Resistance to cerebral ischemic injury in UCP2 knockout mice: evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels.
Uncoupling protein 2 (UCP2) is suggested to be a regulator of reactive oxygen species production in mitochondria. We performed a detailed study of brain injury, including regional and cellular distribution of UCP2 mRNA, as well as measures of oxidative stress markers following permanent middle cerebral artery occlusion in UCP2 knockout (KO) and wild-type (WT) mice. Three days post ischemia, there was a massive induction of UCP2 mRNA confined to microglia in the peri-infarct area of WT mice. KO mice were less sensitive to ischemia as assessed by reduced brain infarct size, decreased densities of deoxyuridine triphosphate nick end-labelling (TUNEL)-labelled cells in the peri-infact area and lower levels of lipid peroxidation compared with WT mice. This resistance may be related to the substantial increase of basal manganese superoxide dismutase levels in neurons of KO mice. Importantly, we found a specific decrease of mitochondrial glutathione (GSH) levels in UCP2 expressing microglia of WT, but not in KO mice after ischemia. This specific association between UCP2 and mitochondrial GSH levels regulation was further confirmed using lipopolysaccharide models of peripheral inflammation, and in purified peritoneal macrophages. Moreover, our data imply that UCP2 is not directly involved in the regulation of ROS production but acts by regulating mitochondrial GSH levels in microglia.
de Bilbao
Fabienne
F
Department of Psychiatry, University Hospitals Geneva, Geneva, Switzerland.
Arsenijevic
Denis
D
Vallet
Philippe
P
Hjelle
Ole Petter
OP
Ottersen
Ole Petter
OP
Bouras
Constantin
C
Raffin
Yvette
Y
Abou
Karin
K
Langhans
Wolfgang
W
Collins
Sheila
S
Plamondon
Julie
J
Alves-Guerra
Marie-Clotilde
MC
Haguenauer
Anne
A
Garcia
Irene
I
Richard
Denis
D
Ricquier
Daniel
D
Giannakopoulos
Panteleimon
P
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005978:Glutathione / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007473:Ion Channels; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000071246:Uncoupling Protein 2
D000975:Antioxidants; D007473:Ion Channels; D008070:Lipopolysaccharides; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D045304:Cytochromes c; D013482:Superoxide Dismutase; D005978:Glutathione