compared to healthy controls³. Symptoms are life-threatening and include brain damage driven by infectious diseases or fever that can severely impact motor movements and limit life expectancy, cause cognitive dysfunction, and induce chronic kidney failure.

While increases in 3-hydroxy glutaric acid are indicative of GA1, elevated 3-hydroxy glutaric acid can also be a marker for a number of other diseases, including macrocephaly, hepatic and uremic encephalopathies, metabolic stroke, urea cycle defects, and mitochondrial disorders, infantile cerebral palsy, or child abuse.

Current treatments include dietary interventions; however, the long-term impact remains unknown and does not alleviate motor impairments.

3-hydroxy glutaric acid and Neuroscience

Since the relationship between 3-hydroxy glutaric acid and GA1 primarily involves significant damage to the central nervous system, this dicarboxylic acid has been referred to as a neurotoxin. Previous studies have demonstrated that 3-hydroxy glutaric acid can moderately impair oxygen consumption in the mitochondria of the cerebral cortex and striatum (important brain regions for coordinating motor movement). This suggests that 3-hydroxy glutaric acid could be orchestrating other processes that result in metabolic failures in GA1⁴.

Other studies have demonstrated that once derived from lysine, 3-hydroxy glutaric acid cannot leave the nervous system. The accumulated 3-hydroxy glutaric acid elicits neurotoxic effects that include excitotoxicity (due to its similarity with glutamate, the primary excitatory neurotransmitter), redox homeostasis, impairs bioenergetics, promotes reactive astrogliosis, and damage to the blood-brain barrier⁴.

In an effort to understand what types of compounds might exert neuroprotective effects against 3-hydroxy glutaric acid, researchers examined the effects of a number of hormones and growth factors that might limit 3-hydroxy glutaric acid-induced toxicity in vitro. Interestingly, basic fibroblast growth factor and insulin-like growth factor, but not glutamate receptor antagonists, were effective in decreasing striatal cell death associated with 3-hydroxy glutaric acid exposure⁵.

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References

1. National Library of Medicine, National Center for Biotechnology Information. PubChem Compound Summary, Glutaric acid (CID 743).
2. Kolker S, Christensen E, Leonard JV et al. Diagnosis and management of glutaric aciduria type I–revised recommendations. J Inherit Metab Dis 2011;34(3): 677–694.
3. Boy N, Muhlhausen C, Maier EM et al. Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision. J Inherit Metab Dis 2023;46(3):482–519.
4. Latini A, Rodriguez M, Borba Rosa R et al. 3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats. Neuroscience 2005;135(1):111–120.
5. Bjugstad KB, Zawada WM, Goodman S et al. IGF-1 and bFGF reduce glutaric acid and 3-hydroxyglutaric acid toxicity in striatal cultures. J Inherit Metab Dis 2001;24(6):631–647.