Concentration-dependent effects of nitric oxide on mitochondrial permeability transition and cytochrome c release.
The mitochondrial permeability transition pore (PTP) and associated release of cytochrome c are thought to be important in the apoptotic process. Nitric oxide (NO( small middle dot)) has been reported to inhibit apoptosis by acting on a variety of extra-mitochondrial targets. The relationship between cytochrome c release and PTP opening, and the effects of NO( small middle dot) are not clearly established. Nitric oxide, S-nitrosothiols and peroxynitrite are reported to variously inhibit or promote PTP opening. In this study the effects of NO( small middle dot) on the PTP were characterized by exposing isolated rat liver mitochondria to physiological and pathological rates of NO( small middle dot) released from NONOate NO( small middle dot) donors. Nitric oxide reversibly inhibited PTP opening with an IC(50) of 11 nm NO( small middle dot)/s, which can be readily achieved in vivo by NO( small middle dot) synthases. The mechanism involved mitochondrial membrane depolarization and inhibition of Ca(2+) accumulation. At supraphysiological release rates (>2 micrometer/s) NO( small middle dot) accelerated PTP opening. Substantial cytochrome c release occurred with only a 20% change in mitochondrial swelling, was an early event in the PTP, and was also inhibited by NO( small middle dot). Furthermore, NO( small middle dot) exposure resulted in significantly lower cytochrome c release for the same degree of PTP opening. It is proposed that this pathway represents an additional mechanism underlying the antiapoptotic effects of NO( small middle dot).
Brookes
P S
PS
Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Salinas
E P
EP
Darley-Usmar
K
K
Eiserich
J P
JP
Freeman
B A
BA
Darley-Usmar
V M
VM
Anderson
P G
PG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism*; D007473:Ion Channels; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D003574:Cytochrome c Group; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020030:Nitric Oxide Donors; D010108:Oxyhemoglobins; D009569:Nitric Oxide; D002118:Calcium