ATP depletion does not account for apoptosis induced by inhibition of mitochondrial electron transport chain in human dopaminergic cells.
As the mitochondrial electron transport chain (ETC) is necessary for life, its inhibition results in cell death. To date, ETC complex (I-IV) inhibitors (ETCIs) have been thought to induce ATP depletion, triggering cellular apoptosis. To clarify whether the depletion of intracellular ATP is relevant to apoptosis induced by ETCIs, we conducted comparative studies using oxidative phosphorylation inhibitors (OPIs), including a specific F(0)F(1)ATP synthase inhibitor oligomycin, an ionophore valinomycin and an uncoupler 2,4-dinitrophenol, as tools to deplete only ATP without influencing the ETC. In human dopaminergic SH-SY5Y cells, ETCIs (rotenone, thenoyltrifluoroacetone, antimycin A and potassium cyanide) depleted ATP and induced apoptosis. However, OPIs failed to induce apoptosis despite ATP being decreased to an extent comparable to that observed with ETCIs. Reactive oxygen species (ROS) production was augmented by ETCIs, but not by OPIs. Furthermore, ETCI-induced apoptosis was inhibited by the addition of an antioxidant N-acetylcysteine. Apoptosis was induced without ATP depletion by H(2)O(2) at a concentration that generated ROS at an amount comparable to that induced by ETCIs. Our findings demonstrate that ROS production is more relevant than ATP depletion to apoptosis induced by ETCIs.
Watabe
Masahiko
M
Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi Ward, Tokyo 173-8605, Japan.
Nakaki
Toshio
T
D000255:Adenosine Triphosphate / Q000172:deficiency*; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009447:Neuroblastoma; D016877:Oxidants / Q000494:pharmacology; D050050:Protein Carbonylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D017304:Annexin A5; D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D016877:Oxidants; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D004298:Dopamine