SOD2 overexpression: enhanced mitochondrial tolerance but absence of effect on UCP activity.
We have created P1 artificial chromosome transgenic mice expressing the human mitochondrial superoxide dismutase 2 (SOD2) and thus generated mice with a physiologically controlled augmentation of SOD2 expression leading to increased SOD2 enzyme activities and lowered superoxide levels. In the transgenic mice, effects on mitochondrial function such as enhanced oxidative capacity and greater resistance against inducers of mitochondrial permeability were observed. Superoxide in the mitochondrial matrix has been proposed to activate uncoupling proteins (UCPs), thus providing a feedback mechanism that will lower respiratory chain superoxide production by increasing a proton leak across the inner mitochondrial membrane. However, UCP1 and UCP3 activities and mitochondrial ATP production rates were not altered in isolated mitochondria from SOD2 transgenic mice, despite lowered superoxide levels. Globally, the transgenic mice displayed normal resting metabolic rates, indicating an absence of effect on any UCP activities, and normal oxygen consumption responses after norepinephrine injection. These results strongly suggest that endogenously generated matrix superoxide does not regulate UCP activity and in vivo energy expenditure.
Silva
José P
JP
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Shabalina
Irina G
IG
Dufour
Eric
E
Petrovic
Natasa
N
Backlund
Emma C
EC
Hultenby
Kjell
K
Wibom
Rolf
R
Nedergaard
Jan
J
Cannon
Barbara
B
Larsson
Nils-Göran
NG
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology*; D051336:Mitochondrial Membranes / Q000502:physiology; D024101:Mitochondrial Proteins; D009132:Muscles / Q000201:enzymology; D010084:Oxidation-Reduction; D010539:Permeability; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics*; D013481:Superoxides / Q000378:metabolism; D014475:Uncoupling Agents / Q000378:metabolism*; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D000099156:Superoxide Dismutase 2
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D013482:Superoxide Dismutase; D013481:Superoxides; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D000099156:Superoxide Dismutase 2; C000604371:UCP1 protein, human; C000604392:UCP3 protein, human; C000604372:Ucp1 protein, mouse; C000604393:Ucp3 protein, mouse