A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury.
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.
Prime
Tracy A
TA
MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, United Kingdom.
Blaikie
Frances H
FH
Evans
Cameron
C
Nadtochiy
Sergiy M
SM
James
Andrew M
AM
Dahm
Christina C
CC
Vitturi
Dario A
DA
Patel
Rakesh P
RP
Hiley
C Robin
CR
Abakumova
Irina
I
Requejo
Raquel
R
Chouchani
Edward T
ET
Hurd
Thomas R
TR
Garvey
John F
JF
Taylor
Cormac T
CT
Brookes
Paul S
PS
Smith
Robin A J
RA
Murphy
Michael P
MP
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
D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D042967:Electron Transport Complex I