title: Inhibition of mitochondrial bioenergetics: the effects on structure of mitochondria in the cell and on apoptosis.
abstract: The effects of specific inhibitors of respiratory chain, F(o)F(1)ATP synthase and uncouplers of oxidative phosphorylation on survival of carcinoma HeLa cells and on the structure of mitochondria in the cells were studied. The inhibitors of respiration (piericidin, antimycin, myxothiazol), the F(1)-component of ATP synthase (aurovertin) and uncouplers (DNP, FCCP) did not affect viability of HeLa cells, apoptosis induced by TNF or staurosporin and the anti-apoptotic action of Bcl-2. Apoptosis was induced by combined action of respiratory inhibitors and uncouplers indicating possible pro-apoptotic action of reactive oxygen species (ROS) generated by mitochondria. Short-term incubation of HeLa cells with the mitochondrial inhibitors and 2-deoxyglucose followed by 24-48 h recovery resulted in massive apoptosis. Apoptosis correlated to transient (3-4 h) and limited (60-70%) depletion of ATP. More prolonged or more complete transient ATP depletion induced pronounced necrosis. The inhibitors of respiration and uncouplers caused fragmentation of tubular mitochondria and formation of small round bodies followed by swelling. These transitions were not accompanied with release of cytochrome c into the cytosol and were fully reversible. The combined effect of respiratory inhibitors and uncouplers developed more rapidly indicating possible involvement of ROS generated by mitochondria. More prolonged (48-72 h) incubation with this combination of inhibitors caused clustering and degradation of mitochondria.
authors.affiliation: A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia.
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Lyamzaev
authors.forename: Denis S
authors.initials: DS
authors.lastname: Izyumov
authors.forename: Armine V
authors.initials: AV
authors.lastname: Avetisyan
authors.forename: Fuyu
authors.initials: F
authors.lastname: Yang
authors.forename: Olga Yu
authors.initials: OY
authors.lastname: Pletjushkina
authors.forename: Boris V
authors.initials: BV
authors.lastname: Chernyak
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D000968:Antimycin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis; D001313:Aurovertins / Q000494:pharmacology; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008689:Methacrylates; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001313:Aurovertins; D008689:Methacrylates; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D017382:Reactive Oxygen Species; D013844:Thiazoles; D014475:Uncoupling Agents; C032456:antimycin; D000968:Antimycin A; C030517:myxothiazol; D000255:Adenosine Triphosphate; C100213:piericidin A; D006180:Proton-Translocating ATPases; D005947:Glucose; D010100:Oxygen