title: A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury.
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.
authors.affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, United Kingdom.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Prime
authors.forename: Frances H
authors.initials: FH
authors.lastname: Blaikie
authors.forename: Cameron
authors.initials: C
authors.lastname: Evans
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.forename: Andrew M
authors.initials: AM
authors.lastname: James
authors.forename: Christina C
authors.initials: CC
authors.lastname: Dahm
authors.forename: Dario A
authors.initials: DA
authors.lastname: Vitturi
authors.forename: Rakesh P
authors.initials: RP
authors.lastname: Patel
authors.forename: C Robin
authors.initials: CR
authors.lastname: Hiley
authors.forename: Irina
authors.initials: I
authors.lastname: Abakumova
authors.forename: Raquel
authors.initials: R
authors.lastname: Requejo
authors.forename: Edward T
authors.initials: ET
authors.lastname: Chouchani
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hurd
authors.forename: John F
authors.initials: JF
authors.lastname: Garvey
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D042967:Electron Transport Complex I / Q000378:metabolism; D006367:HeLa Cells; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D026403:S-Nitrosothiols / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D042967:Electron Transport Complex I