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Meyer MJ, Mosely DE, Amarnath V, Picklo MJ Sr: Metabolism of 4-hydroxy-trans-2-nonenal by central nervous system mitochondria is dependent on age and NAD+ availability. Chem Res Toxicol. 2004 Sep;17(9):1272-9.
Lipid peroxidation and mitochondrial dysfunction are associated with multiple neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. 4-Hydroxy-trans-2-nonenal (HNE) is a major, neurotoxic product of lipid peroxidation whose levels are elevated in these diseases. Previous data from this laboratory demonstrate that mitochondria play an important role in the detoxification of HNE particularly through the oxidation of HNE to 4-hydroxy-trans-2-nonenoate (HNEAcid). In this work, we examined the disposition of HNE when incubated with intact, well-coupled, rat brain mitochondria. Our results demonstrated that HNE loss occurred in a time- and concentration-dependent, saturable manner with a K (M) of 28.0 +/- 11.8 microM HNE and a V (Max) of 10.0 +/- 1.7 nmol/min/mg. HNEAcid formation occurred in a saturable manner with a K (M) of 25.3 +/- 6.3 microM HNE and a V (Max) of 4.4 +/- 0.43 nmol/min/mg. The formation of HNE-glutathione adducts and HNE-protein adducts comprised only a small percentage of HNE consumption. HNE metabolism was significantly diminished in rat brain mitochondria isolated from older animals. We then tested the hypothesis that the mitochondrial NADH/NAD (+) ratio regulated matrix aldehyde dehydrogenase activity. Our results demonstrate that HNE oxidation was significantly inhibited to a greater extent with pyruvate and malate as substrates vs succinate. Complex I inhibition with respiratory substrates further blocked HNE detoxification. Rotenone (100 nM) inhibited respiration by 15% whereas HNEAcid formation was decreased to 72% of control levels. These results demonstrate that in situ mitochondrial aldehyde detoxification is affected by decrements in NAD (+) availability and complex I activity. |
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