A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury.

TitleA mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury.
Publication TypeJournal Article
Year of Publication2009
AuthorsPrime, TA, Blaikie, FH, Evans, C, Nadtochiy, SM, James, AM, Dahm, CC, Vitturi, DA, Patel, RP, C Hiley, R, Abakumova, I, Requejo, R, Chouchani, ET, Hurd, TR, Garvey, JF, Taylor, CT, Brookes, PS, Smith, RAJ, Murphy, MP
JournalProc Natl Acad Sci U S A
Volume106
Issue26
Pagination10764-9
Date Published2009 Jun 30
ISSN1091-6490
KeywordsAnimals, Aorta, Thoracic, Cell Line, Electron Transport Complex I, Heart, HeLa Cells, Humans, In Vitro Techniques, Male, Mass Spectrometry, Membrane Potential, Mitochondrial, Mice, Mice, Inbred C57BL, Mitochondria, Mitochondria, Heart, Myoblasts, Nitric Oxide, Nitrosation, Oxygen Consumption, Rats, Rats, Sprague-Dawley, Reperfusion Injury, S-Nitrosothiols, Sulfhydryl Compounds, Vasodilation
Abstract

Nitric oxide (NO(*)) competitively inhibits oxygen consumption by mitochondria at cytochrome c oxidase and S-nitrosates thiol proteins. We developed mitochondria-targeted S-nitrosothiols (MitoSNOs) that selectively modulate and protect mitochondrial function. The exemplar MitoSNO1, produced by covalently linking an S-nitrosothiol to the lipophilic triphenylphosphonium cation, was rapidly and extensively accumulated within mitochondria, driven by the membrane potential, where it generated NO(*) and S-nitrosated thiol proteins. MitoSNO1-induced NO(*) production reversibly inhibited respiration at cytochrome c oxidase and increased extracellular oxygen concentration under hypoxic conditions. MitoSNO1 also caused vasorelaxation due to its NO(*) generation. Infusion of MitoSNO1 during reperfusion was protective against heart ischemia-reperfusion injury, consistent with a functional modification of mitochondrial proteins, such as complex I, following S-nitrosation. These results support the idea that selectively targeting NO(*) donors to mitochondria is an effective strategy to reversibly modulate respiration and to protect mitochondria against ischemia-reperfusion injury.

DOI10.1073/pnas.0903250106
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.0903250106
PubMed ID19528654
PubMed Central IDPMC2696550
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
R01 HL071158 / HL / NHLBI NIH HHS / United States
#HL-071158 / HL / NHLBI NIH HHS / United States
/ / Medical Research Council / United Kingdom