title: Lipid peroxidation-derived reactive aldehydes directly and differentially impair spinal cord and brain mitochondrial function.
abstract: Mitochondrial bioenergetic dysfunction in traumatic spinal cord and brain injury is associated with post-traumatic free radical-mediated oxidative damage to proteins and lipids. Lipid peroxidation by-products, such as 4-hydroxy-2-nonenal and acrolein, can form adducts with proteins and exacerbate the effects of direct free radical-induced protein oxidation. The aim of the present investigation was to determine and compare the direct contribution of 4-hydroxy-2-nonenal and acrolein to spinal cord and brain mitochondrial dysfunction. Ficoll gradient-isolated mitochondria from normal rat spinal cords and brains were treated with carefully selected doses of 4-hydroxy-2-nonenal or acrolein, followed by measurement of complex I- and complex II-driven respiratory rates. Both compounds were potent inhibitors of mitochondrial respiration in a dose-dependent manner. 4-Hydroxy-2-nonenal significantly compromised spinal cord mitochondrial respiration at a 0.1-muM concentration, whereas 10-fold greater concentrations produced a similar effect in brain. Acrolein was more potent than 4-hydroxy-2-nonenal, significantly decreasing spinal cord and brain mitochondrial respiration at 0.01 muM and 0.1 muM concentrations, respectively. The results of this study show that 4-hydroxy-2-nonenal and acrolein can directly and differentially impair spinal cord and brain mitochondrial function, and that the targets for the toxic effects of aldehydes appear to include pyruvate dehydrogenase and complex I-associated proteins. Furthermore, they suggest that protein modification by these lipid peroxidation products may directly contribute to post-traumatic mitochondrial damage, with spinal cord mitochondria showing a greater sensitivity than those in brain.
authors.affiliation: Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA.
authors.forename: Radhika A
authors.initials: RA
authors.lastname: Vaishnav
authors.forename: Indrapal N
authors.initials: IN
authors.lastname: Singh
authors.forename: Darren M
authors.initials: DM
authors.lastname: Miller
authors.forename: Edward D
authors.initials: ED
authors.lastname: Hall
mesh_terms: D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D013347:Subcellular Fractions
chemical_list: D000447:Aldehydes
references.citation: Free Radic Biol Med. 2008 Nov 15;45(10):1457-67
references.pmid: 18801426
references.citation: NeuroRx. 2004 Jan;1(1):80-100
references.pmid: 15717009
references.citation: J Neurochem. 1999 Feb;72(2):751-6
references.pmid: 9930749
references.citation: Arch Biochem Biophys. 1989 Mar;269(2):623-38
references.pmid: 2919886
references.citation: Biochim Biophys Acta. 2001 Feb 14;1535(2):145-52
references.pmid: 11342003
references.citation: Brain Res Mol Brain Res. 2000 May 5;77(2):176-84
references.pmid: 10837913
references.citation: Exp Neurol. 2009 Mar;216(1):105-14
references.pmid: 19111721
references.citation: J Neurochem. 2007 Feb;100(3):639-49
references.pmid: 17181549
references.citation: CNS Neurol Disord Drug Targets. 2007 Dec;6(6):411-23
references.pmid: 18220780
references.citation: Toxicology. 2002 Dec 27;181-182:229-36
references.pmid: 12505316
references.citation: J Cereb Blood Flow Metab. 2006 Nov;26(11):1407-18
references.pmid: 16538231
references.citation: J Neurotrauma. 2004 Oct;21(10):1396-404
references.pmid: 15672630
references.citation: Neurology. 1984 Nov;34(11):1477-81
references.pmid: 6493495
references.citation: Drugs Aging. 2001;18(9):685-716
references.pmid: 11599635
references.citation: Free Radic Biol Med. 2008 Aug 15;45(4):443-52
references.pmid: 18501200
references.citation: Neurochem Res. 2009 Nov;34(11):1924-34
references.pmid: 19408115
