Mechanisms of the interaction of nitroxyl with mitochondria.
It is now thought that NO* (nitric oxide) and its redox congeners may play a role in the physiological regulation of mitochondrial function. The inhibition of cytochrome c oxidase by NO* is characterized as being reversible and oxygen dependent. In contrast, peroxynitrite, the product of the reaction of NO* with superoxide, irreversibly inhibits several of the respiratory complexes. However, little is known about the effects of HNO (nitroxyl) on mitochondrial function. This is especially important, since HNO has been shown to be more cytotoxic than NO*, may potentially be generated in vivo, and elicits biological responses with some of the characteristics of NO and peroxynitrite. In the present study, we present evidence that isolated mitochondria, in the absence or presence of substrate, convert HNO into NO* by a process that is dependent on mitochondrial concentration as well as the concentration of the HNO donor Angeli's salt. In addition, HNO is able to inhibit mitochondrial respiration through the inhibition of complexes I and II, most probably via modification of specific cysteine residues in the proteins. Using a proteomics approach, extensive modification of mitochondrial protein thiols was demonstrated. From these data it is evident that HNO interacts with mitochondria through mechanisms distinct from those of either NO* or peroxynitrite, including the generation of NO*, the modification of thiols and the inhibition of complexes I and II.
Shiva
Sruti
S
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Crawford
Jack H
JH
Ramachandran
Anup
A
Ceaser
Erin K
EK
Hillson
Tess
T
Brookes
Paul S
PS
Patel
Rakesh P
RP
Darley-Usmar
Victor M
VM
D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism; D042963:Electron Transport Complex II / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008314:Malonates / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D009573:Nitrites / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008314:Malonates; D024101:Mitochondrial Proteins; D009573:Nitrites; D009589:Nitrogen Oxides; C021229:oxyhyponitrite; D009569:Nitric Oxide; C030290:malonic acid; D042963:Electron Transport Complex II; D005978:Glutathione; C039900:nitroxyl; D003545:Cysteine