Congenital deficiency of two polypeptide subunits of the iron-protein fragment of mitochondrial complex I.

Abstract

Recently, we described a patient with severe lactic acidosis due to congenital complex I (NADH-ubiquinone oxidoreductase) deficiency. We now report further enzymatic and immunological characterizations. Both NADH and ferricyanide titrations of complex I activity (measured as NADH-ferricyanide reductase) were distinctly altered in the mitochondria from the patient's tissues. In addition, antisera against complex I immunoprecipitated NADH-ferricyanide reductase from the control but not the patient's mitochondria. However, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of complex I polypeptides demonstrated that the majority of the 25 polypeptides comprising complex I were present in the affected mitochondria. A more detailed analysis using subunit selective antisera against the main polypeptides of the iron-protein fragments of complex I revealed a selective absence of the 75-and 13-kD polypeptides. These findings suggest that the underlying basis for this patient's disease was a congenital deficiency of at least two polypeptides comprising the iron-protein fragment of complex I, which resulted in the inability to correctly assemble a functional enzyme complex.

Impaired mitochondrial beta-oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria.

“…Low concentrations of all immunoreactive peptides of complex I have been found in other cases of complex I deficiency (14,15). However, several cases have been reported in which one or more individual subunit could not be detected; Moreadith et al (13) demonstrated lack of the 75-kD (nuclear coded) and 1 3-kD (nuclear coded) subunits, and Schapira et al (15) found a deficiency of the 24 kD FeS-protein (nuclear coded). There are several possible explanations for the severe deficiency of complex I and the less severe deficiencies of complexes III and IV.…”

“…Investigation of complex I deficiency has concentrated on identifying the defective subunit or subunits by electron paramagnetic resonance spectroscopy (7), Western blotting (13,14,15), and analysis of the mitochondrial genome (16). There have, however, been no investigations of the secondary effects of complex I deficiency on other metabolic pathways.…”

Oxidative Phosphorylation Diseases

“…In 19 biochemically characterized cases which fit our definition of LIMD, the mean age of onset was 3 weeks, with death occurring on the average at 5 months and associated with overwhelming lactic acidosis Rimoldi et al, 1982;Sengers et al, 1984;Bresolin et al, 1985;DiMauro et al , 1980;Heiman-Patterson et al, 1982;Moreadith et al , 1984Moreadith et al , , 1987Boustany et al , 1983;Aprille, 1985;Van Biervliet et al, 1977;Stansbie et al, 1982;Minchom et al, 1983;Muller-Hocker et al, 1983;Trijbels et al , 1983;Robinson et al, 1985Robinson et al, , 1986Zheng et al, 1989). While the clinical course was similar in all cases, only a few patients had a multiorgan pathological or biochemical assessment which could evaluate the extent of tissue dysfunction.…”

“…Case IV, DiMauro et al (1980). Case V, Moreadith et al (1984Moreadith et al ( , 1987. Case VI, Zheng et al (1989).…”

Genomic organization of the human complex I 13-kDa subunit gene NDUFA5

“…The physical mapping data for NDUFA5 exclude it as a candidate gene for WPW and DFN4, which map telomeric and centromeric of NDUFA5, respectively. Moreadith et al (1987) have described a patient with cardiomyopathy who lacks mature 75 and 13-kDa subunits of complex I according to Western blot data. Thus the results and materials reported in this study provide the necessary genetic tools to define the possible role of NDUFA5 in human disease.…”