Nitric oxide donors, nitrosothiols and mitochondrial respiration inhibitors induce caspase activation by different mechanisms.
We investigated to what extent different types of NO donors induce caspase activation by opening of the mitochondrial permeability transition pore (PTP) or inhibition of mitochondrial respiration. We found that nitrosothiols can directly open the PTP in isolated mitochondria and cause cytochrome c release, whereas NONOate donors can not. In macrophages nitrosothiols cause caspase activation that is blocked by cyclosporin A or calcium chelation, both of which prevent PTP opening, whereas caspase activation caused by NONOates is much less sensitive to these agents. Inhibitors of mitochondrial respiration did not promote PTP opening in isolated mitochondria, and although they cause caspase activation in macrophages, this activation was slower than that caused by NO donors, and was relatively insensitive to cyclosporin and calcium chelators suggesting that PTP opening was not involved.
Borutaite
V
V
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK. vb207@mole.bio.cam.ac.uk
Morkuniene
R
R
Brown
G C
GC
D000818:Animals; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007473:Ion Channels; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D013438:Sulfhydryl Compounds; D020169:Caspases