Abstract
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 2O 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.
| Original language | English |
|---|---|
| Pages (from-to) | 10374-10380 |
| Number of pages | 7 |
| Journal | Journal of Biological Chemistry |
| Volume | 281 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - Apr 14 2006 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Dysfunctions of cellular oxidative metabolism in patients with mutations in the NDUFS1 and NDUFS4 genes of complex I. / Iuso, Arcangela; Scacco, Salvatore; Piccoli, Claudia; Bellomo, Francesco; Petruzzella, Vittoria; Trentadue, Raffaella; Minuto, Michele; Ripoli, Maria; Capitanio, Nazzareno; Zeviani, Massimo; Papa, Sergio.
In: Journal of Biological Chemistry, Vol. 281, No. 15, 14.04.2006, p. 10374-10380.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Dysfunctions of cellular oxidative metabolism in patients with mutations in the NDUFS1 and NDUFS4 genes of complex I
AU - Iuso, Arcangela
AU - Scacco, Salvatore
AU - Piccoli, Claudia
AU - Bellomo, Francesco
AU - Petruzzella, Vittoria
AU - Trentadue, Raffaella
AU - Minuto, Michele
AU - Ripoli, Maria
AU - Capitanio, Nazzareno
AU - Zeviani, Massimo
AU - Papa, Sergio
PY - 2006/4/14
Y1 - 2006/4/14
N2 - 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 2O 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.
AB - 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 2O 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.
UR - http://www.scopus.com/inward/record.url?scp=33744515907&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33744515907&partnerID=8YFLogxK
U2 - 10.1074/jbc.M513387200
DO - 10.1074/jbc.M513387200
M3 - Article
C2 - 16478720
AN - SCOPUS:33744515907
VL - 281
SP - 10374
EP - 10380
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 15
ER -