Christina C. Dahm

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Tracy A Prime, Denmark
  • Frances H Blaikie, Denmark
  • Cameron Evans, Denmark
  • Sergiy M Nadtochiy, Denmark
  • Andrew M James, Denmark
  • Christina C Dahm
  • Dario A Vitturi, Denmark
  • Rakesh P Patel, Denmark
  • C Robin Hiley, Denmark
  • Irina Abakumova, Denmark
  • Raquel Requejo, Denmark
  • Edward T Chouchani, Denmark
  • Thomas R Hurd, Denmark
  • John F Garvey, Denmark
  • Cormac T Taylor, Denmark
  • Paul S Brookes, Denmark
  • Robin A J Smith, Denmark
  • Michael P Murphy, Denmark
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.
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue26
Pages (from-to)10764-9
Number of pages5
ISSN0027-8424
DOIs
Publication statusPublished - 2009
Externally publishedYes

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