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. Nitr ic oxide (NO.) has been reported to inhibit apoptosis by acting on a variet y of extra-mitochondrial targets. The relationship between cytochrome c rel ease and PTP opening, and the effects of NO. are not clearly established. N itric oxide, S-nitrosothiols and peroxynitrite are reported to variously in hibit or promote PTP opening. In this study the effects of NO. on the PTP w ere characterized by exposing isolated rat liver mitochondria to physiologi cal and pathological rates of NO. released from NONOate NO. donors. Nitric oxide reversibly inhibited PTP opening with an IC50 of 11 nar NO./s, which can be readily achieved in vivo by NO. synthases. The mechanism involved mi tochondrial membrane depolarization and inhibition of Ca2+ accumulation. At supraphysiological release rates (>2 mu M/s) NO. accelerated PTP opening. Substantial cytochrome c release occurred with only a 20% change in mitocho ndrial swelling, was an early event in the PTP, and was also inhibited by N O.. Furthermore, NO. exposure resulted in significantly lower cytochrome c release for the same degree of PTP opening. It is proposed that this pathwa y represents an additional mechanism underlying the antiapoptotic effects o f NO..