Lipid peroxidation-derived reactive aldehydes directly and differentially impair spinal cord and brain mitochondrial function.
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.
Vaishnav
Radhika A
RA
Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA.
Singh
Indrapal N
IN
Miller
Darren M
DM
Hall
Edward D
ED
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
D000447:Aldehydes
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