title: Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
abstract: 3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is an inherited disorder of organic acid metabolism biochemically characterized by tissue accumulation and high urinary excretion of 3-hydroxy-3-methylgutarate, 3-methylglutarate, 3-methylglutaconate and 3-hydroxyisovalerate. Affected patients predominantly present neurological symptoms that are accompanied by mild hepatopathy during episodes of catabolic crisis. The pathophysiology of this disease is poorly known, although recent animal and human in vitro and in vivo studies have suggested that oxidative stress caused by the major accumulating organic acids may represent a pathomechanism of brain and liver damage in HL deficiency. In this review we focus on the deleterious effects of these carboxylic acids on redox homeostasis in rat and human tissues that may offer new perspectives for potential novel adjuvant therapeutic strategies in this disorder.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600 - Attached, CEP 90035-003, Alegre Porto, RS, Brazil.
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600 - Attached, CEP 90035-003, Alegre Porto, RS, Brazil.|Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Carmen Regla
authors.initials: CR
authors.lastname: Vargas
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600 - Attached, CEP 90035-003, Alegre Porto, RS, Brazil. mwajner@ufrgs.br.|Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. mwajner@ufrgs.br.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency*; D000592:Amino Acid Metabolism, Inborn Errors / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D005977:Glutarates / Q000652:urine; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000473:pathology*; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats
chemical_list: D005977:Glutarates; D000101:Acetyl-CoA C-Acetyltransferase