title: 3-Hydroxy-3-methylglutaric and 3-methylglutaric acids impair redox status and energy production and transfer in rat heart: relevance for the pathophysiology of cardiac dysfunction in 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.
abstract: 3-Hydroxy-3-methylglutaryl-coenzyme A lyase (HL) deficiency is characterized by tissue accumulation of 3-hydroxy-3-methylglutaric (HMG), and 3-methylglutaric (MGA) acids. Affected patients present cardiomyopathy, whose pathomechanisms are not yet established. We investigated the effects of HMG and MGA on energy and redox homeostasis in rat heart using in vivo and in vitro models. In vivo experiments showed that intraperitoneal administration of HMG and MGA decreased the activities of the respiratory chain complex II and creatine kinase (CK), whereas HMG also decreased the activity of complex II-III. Furthermore, HMG and MGA injection increased reactive species production and carbonyl formation, and decreased glutathione concentrations. Regarding the enzymatic antioxidant defenses, HMG and MGA increased glutathione peroxidase (GPx) and glutathione reductase (GR) activities, while only MGA diminished the activities of superoxide dismutase (SOD) and catalase, as well as the protein content of SOD1. Pre-treatment with melatonin (MEL) prevented MGA-induced decrease of CK activity and SOD1 levels. In vitro results demonstrated that HMG and MGA increased reactive species formation, induced lipid peroxidation and decreased glutathione. We also verified that reactive species overproduction and glutathione decrease provoked by HMG and MGA were abrogated by MEL and lipoic acid (LA), while only MEL prevented HMG- and MGA-induced lipoperoxidation. Allopurinol (ALP) also prevented reactive species overproduction caused by both metabolites. Our data provide solid evidence that bioenergetics dysfunction and oxidative stress are induced by HMG and MGA in heart, which may explain the cardiac dysfunction observed in HL deficiency, and also suggest that antioxidant supplementation could be considered as adjuvant therapy for affected patients.
authors.affiliation: a Programa de Pós-Graduação em Ciências Biológicas: Bioquímica , Instituto de Ciências Básicas da Saúde , UFRGS , Porto Alegre, RS , Brazil ;
authors.forename: Mateus Struecker
authors.initials: MS
authors.lastname: da Rosa
authors.affiliation: a Programa de Pós-Graduação em Ciências Biológicas: Bioquímica , Instituto de Ciências Básicas da Saúde , UFRGS , Porto Alegre, RS , Brazil ;
authors.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.affiliation: b Centro de Ciências Naturais e Humanas , Universidade Federal do ABC , São Bernardo do Campo , SP , Brazil ;
authors.forename: César Augusto João
authors.initials: CA
authors.lastname: Ribeiro
authors.affiliation: a Programa de Pós-Graduação em Ciências Biológicas: Bioquímica , Instituto de Ciências Básicas da Saúde , UFRGS , Porto Alegre, RS , Brazil ;
authors.forename: Belisa
authors.initials: B
authors.lastname: Parmeggiani
authors.affiliation: a Programa de Pós-Graduação em Ciências Biológicas: Bioquímica , Instituto de Ciências Básicas da Saúde , UFRGS , Porto Alegre, RS , Brazil ;
authors.forename: Mateus
authors.initials: M
authors.lastname: Grings
authors.affiliation: a Programa de Pós-Graduação em Ciências Biológicas: Bioquímica , Instituto de Ciências Básicas da Saúde , UFRGS , Porto Alegre, RS , Brazil ;|c Departamento de Bioquímica , Instituto de Ciências Básicas da Saúde , UFRGS , Porto Alegre, RS , Brazil ;|d Serviço de Genética Médica , Hospital de Clínicas de Porto Alegre , Porto Alegre , RS , Brazil.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.affiliation: a Programa de Pós-Graduação em Ciências Biológicas: Bioquímica , Instituto de Ciências Básicas da Saúde , UFRGS , Porto Alegre, RS , Brazil ;|c Departamento de Bioquímica , Instituto de Ciências Básicas da Saúde , UFRGS , Porto Alegre, RS , Brazil ;
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D015093:Meglutol / Q000031:analogs & derivatives; D010084:Oxidation-Reduction; D007652:Oxo-Acid-Lyases / Q000172:deficiency*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C033686:3-methylglutaric acid; D015093:Meglutol; D007652:Oxo-Acid-Lyases; C021410:3-hydroxy-3-methylglutaryl-coenzyme A lyase
keywords: 3-Hydroxy-3-methylglutaric acid; 3-methylglutaric acid; energy metabolism; heart; oxidative stress