Dysfunctions of cellular oxidative metabolism in patients with mutations in the NDUFS1 and NDUFS4 genes of complex I.
The pathogenic mechanism of a G44A nonsense mutation in the NDUFS4 gene and a C1564A mutation in the NDUFS1 gene of respiratory chain complex I was investigated in fibroblasts from human patients. As previously observed the NDUFS4 mutation prevented complete assembly of the complex and caused full suppression of the activity. The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa Fe-S subunit of the complex, was associated with (a) reduced level of the mature complex, (b) marked, albeit not complete, inhibition of the activity, (c) accumulation of H(2)O(2) and O(2)(.-) in mitochondria, (d) decreased cellular content of glutathione, (e) enhanced expression and activity of glutathione peroxidase, and (f) decrease of the mitochondrial potential and enhanced mitochondrial susceptibility to reactive oxygen species (ROS) damage. No ROS increase was observed in the NDUFS4 mutation. Exposure of the NDUFS1 mutant fibroblasts to dibutyryl-cAMP stimulated the residual NADH-ubiquinone oxidoreductase activity, induced disappearance of ROS, and restored the mitochondrial potential. These are relevant observations for a possible therapeutical strategy in NDUFS1 mutant patients.
Iuso
Arcangela
A
Department of Medical Biochemistry, Biology, and Physics, University of Bari, Policlinico, Piazza Giulio Cesare, 70124 Bari, Italy.
Scacco
Salvatore
S
Piccoli
Claudia
C
Bellomo
Francesco
F
Petruzzella
Vittoria
V
Trentadue
Raffaella
R
Minuto
Michele
M
Ripoli
Maria
M
Capitanio
Nazzareno
N
Zeviani
Massimo
M
Papa
Sergio
S
D000255:Adenosine Triphosphate / Q000737:chemistry; D000975:Antioxidants / Q000378:metabolism; D002384:Catalysis; D002460:Cell Line; D019069:Cell Respiration; D018389:Codon, Nonsense; D000242:Cyclic AMP / Q000378:metabolism; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015180:Electrophoresis, Gel, Two-Dimensional; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007700:Kinetics; D008564:Membrane Potentials; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009245:NADH Dehydrogenase; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D000975:Antioxidants; D018389:Codon, Nonsense; C487793:NDUFS1 protein, human; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D009247:NADH, NADPH Oxidoreductases; C014227:ferricyanide reductase; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C427643:NDUFS4 protein, human; D005978:Glutathione; D010100:Oxygen