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

Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10764-9. doi: 10.1073/pnas.0903250106. Epub 2009 Jun 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / physiology
  • Cell Line
  • Electron Transport Complex I / metabolism
  • HeLa Cells
  • Heart / drug effects
  • Heart / physiopathology
  • Humans
  • In Vitro Techniques
  • Male
  • Mass Spectrometry
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Mitochondria / physiology
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / physiology
  • Myoblasts / cytology
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Nitric Oxide / metabolism
  • Nitrosation / drug effects
  • Oxygen Consumption / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / physiopathology
  • Reperfusion Injury / prevention & control*
  • S-Nitrosothiols / chemical synthesis
  • S-Nitrosothiols / metabolism
  • S-Nitrosothiols / pharmacology*
  • Sulfhydryl Compounds / metabolism*
  • Vasodilation / drug effects

Substances

  • S-Nitrosothiols
  • Sulfhydryl Compounds
  • Nitric Oxide
  • Electron Transport Complex I