title: A mouse model of L-2-hydroxyglutaric aciduria, a disorder of metabolite repair.
abstract: The purpose of the present work was to progress in our understanding of the pathophysiology of L-2-hydroxyglutaric aciduria, due to a defect in L-2-hydroxyglutarate dehydrogenase, by creating and studying a mouse model of this disease. L-2-hydroxyglutarate dehydrogenase-deficient mice (l2hgdh-/-) accumulated L-2-hydroxyglutarate in tissues, most particularly in brain and testis, where the concentration reached ≈ 3.5 μmol/g. Male mice showed a 30% higher excretion of L-2-hydroxyglutarate compared to female mice, supporting that this dicarboxylic acid is partially made in males by lactate dehydrogenase C, a poorly specific form of this enzyme exclusively expressed in testes. Involvement of mitochondrial malate dehydrogenase in the formation of L-2-hydroxyglutarate was supported by the commensurate decrease in the formation of this dicarboxylic acid when down-regulating this enzyme in mouse l2hgdh-/- embryonic fibroblasts. The concentration of lysine and arginine was markedly increased in the brain of l2hgdh-/- adult mice. Saccharopine was depleted and glutamine was decreased by ≈ 40%. Lysine-α-ketoglutarate reductase, which converts lysine to saccharopine, was inhibited by L-2-hydroxyglutarate with a Ki of ≈ 0.8 mM. As low but significant activities of the bifunctional enzyme lysine-α-ketoglutarate reductase/saccharopine dehydrogenase were found in brain, these findings suggest that the classical lysine degradation pathway also operates in brain and is inhibited by the high concentrations of L-2-hydroxyglutarate found in l2hgdh-/- mice. Pathological analysis of the brain showed significant spongiosis. The vacuolar lesions mostly affected oligodendrocytes and myelin sheats, as in other dicarboxylic acidurias, suggesting that the pathophysiology of this model of leukodystrophy may involve irreversible pumping of a dicarboxylate in oligodendrocytes. Neurobehavioral testing indicated that the mice mostly suffered from a deficit in learning capacity. In conclusion, the findings support the concept that L-2-hydroxyglutaric aciduria is a disorder of metabolite repair. The accumulation of L-2-hydroxyglutarate exerts toxic effects through various means including enzyme inhibition and glial cell swelling.
authors.affiliation: Welbio and Laboratory of Physiological Chemistry, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Rim
authors.initials: R
authors.lastname: Rzem
authors.affiliation: Welbio and Laboratory of Physiological Chemistry, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Younes
authors.initials: Y
authors.lastname: Achouri
authors.affiliation: Cell Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Marbaix
authors.affiliation: Laboratory of Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schakman
authors.affiliation: Welbio and Laboratory of Physiological Chemistry, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Elsa
authors.initials: E
authors.lastname: Wiame
authors.affiliation: Laboratory of Metabolic Diseases, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marie
authors.affiliation: Laboratory of Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gailly
authors.affiliation: Laboratory of Metabolic Diseases, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Vincent
authors.affiliation: Welbio and Laboratory of Physiological Chemistry, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Veiga-da-Cunha
authors.affiliation: Welbio and Laboratory of Physiological Chemistry, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Emile
authors.initials: E
authors.lastname: Van Schaftingen
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005977:Glutarates / Q000378:metabolism*; D007658:Ketone Oxidoreductases / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013737:Testis / Q000378:metabolism*
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D001120:Arginine; D000429:Alcohol Oxidoreductases; C000603057:L2HGDH protein, mouse; D007658:Ketone Oxidoreductases; C023096:2-oxoglutarate synthase; D008239:Lysine