Disproportionate deficiency of iron-sulfur clusters and subunits of complex I in mitochondrial encephalomyopathy.
To investigate the molecular abnormality in the mitochondria from various tissues of an autopsied patient exhibiting mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, we have examined the enzymatic activity, iron-sulfur cluster, and subunit composition of the NADH-ubiquinone oxidoreductase (complex I). Rotenone-sensitive NADH-cytochrome c reductase activity was found to be decreased in all the tissues examined. A detailed study of the liver mitochondria has shown that NADH-ubiquinone oxidoreductase activity was greatly diminished. Analysis of the electron paramagnetic resonance spectra of the liver submitochondrial particles revealed a disproportionate deficiency of iron-sulfur clusters in the complex I segment of the respiratory chain. Signals from the clusters N-2 and N-3 diminished more drastically than those from clusters N-1b and N-4. Immunoblotting analysis showed that the 75-kD, 51-kD, and several other subunits were markedly diminished among multiple subunit polypeptides of complex I. These findings suggest that the underlying bases for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are defects, at least, in the complex I subunits containing a flavin and/or iron-sulfur cluster(s), which resulted in deficiencies of some iron-sulfur clusters.
Ichiki
T
T
Department of Pediatrics, Nagoya City University Medical School, Japan.
Tanaka
M
M
Kobayashi
M
M
Sugiyama
N
N
Suzuki
H
H
Nishikimi
M
M
Ohnishi
T
T
Nonaka
I
I
Wada
Y
Y
Ozawa
T
T
D000140:Acidosis, Lactic / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D000293:Adolescent; D001927:Brain Diseases / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D002561:Cerebrovascular Disorders / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000172:deficiency*; D008297:Male; D008667:Metalloproteins / Q000172:deficiency*; D008930:Mitochondria, Liver / Q000201:enzymology / Q000473:pathology; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases / Q000172:deficiency*; D013577:Syndrome
D007506:Iron-Sulfur Proteins; D008667:Metalloproteins; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases