Abstract
Acute neurological crises involving striatal degeneration induced by a deficiency of glutaryl-CoA dehydrogenase (GCDH) and the accumulation of glutaric (GA) and 3-hydroxyglutaric acid (3-OHGA) are considered to be the most striking features of glutaric aciduria type I (GA1). In the present study, we investigated the mechanisms of apoptosis and energy metabolism impairment in our novel GA1 neuronal model. We also explored the effects of appropriate amounts of amino acids (2 mM arginine, 2 mM homoarginine, 0.45 g/L tyrosine and 10 mM leucine) and 2 g/L glucose on these cells. Our results revealed that the novel GA1 neuronal model effectively simulates the hypermetabolic state of GA1. We found that leucine, tyrosine, arginine, homoarginine or glucose treatment of the GA1 model cells reduced the gene expression of caspase-3, caspase-8, caspase-9, bax, fos, and jun and restored the intracellular NADH and ATP levels. Tyrosine, arginine or homoarginine treatment in particular showed anti-apoptotic effects; increased α-ketoglutarate dehydrogenase complex (OGDC), fumarase (FH), and citrate synthase (CS) expression; and relieved the observed impairment in energy metabolism. To the best of our knowledge, this study is the first to investigate the protective mechanisms of amino acids and glucose in GA1 at the cellular level from the point of view of apoptosis and energy metabolism. Our data support the results of previous studies, indicating that supplementation of arginine and homoarginine as a dietary control strategy can have a therapeutic effect on GA1. All of these findings facilitate the understanding of cell apoptosis and energy metabolism impairment in GA1 and reveal new therapeutic perspectives for this disease.
Highlights
The mitochondrial catabolism of lysine and tryptophan is disrupted by a deficiency of glutaryl-coenzyme A dehydrogenase (EC 1.3.99.7) (GCDH), causing glutaric aciduria type 1 (GA1) (OMIM #231670), which leads to the accumulation of glutarylCoA, glutaric acid (GA), 3-hydroxyglutaric acid (3-OHGA) and glutaconic acid (GC) in body fluids and tissues [1,2,3,4]
We explored whether appropriate concentrations of leucine, tyrosine, arginine, homoarginine and glucose have neuroprotective effects on GA1 model cells by assessing nuclear morphology, apoptosis, the intracellular levels of ATP and the reduced form of nicotinamide adenine dinucleotide (NADH), and the expression levels of key enzymes involved in the apoptosis pathway and the TCA cycle
Following nuclear staining using Hoechst 33342, neuronal nuclei exhibiting an apoptosis-related morphology, such as shrunken and irregularly shaped nuclei, were frequently detected in the GA1 model cells, whereas healthy nuclei were observed in the negative control (NC) cells in medium containing 5 mM lysine (Figure 1 A&B)
Summary
The mitochondrial catabolism of lysine and tryptophan is disrupted by a deficiency of glutaryl-coenzyme A dehydrogenase (EC 1.3.99.7) (GCDH), causing glutaric aciduria type 1 (GA1) (OMIM #231670), which leads to the accumulation of glutarylCoA, glutaric acid (GA), 3-hydroxyglutaric acid (3-OHGA) and glutaconic acid (GC) in body fluids and tissues [1,2,3,4]. Elevated levels of GA and 3-OHGA may cause neuronal damage by blocking the tricarboxylic acid cycle (TCA cycle) [5]. Glutaryl-CoA can inhibit the activity of the a-ketoglutarate dehydrogenase complex (OGDC), which is the rate-limiting enzyme in the TCA cycle [6]. GA1 may be triggered by a catabolic state or stress, such as inflammation, vaccination or surgery, and the affected individual may subsequently develop neurological/behavioral abnormalities by the age of two years [9]
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