Impaired mitochondrial beta-oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria.
Defects of complex I of the mitochondrial respiratory chain are important causes of neurological disease. We report studies that demonstrate a severe deficiency of complex I activity with less severe abnormalities of complexes III and IV (less than 5, 63, and 30% of control values, respectively) in a skeletal muscle mitochondrial fraction from a 22-yr-old female with weakness, lactic acidemia, and the deposition of intramuscular neutral lipid. The observation that lipid accumulates in this and other patients with complex I deficiency suggests impaired mitochondrial fatty acid oxidation. To investigate this mechanism we have shown impaired flux through beta-oxidation [( U-14C]hexadecanoate oxidation was 66% of control rate) and accumulation of specific acyl-CoA ester intermediates. The changes in fatty acid metabolism in complex I deficiency are secondary to the reduced state within the mitochondrial matrix with low NAD+/NADH ratios.
Watmough
N J
NJ
Department of Clinical Neuroscience, University of Newcastle upon Tyne, England.
Bindoff
L A
LA
Birch-Machin
M A
MA
Jackson
S
S
Bartlett
K
K
Ragan
C I
CI
Poulton
J
J
Gardiner
R M
RM
Sherratt
H S
HS
Turnbull
D M
DM
D000328:Adult; D030401:Cytochrome-c Oxidase Deficiency; D003580:Cytochromes / Q000378:metabolism; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D007700:Kinetics; D008661:Metabolism, Inborn Errors / Q000378:metabolism* / Q000473:pathology; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009132:Muscles / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone); D009468:Neuromuscular Diseases / Q000378:metabolism* / Q000473:pathology; D010088:Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption; D011808:Quinone Reductases / Q000172:deficiency* / Q000378:metabolism; D012016:Reference Values; D013385:Succinate Dehydrogenase / Q000378:metabolism
D003580:Cytochromes; D009097:Multienzyme Complexes; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases; D003576:Electron Transport Complex IV; D014450:Electron Transport Complex III