Overexpression of glutaredoxin 2 attenuates apoptosis by preventing cytochrome c release.
Human mitochondrial glutaredoxin 2 (Grx2) catalyzes glutathione-dependent dithiol reaction mechanisms, reducing protein disulfides, and monothiol reactions, reducing mixed disulfides between proteins and GSH (de-/glutathionylation). Here, we have overexpressed Grx2 in HeLa cells in its mitochondrial form (mGrx2-HeLa) as well as a truncated cytosolic form, lacking the mitochondrial translocation signal (tGrx2-HeLa). The resulting clones were less susceptible to apoptosis induced by 2-deoxy-d-glucose (2-DG) or doxorubicin (Dox). Overexpression of Grx2 inhibited cytochrome c release and caspase activation induced by both agents. In addition, Grx2 prevented 2-DG- and Dox-induced loss of cardiolipin, the phospholipid anchoring cytochrome c to the inner mitochondrial membrane. Overexpression of mGrx2 provided better protection than tGrx2 overexpression, especially after treatment with 2-DG. We propose that Grx2 facilitates the maintenance of cellular redox homeostasis upon treatment with apoptotic agents, thereby preventing cardiolipin oxidation and cytochrome c release.
Enoksson
Mari
M
Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Mari.Enoksson@imm.ki.se
Fernandes
Aristi Potamitou
AP
Prast
Stefanie
S
Lillig
Christopher Horst
CH
Holmgren
Arne
A
Orrenius
Sten
S
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002308:Cardiolipins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation; D054477:Glutaredoxins; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D002308:Cardiolipins; C516008:GLRX2 protein, human; D054477:Glutaredoxins; D004317:Doxorubicin; D045304:Cytochromes c; D003847:Deoxyglucose; D010088:Oxidoreductases; D020169:Caspases