Depressant effect of mitochondrial respiratory complex inhibitors on proteasome inhibitor-induced mitochondrial dysfunction and cell death in PC12 cells.
The addition of rotenone (inhibitor of respiratory complex I), 3-nitropropionic acid (complex II inhibitor), harmine (inhibitor of complexes I and II) and cyclosporin A (CsA, an inhibitor of the mitochondrial permeability transition) reduced the nuclear damage, loss in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species and depletion of GSH in differentiated PC12 cells treated with MG132, a proteasome inhibitor. Meanwhile, rotenone, 3-nitropropionic acid and harmine did not affect the inhibitory effect of CsA or trifluoperazine (an inhibitor of the mitochondrial permeability transition and calmodulin antagonist) on the cytotoxicity of MG132. The results suggest that proteasome inhibition-induced mitochondrial dysfunction and cell injury may be attenuated by the inhibitions of respiratory chain complex I and II. The cytoprotective effect of the mitochondrial permeability transition prevention not appears to be modulated by respiratory complex inhibition.
Lee
Sun-Joo
SJ
Department of Pharmacology, College of Medicine, Chung-Ang University, 156-756, Seoul, South Korea. leecs@cau.ac.kr
Youn
Young Chul
YC
Han
Eun Sook
ES
Lee
Chung Soo
CS
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002463:Cell Membrane Permeability; D016572:Cyclosporine / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006247:Harmine / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009574:Nitro Compounds / Q000378:metabolism; D016716:PC12 Cells; D011422:Propionates / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000378:metabolism; D014268:Trifluoperazine / Q000378:metabolism; D014475:Uncoupling Agents / Q000378:metabolism
D004791:Enzyme Inhibitors; D007976:Leupeptins; D009574:Nitro Compounds; D011422:Propionates; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D014268:Trifluoperazine; D006247:Harmine; D016572:Cyclosporine; D005978:Glutathione; C015392:3-nitropropionic acid; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde