Cited by 321Mitochondrial Function and PathologyCell death mechanisms and regulationNitric Oxide and Endothelin Effects

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Concentration-dependent Effects of Nitric Oxide on Mitochondrial Permeability Transition and Cytochrome cRelease

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Brookes, Paul S., Salinas, Emmanuel Padilla, Darley-Usmar, Kenta, Eiserich, Jason P., Freeman, Bruce A., Darley-Usmar, Victor M., Anderson, Peter G.·2000·Journal of Biological Chemistry

DOI 10.1074/jbc.m001077200

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Abstract

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).

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Authors: Brookes, P. S., Salinas, E. P., Darley-Usmar, K., Eiserich, J. P., Freeman, B. A., Darley-Usmar, V. M., & Anderson, P. G.
Affiliations: University of Alabama at Birmingham (US)
Corresponding author: Anderson, Peter G.
ORCID: Darley-Usmar, Victor M.
Anderson, Peter G.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2000-07
Volume: 275
Issue: 27
Pages: 20474-20479
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m001077200
OpenAlex: W1978791657
Cited by: 321
References: 47
Citations by year: 2025: 1 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 6 · 2020: 16 · 2019: 8 · 2018: 7 · 2017: 7 · 2016: 7 · 2015: 5 · 2014: 7 · 2013: 10 · 2012: 15
FWCI: 8.67
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 7407 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health (5p60hl058418-05)
National Heart, Lung, and Blood Institute (R01HL64937, R01HL064937, P6-HL-58418, R01HL058115, R01-HL-58115)
National Cancer Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Keywords: nitric oxide, mitochondrial permeability transition pore, cytochrome c release, apoptosis, mitochondrial depolarization, calcium accumulation, mitochondrial swelling, liver mitochondria, S-nitrosothiols, peroxynitrite
MeSH terms: Mitochondrial Permeability Transition Pore, Animals, Calcium, Cytochrome c Group, Ion Channels, Male, Membrane Potentials, Membrane Proteins, Mitochondria, Liver, Mitochondrial Swelling, Nitric Oxide, Oxyhemoglobins, Rats, Sprague-Dawley, Apoptosis, Nitric Oxide Donors, Mitochondrial Membrane Transport Proteins, Rats

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Concentration-dependent Effects of Nitric Oxide on Mitochondrial Permeability Transition and Cytochrome cRelease

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