IMS (intermembrane space) SOD1 (Cu/Zn-superoxide dismutase) is inactive in isolated intact rat liver mitochondria and is activated following oxidative modification of its critical thiol groups. The present study aimed to identify biochemical pathways implicated in the regulation of IMS SOD1 activity and to assess the impact of its functional state on key mitochondrial events. Exogenous H2O2 (5 μM) activated SOD1 in intact mitochondria. However, neither H2O2 alone nor H2O2 in the presence of mitochondrial peroxiredoxin III activated SOD1, which was purified from mitochondria and subsequently reduced by dithiothreitol to an inactive state. The reduced enzyme was activated following incubation with the superoxide generating system, xanthine and xanthine oxidase. In intact mitochondria, the extent and duration of SOD1 activation was inversely correlated with mitochondrial superoxide production. The presence of TxrR-1 (thioredoxin reductase-1) was demonstrated in the mitochondrial IMS by Western blotting. Inhibitors of TxrR-1, CDNB (1-chloro-2,4-dinitrobenzene) or auranofin, prolonged the duration of H2O2-induced SOD1 activity in intact mitochondria. TxrR-1 inactivated SOD1 purified from mitochondria in an active oxidized state. Activation of IMS SOD1 by exogenous H2O2 delayed CaCl2-induced loss of transmembrane potential, decreased cytochrome c release and markedly prevented superoxide-induced loss of aconitase activity in intact mitochondria respiring at state-3. These findings suggest that H2O2, superoxide and TxrR-1 regulate IMS SOD1 activity reversibly, and that the active enzyme is implicated in protecting vital mitochondrial functions.
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Research Article|
June 13 2007
Mitochondrial respiratory chain and thioredoxin reductase regulate intermembrane Cu,Zn-superoxide dismutase activity: implications for mitochondrial energy metabolism and apoptosis
Pedro Iñarrea;
Pedro Iñarrea
1
*Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009-Zaragoza, Spain
1To whom correspondence should be addressed (email inarrea@unizar.es).
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Hadi Moini;
Hadi Moini
†Department of Molecular Pharmacology & Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, U.S.A.
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Derick Han;
Derick Han
†Department of Molecular Pharmacology & Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, U.S.A.
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Daniel Rettori;
Daniel Rettori
†Department of Molecular Pharmacology & Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, U.S.A.
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Ignacio Aguiló;
Ignacio Aguiló
*Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009-Zaragoza, Spain
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Maria Angeles Alava;
Maria Angeles Alava
*Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009-Zaragoza, Spain
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María Iturralde;
María Iturralde
*Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009-Zaragoza, Spain
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Enrique Cadenas
Enrique Cadenas
†Department of Molecular Pharmacology & Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, U.S.A.
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Publisher: Portland Press Ltd
Received:
December 05 2006
Revision Received:
March 22 2007
Accepted:
March 30 2007
Accepted Manuscript online:
March 30 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2007 Biochemical Society
2007
Biochem J (2007) 405 (1): 173–179.
Article history
Received:
December 05 2006
Revision Received:
March 22 2007
Accepted:
March 30 2007
Accepted Manuscript online:
March 30 2007
Citation
Pedro Iñarrea, Hadi Moini, Derick Han, Daniel Rettori, Ignacio Aguiló, Maria Angeles Alava, María Iturralde, Enrique Cadenas; Mitochondrial respiratory chain and thioredoxin reductase regulate intermembrane Cu,Zn-superoxide dismutase activity: implications for mitochondrial energy metabolism and apoptosis. Biochem J 1 July 2007; 405 (1): 173–179. doi: https://doi.org/10.1042/BJ20061809
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