Effects of mitochondrial inhibitors on cell viability in U937 monocytes under glucose deprivation.
We studied cytotoxic mechanism of mitochondrial inhibitors in U937 cells. U937 cells were sensitive to cytotoxicity of mitochondrial inhibitors under glucose deprivation condition, whereas PC12 neuronal cells were not. In glucose deprivation condition, intracellular ATP content is decreased and thereby AMP-activated protein kinase (AMPK) is activated. And also activation of JNK, inactivation of ERK, and enhanced expression of Bcl-2 were observed. Mitochondrial inhibitors such as rotenone, TTFA, antimycin A, sodium azide, oligomycin, and valinomycin were used in this study. Inhibitors did not much influence intracellular ATP contents and activity of AMPK under glucose deprivation condition. Activities of Akt and p38 MAPK, however, were decreased by the inhibitors under glucose deprivation condition except TTFA. Furthermore, intracellular Ca2+ concentration was also greatly increased by the inhibitors. Finally, mitochondrial membrane potential was decreased by the inhibitors but TTFA increase the potential and oligomycin maintains it. In the present study, results suggest that under glucose deprivation condition mitochondrial inhibitors may induce severe cytotoxicity of U937 cells through inhibition of Akt and p38 MAPK, increase of [Ca2+]i, and decrease of MMP, but not through inhibition of ATP production and activation of AMPK.
Han
Mijin
M
Laboratory of Pharmacology, College of Pharmacy (BK21 Project) and Longevity Life Science and Technology Institutes, Pusan National University, Busan, 609-735, Korea.
Im
Dong-Soon
DS
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009097:Multienzyme Complexes / Q000378:metabolism; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D020298:U937 Cells; D014475:Uncoupling Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D002118:Calcium