 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
The Journal of Neuroscience, January 5, 2005, 25(1):164-172; doi:10.1523/JNEUROSCI.3829-04.2005
Previous Article | Next Article
Neurobiology of Disease
Cytochrome c Association with the Inner Mitochondrial Membrane Is Impaired in the CNS of G93A-SOD1 Mice
Ilias G. Kirkinezos,1 Sandra R. Bacman,2 Dayami Hernandez,2 Jose Oca-Cossio,2 Laura J. Arias,3 Miguel A. Perez-Pinzon,2,3 Walter G. Bradley,2,3 andCarlos T. Moraes1,2,3 Departments of 1Cell Biology and Anatomy and 2Neurology, and 3Neuroscience Program, University of Miami School of Medicine, Miami, Florida 33136
A "gain-of-function" toxic property of mutant Cu-Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of the human SOD1 gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS. We observed a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochrome c was used as an electron donor, pinpointing the defect to cytochrome c. Submitochondrial studies showed that cytochrome c in the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program.
Key words: amyotrophic lateral sclerosis; superoxide dismutase; mitochondria; cytochrome c; G93A-SOD1; lipid peroxidation
Received June 25, 2004; revised November 8, 2004; accepted November 8, 2004.
This article has been cited by other articles:
J. Magrane, I. Hervias, M. S. Henning, M. Damiano, H. Kawamata, and G. Manfredi
Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities
Hum. Mol. Genet., December 1, 2009; 18(23): 4552 - 4564.
[Abstract] [Full Text] [PDF]
D. J. Mahad, I. Ziabreva, G. Campbell, N. Lax, K. White, P. S. Hanson, H. Lassmann, and D. M. Turnbull
Mitochondrial changes within axons in multiple sclerosis
Brain, May 1, 2009; 132(5): 1161 - 1174.
[Abstract] [Full Text] [PDF]
K. T. Nguyen, L. E. Garcia-Chacon, J. N. Barrett, E. F. Barrett, and G. David
The {Psi}m depolarization that accompanies mitochondrial Ca2+ uptake is greater in mutant SOD1 than in wild-type mouse motor terminals
PNAS, February 10, 2009; 106(6): 2007 - 2011.
[Abstract] [Full Text] [PDF]
H. Kawamata and G. Manfredi
Different regulation of wild-type and mutant Cu,Zn superoxide dismutase localization in mammalian mitochondria
Hum. Mol. Genet., November 1, 2008; 17(21): 3303 - 3317.
[Abstract] [Full Text] [PDF]
H. Kawamata, J. Magrane, C. Kunst, M. P. King, and G. Manfredi
Lysyl-tRNA Synthetase Is a Target for Mutant SOD1 Toxicity in Mitochondria
J. Biol. Chem., October 17, 2008; 283(42): 28321 - 28328.
[Abstract] [Full Text] [PDF]
M. Son, S. C. Leary, N. Romain, F. Pierrel, D. R. Winge, R. G. Haller, and J. L. Elliott
Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein
J. Biol. Chem., May 2, 2008; 283(18): 12267 - 12275.
[Abstract] [Full Text] [PDF]
P. Cassina, A. Cassina, M. Pehar, R. Castellanos, M. Gandelman, A. de Leon, K. M. Robinson, R. P. Mason, J. S. Beckman, L. Barbeito, et al.
Mitochondrial Dysfunction in SOD1G93A-Bearing Astrocytes Promotes Motor Neuron Degeneration: Prevention by Mitochondrial-Targeted Antioxidants
J. Neurosci., April 16, 2008; 28(16): 4115 - 4122.
[Abstract] [Full Text] [PDF]
G. Goldsteins, V. Keksa-Goldsteine, T. Ahtoniemi, M. Jaronen, E. Arens, K. Akerman, P. H. Chan, and J. Koistinaho
Deleterious Role of Superoxide Dismutase in the Mitochondrial Intermembrane Space
J. Biol. Chem., March 28, 2008; 283(13): 8446 - 8452.
[Abstract] [Full Text] [PDF]
Q. Ran, H. Liang, Y. Ikeno, W. Qi, T. A. Prolla, L. J. Roberts II, N. Wolf, H. VanRemmen, and A. Richardson
Reduction in Glutathione Peroxidase 4 Increases Life Span Through Increased Sensitivity to Apoptosis
J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2007; 62(9): 932 - 942.
[Abstract] [Full Text] [PDF]
M. Son, K. Puttaparthi, H. Kawamata, B. Rajendran, P. J. Boyer, G. Manfredi, and J. L. Elliott
Overexpression of CCS in G93A-SOD1 mice leads to accelerated neurological deficits with severe mitochondrial pathology
PNAS, April 3, 2007; 104(14): 6072 - 6077.
[Abstract] [Full Text] [PDF]
A. Ferri, M. Cozzolino, C. Crosio, M. Nencini, A. Casciati, E. B. Gralla, G. Rotilio, J. S. Valentine, and M. T. Carri
Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials
PNAS, September 12, 2006; 103(37): 13860 - 13865.
[Abstract] [Full Text] [PDF]
T. W. Gould, R. R. Buss, S. Vinsant, D. Prevette, W. Sun, C. M. Knudson, C. E. Milligan, and R. W. Oppenheim
Complete Dissociation of Motor Neuron Death from Motor Dysfunction by Bax Deletion in a Mouse Model of ALS.
J. Neurosci., August 23, 2006; 26(34): 8774 - 8786.
[Abstract] [Full Text] [PDF]
D. Bergemalm, P. A. Jonsson, K. S. Graffmo, P. M. Andersen, T. Brannstrom, A. Rehnmark, and S. L. Marklund
Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models.
J. Neurosci., April 19, 2006; 26(16): 4147 - 4154.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|