Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis.
Heart mitochondria from heterozygous (Sod2(-/+)) knockout mice have a 50% reduction in manganese superoxide dismutase (MnSOD) activity. The decrease in MnSOD activity was associated with increased mitochondrial oxidative damage as demonstrated by a decrease in the activities of iron sulfhydryl proteins sensitive to oxygen stress (aconitase and reduced nicotinamide adenine dinucleotide-oxidoreductase). Mitochondrial function was altered in the Sod2(-/+) mice, as shown by decreased respiration by complex I and an increase in the sensitivity of the permeability transition to induction by calcium and t-butylhydroperoxide. The increased induction of the permeability transition in heart mitochondria from Sod2(-/+.)mice was associated with increased release of cytochrome c and an increase in DNA fragmentation. Cardiomyocytes isolated from neonatal Sod2(-/+) and Sod2(-/-) mice were more sensitive to cell death than cardiomyocytes from Sod2(+/+) mice after t-butylhydroperoxide treatment, and this increased sensitivity was prevented by inhibiting the permeability transition with cyclosporin A. These experiments demonstrate that MnSOD may play an important role in the induction of the mitochondrial pathway of apoptosis in the heart, and this appears to occur primarily through the permeability transition.
Van Remmen
H
H
Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284, USA. vanremmen@uthscsa.edu
Williams
M D
MD
Guo
Z
Z
Estlack
L
L
Yang
H
H
Carlson
E J
EJ
Epstein
C J
CJ
Huang
T T
TT
Richardson
A
A
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation / Q000502:physiology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006579:Heterozygote; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D010101:Oxygen Consumption / Q000502:physiology; D010539:Permeability / Q000187:drug effects; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D020122:tert-Butylhydroperoxide / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
D000154:Aconitate Hydratase; D005974:Glutamate-Ammonia Ligase; D005978:Glutathione; D016877:Oxidants; D013482:Superoxide Dismutase; D020122:tert-Butylhydroperoxide; D000099156:Superoxide Dismutase 2