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J. Biol. Chem., Vol. 275, Issue 27, 20474-20479, July 7, 2000
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§¶,
,
,
§§§, and
§¶¶
From the Departments of The mitochondrial permeability transition pore
(PTP) and associated release of cytochrome c are thought to
be important in the apoptotic process. Nitric oxide (NO·) 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·
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· on the PTP were characterized
by exposing isolated rat liver mitochondria to physiological and
pathological rates of NO· released from NONOate NO·
donors. Nitric oxide reversibly inhibited PTP opening with an IC50 of 11 nM NO·/s, which can be
readily achieved in vivo by NO· synthases. The
mechanism involved mitochondrial membrane depolarization and inhibition
of Ca2+ accumulation. At supraphysiological release rates
(>2 µM/s) NO· 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·. Furthermore, NO· 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·.
Pathology and
** Anesthesiology and the § Center for Free Radical
Biology, University of Alabama at Birmingham,
Birmingham, Alabama 35294
Participant in the NASA SHARP plus program in the laboratories
of V. M. D. U. and P. G. A.

Supported by NIH Grants RO1-HL64937, RO1-HL58115, and
P6-HL58418.
§§
Supported by the American Heart Association, American Diabetes
Association, and NIH Grant RO1 58031.
¶¶
Supported by NIH Grants RO1-HL058895 and RO1-HL58209.
To whom correspondence should be addressed. Tel.: 205-9342414; Fax: 205-9341775; E-mail: pga@uab.edu.
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