Coordinated and reversible reduction of enzymes involved in terminal oxidative metabolism in skeletal muscle mitochondria from a riboflavin-responsive, multiple acyl-CoA dehydrogenase deficiency patient.
In this case report we studied alterations in mitochondrial proteins in a patient suffering from recurrent profound muscle weakness, associated with ethylmalonic-adipic aciduria, who had benefited from high dose of riboflavin treatment. Morphological and biochemical alterations included muscle lipid accumulation, low muscle carnitine content, reduction in fatty acid beta-oxidation and reduced activity of complexes I and II of the respiratory chain. Riboflavin therapy partially or totally reversed these symptoms and increased the level of muscle flavin adenine dinucleotide, suggesting that aberrant flavin cofactor metabolism accounted for the disease. Proteomic investigation of muscle mitochondria revealed decrease or absence of several flavoenzymes, enzymes related to flavin cofactor-dependent mitochondrial pathways and mitochondrial or mitochondria-associated calcium-binding proteins. All these deficiencies were completely rescued after riboflavin treatment. This study indicates for the first time a profound involvement of riboflavin/flavin cofactors in modulating the level of a number of functionally coordinated polypeptides involved in fatty acyl-CoA and amino acid metabolism, extending the number of enzymatic pathways altered in riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.
Dipartimento di Scienze Farmacologiche, Gruppo di Studio per la Proteomica e la Struttura delle Proteine, Università degli Studi, Milano, Italy.
Elisabetta
E
Gianazza
Lodovica
L
Vergani
Robin
R
Wait
Carmen
C
Brizio
Daniela
D
Brambilla
Shajna
S
Begum
Teresa A
TA
Giancaspero
Francesca
F
Conserva
Ivano
I
Eberini
Daniela
D
Bufano
Corrado
C
Angelini
Elena
E
Pegoraro
Anna
A
Tramontano
Maria
M
Barile
D044944:Acyl-CoA Dehydrogenases / Q000172:deficiency*; D000596:Amino Acids / Q000378:metabolism; D042967:Electron Transport Complex I / Q000172:deficiency; D042963:Electron Transport Complex II / Q000172:deficiency; D015180:Electrophoresis, Gel, Two-Dimensional; D005227:Fatty Acids / Q000378:metabolism; D005486:Flavin Mononucleotide / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D006651:Histocytochemistry; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D040901:Proteomics; D012256:Riboflavin / Q000627:therapeutic use*; D021241:Spectrometry, Mass, Electrospray Ionization
D000596:Amino Acids; D005227:Fatty Acids; C478189:respiratory complex II; D005182:Flavin-Adenine Dinucleotide; D005486:Flavin Mononucleotide; D044944:Acyl-CoA Dehydrogenases; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; D012256:Riboflavin