title: Mechanistic effects of amino acids and glucose in a novel glutaric aciduria type 1 cell model.
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.
authors.affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Fengyan
authors.initials: F
authors.lastname: Tian
authors.affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jinzhi
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Lou
authors.affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ning
authors.affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Luo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001928:Brain Diseases, Metabolic / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques; D002470:Cell Survival; D002478:Cells, Cultured; D002952:Citric Acid Cycle / Q000235:genetics; D003342:Corpus Striatum / Q000166:cytology; D005434:Flow Cytometry; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051381:Rats
chemical_list: D000596:Amino Acids; D051017:Apoptosis Regulatory Proteins; D009243:NAD; D000255:Adenosine Triphosphate; D050770:Glutaryl-CoA Dehydrogenase; D005947:Glucose