Regulation of cellular oncosis by uncoupling protein 2.
Cell death can proceed through at least two distinct pathways. Apoptosis is an energy-dependent process characterized morphologically by cell shrinkage, whereas oncosis is a form of cell death induced by energy depletion and initially characterized by cell swelling. We demonstrate in HeLa cells but not in normal diploid fibroblasts that modest increases in the expression level of uncoupling protein 2 (UCP-2) leads to a rapid and dramatic fall in mitochondrial membrane potential and to a reduction of mitochondrial NADH and intracellular ATP. In HeLa cells, increased UCP-2 expression leads to a form of cell death that is not inhibited by the anti-apoptotic gene product Bcl-2 and that morphologically resembles cellular oncosis. We further describe the creation of a dominant interfering mutant of UCP-2 whose expression increases resting mitochondrial membrane potential and selectively increases the resistance to cell death following oncotic but not apoptotic stimuli. These results suggest that distinct genetic programs may regulate the cellular response to either apoptotic or oncotic stimuli.
Mills
Edward M
EM
Cardiovascular Branch, NHLBI/National Institutes of Health, 10 Center Drive, Bldg. 10/6N-240, Bethesda, MD 20892, USA.
Xu
Dong
D
Fergusson
Maria M
MM
Combs
Christian A
CA
Xu
Yuhui
Y
Finkel
Toren
T
D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D002469:Cell Separation; D017259:Dimaprit / Q000031:analogs & derivatives* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007473:Ion Channels; D008164:Luminescent Proteins / Q000378:metabolism; D008564:Membrane Potentials; D026901:Membrane Transport Proteins; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D009154:Mutation; D009243:NAD / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000071246:Uncoupling Protein 2
D007473:Ion Channels; D008164:Luminescent Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D009243:NAD; D049452:Green Fluorescent Proteins; C071989:APT; D017259:Dimaprit