references.citation: Nat Rev Drug Discov. 2007 Aug;6(8):662-80
references.pmid: 17667957
references.citation: J Neurochem. 2008 Nov;107(3):712-21
references.pmid: 18710419
references.citation: Neurochem Res. 2005 Mar;30(3):291-5
references.pmid: 16018572
references.citation: J Neurochem. 2002 Mar;80(5):780-7
references.pmid: 11948241
references.citation: Free Radic Res Commun. 1993;18(4):195-9
references.pmid: 8396550
references.citation: J Spinal Cord Med. 2001 Fall;24(3):142-6
references.pmid: 11585231
references.citation: J Neurotrauma. 2007 Jun;24(6):991-9
references.pmid: 17600515
references.citation: Free Radic Res. 2009 Jun;43(6):604-12
references.pmid: 19513907
references.citation: Biochem J. 2009 Jan 15;417(2):513-24
references.pmid: 18800966
references.citation: J Neurochem. 1992 Nov;59(5):1609-23
references.pmid: 1402908
references.citation: Neurochem Int. 2005 Feb;46(3):243-52
references.pmid: 15670641
references.citation: Mol Nutr Food Res. 2008 Jan;52(1):7-25
references.pmid: 18203133
references.citation: Chem Res Toxicol. 2008 Jan;21(1):172-88
references.pmid: 18052107
references.citation: Mech Ageing Dev. 2001 Jul 15;122(9):945-62
references.pmid: 11348660
references.citation: J Comp Neurol. 2004 Jul 5;474(4):524-34
references.pmid: 15174070
references.citation: J Neurotrauma. 2005 Feb;22(2):252-65
references.pmid: 15716631
references.citation: J Neurosci. 1997 Jul 1;17(13):5089-100
references.pmid: 9185546
references.citation: Crit Care Clin. 1989 Oct;5(4):793-805
references.pmid: 2676100
references.citation: Exp Neurol. 2007 May;205(1):154-65
references.pmid: 17349624
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2005 Mar;29(3):407-10
references.pmid: 15795049
references.citation: Neurotherapeutics. 2010 Jan;7(1):51-61
references.pmid: 20129497
references.citation: Mitochondrion. 2004 Sep;4(5-6):705-13
references.pmid: 16120426
references.citation: J Cereb Blood Flow Metab. 2008 Jun;28(6):1114-26
references.pmid: 18319733
references.citation: Ann N Y Acad Sci. 1999;890:462-8
references.pmid: 10668450
references.citation: J Neurochem. 2008 Feb;104(3):708-18
references.pmid: 17995940
references.citation: Biochem J. 1980 Nov 1;191(2):421-7
references.pmid: 6263247
references.citation: J Neurotrauma. 2009 Aug;26(8):1369-78
references.pmid: 19419247
references.citation: Pharmacol Ther. 2007 Jul;115(1):13-24
references.pmid: 17570531
references.citation: Neurology. 2006 May 23;66(10 Suppl 4):S24-36
references.pmid: 16717250
references.citation: Free Radic Biol Med. 2004 Oct 1;37(7):937-45
references.pmid: 15336309
references.citation: Biochem J. 1973 Jul;134(3):707-16
references.pmid: 4749271
references.citation: Biochem J. 1976 May 15;156(2):435-44
references.pmid: 182149
references.citation: J Neurotrauma. 2004 Jan;21(1):9-20
references.pmid: 14987461
references.citation: J Neurosci Res. 2007 Aug 1;85(10):2216-23
references.pmid: 17510982
references.citation: Cell Death Differ. 1999 Sep;6(9):825-32
references.pmid: 10510464
references.citation: J Neurotrauma. 2004 Oct;21(10):1405-14
references.pmid: 15672631
references.citation: Neurochem Int. 2005 Dec;47(7):449-57
references.pmid: 16140421
references.citation: J Bioenerg Biomembr. 2000 Apr;32(2):153-62
references.pmid: 11768748
references.citation: J Neurochem. 1999 Apr;72(4):1617-24
references.pmid: 10098869
references.citation: Am J Physiol Cell Physiol. 2007 Feb;292(2):C670-86
references.pmid: 17020935
references.citation: Neurochem Int. 2004 Jun;44(7):475-86
references.pmid: 15209416
references.citation: J Neurotrauma. 1992 Mar;9 Suppl 1:S1-7
references.pmid: 1588600
references.citation: Neurobiol Aging. 2001 Mar-Apr;22(2):187-94
references.pmid: 11182468
references.citation: Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1150-7
references.pmid: 16115018