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: Tracy A Prime, Frances H Blaikie, Cameron Evans, Sergiy M Nadtochiy, Andrew M James, Christina C Dahm, Dario A Vitturi, Rakesh P Patel, C Robin Hiley, Irina Abakumova, Raquel Requejo, Edward T Chouchani, Thomas R Hurd, John F Garvey, Cormac T Taylor, Paul S Brookes, Robin A J Smith, Michael P Murphy
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 26 Pg. 10764-9 (Jun 30 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19528654 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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