title: Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies.
abstract: Mitochondrial fatty acid oxidation (FAO) plays a pivotal role in maintaining body energy homoeostasis mainly during catabolic states. Oxidation of fatty acids requires approximately 25 proteins. Inherited defects of FAO have been identified in the majority of these proteins and constitute an important group of inborn errors of metabolism. Affected patients usually present with severe hepatopathy, cardiomyopathy and skeletal myopathy, whereas some patients may suffer acute and/or progressive encephalopathy whose pathogenesis is poorly known. In recent years growing evidence has emerged indicating that energy deficiency/disruption of mitochondrial homoeostasis is involved in the pathophysiology of some fatty acid oxidation defects (FAOD), although the exact underlying mechanisms are not yet established. Characteristic fatty acids and carnitine derivatives are found at high concentrations in these patients and more markedly during episodes of metabolic decompensation that are associated with worsening of clinical symptoms. Therefore, it is conceivable that these compounds may be toxic. We will briefly summarize the current knowledge obtained from patients and genetic mouse models with these disorders indicating that disruption of mitochondrial energy, redox and calcium homoeostasis is involved in the pathophysiology of the tissue damage in the more common FAOD, including medium-chain acyl-CoA dehydrogenase (MCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. We will also provide evidence that the fatty acids and derivatives that accumulate in these diseases disrupt mitochondrial homoeostasis. The elucidation of the toxic mechanisms of these compounds may offer new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Porto Alegre, RS 90035-003, Brazil Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil mwajner@ufrgs.br.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Porto Alegre, RS 90035-003, Brazil.
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D006801:Humans; D052439:Lipid Metabolism Disorders / Q000235:genetics / Q000378:metabolism; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D005227:Fatty Acids
keywords: calcium homoeostasis; energy metabolism; fatty acid oxidation disorders; fatty acids; mitochondrial dysfunction; redox homoeostasis