title: Decreased fatty acid beta-oxidation in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3.
abstract: Riboflavin-responsive, multiple acylcoenzyme A dehydrogenase deficiency (RR-MAD), a lipid storage myopathy, is characterized by, among others, a decrease in fatty acid (FA) beta-oxidation capacity. Muscle uncoupling protein 3 (UCP3) is up-regulated under conditions that either increase the levels of circulating free FA and/or decrease FA beta-oxidation. Using a relatively large cohort of seven RR-MAD patients, we aimed to better characterize the metabolic disturbances of this disease and to explore the possibility that it might increase UCP3 expression. A battery of biochemical and molecular tests were performed, which demonstrated decreases in FA beta-oxidation and in the activities of respiratory chain complexes I and II. These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. We postulate that the up-regulation of UCP3 in RR-MAD is due to the accumulation of muscle FA/acylCoA. RR-MAD is an optimal model to support the hypothesis that UCP3 is involved in the outward translocation of an excess of FA from the mitochondria and to show that, in humans, the effects of FA on UCP3 expression are direct and independent of fatty acid beta-oxidation.
authors.affiliation: Department of Medical Biochemistry, University of Geneva Medical Center, 1206 Geneva, Switzerland. aaron.russell@crr-suva.ch
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Somm
authors.forename: Giacomo
authors.initials: G
authors.lastname: Gastaldi
authors.forename: Matthijs K C
authors.initials: MK
authors.lastname: Hesselink
authors.forename: Gert
authors.initials: G
authors.lastname: Schaart
authors.forename: Esther
authors.initials: E
authors.lastname: Kornips
authors.forename: Sing Kai
authors.initials: SK
authors.lastname: Lo
authors.forename: Daniela
authors.initials: D
authors.lastname: Bufano
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Giacobino
authors.forename: Patrick
authors.initials: P
authors.lastname: Muzzin
authors.forename: Mara
authors.initials: M
authors.lastname: Ceccon
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Lodovica
authors.initials: L
authors.lastname: Vergani
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency*; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D042967:Electron Transport Complex I / Q000172:deficiency; D042963:Electron Transport Complex II / Q000172:deficiency; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007473:Ion Channels; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D012256:Riboflavin / Q000627:therapeutic use*; D000071247:Uncoupling Protein 3
chemical_list: D002352:Carrier Proteins; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3; C478189:respiratory complex II; D042963:Electron Transport Complex II; D042964:Acyl-CoA Dehydrogenase; D042967:Electron Transport Complex I; D012256:Riboflavin