|
Guest
|
This has been at PubMed for a while now, but I don't believe it has
been previously posted here.
J Biol Chem. 2003 Dec 5;278(49):48534-45. Epub 2003 Sep 12.
Superoxide activates uncoupling proteins by generating carbon-centered
radicals and initiating lipid peroxidation: studies using a
mitochondria-targeted spin trap derived from
alpha-phenyl-N-tert-butylnitrone.
Murphy MP, Echtay KS, Blaikie FH, Asin-Cayuela J, Cocheme HM, Green K,
Buckingham JA, Taylor ER, Hurrell F, Hughes G, Miwa S, Cooper CE,
Svistunenko DA, Smith RA, Brand MD.
Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust-MRC
Building, Hills Road, Cambridge CB2 2XY, United Kingdom.
mpm@[r_emove]mrc-dunn.cam.ac.uk
Although the physiological role of uncoupling proteins (UCPs) 2 and 3
is uncertain, their activation by superoxide and by lipid peroxidation
products suggest that UCPs are central to the mitochondrial response
to reactive oxygen species. We examined whether superoxide and lipid
peroxidation products such as 4-hydroxy-2-trans-nonenal act
independently to activate UCPs, or if they share a common pathway,
perhaps by superoxide exposure leading to the formation of lipid
peroxidation products. This possibility can be tested by blocking the
putative reactive oxygen species cascade with selective antioxidants
and then reactivating UCPs with distal cascade components. We
synthesized a mitochondria-targeted derivative of the spin trap
alpha-phenyl-N-tert-butylnitrone, which reacts rapidly with
carbon-centered radicals but is unreactive with superoxide and lipid
peroxidation products.
[4-[4-[[(1,1-Dimethylethyl)-oxidoimino]methyl]phenoxy]butyl]triphenylphosphonium
bromide (MitoPBN) prevented the activation of UCPs by superoxide but
did not block activation by hydroxynonenal. This was not due to
MitoPBN reacting with superoxide or the hydroxyl radical or by acting
as a chain-breaking antioxidant. MitoPBN did react with
carbon-centered radicals and also prevented lipid peroxidation by the
carbon-centered radical generator 2,2'-azobis(2-methyl propionamidine)
dihydrochloride (AAPH). Furthermore, AAPH activated UCPs, and this was
blocked by MitoPBN. These data suggest that superoxide and lipid
peroxidation products share a common pathway for the activation of
UCPs. Superoxide releases iron from iron-sulfur center proteins, which
then generates carbon-centered radicals that initiate lipid
peroxidation, yielding breakdown products that activate UCPs.
PMID: 12972420 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12972420 |
|
|
