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4‐Hydroxy‐2( E )‐Nonenal Inhibits CNS Mitochondrial Respiration at Multiple Sites
Author(s) -
Picklo Matthew J.,
Amarnath Venkataraman,
McIntyre J. Oliver,
Graham Doyle G.,
Montine Thomas J.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.721617.x
Subject(s) - respiration , mitochondrion , oxidative stress , oxidative phosphorylation , lipid peroxidation , biochemistry , chemistry , reactive oxygen species , biology , anatomy
A destructive cycle of oxidative stress and mitochondrial dysfunction is proposed in neurodegenerative disease. Lipid peroxidation, one outcome of oxidative challenge, can lead to the formation of 4‐hydroxy‐2( E )‐nonenal (HNE), a lipophilic alkenal that forms stable adducts on mitochondrial proteins. In this study, we characterized the effects of HNE on brain mitochondrial respiration. We used whole rat brain mitochondria and concentrations of HNE comparable to those measured in patients with Alzheimer’s disease. Our results showed that HNE inhibited respiration at multiple sites. Complex I‐linked and complex II‐linked state 3 respirations were inhibited by HNE with IC 50 values of ∼200 μ M HNE. Respiration was apparently diminished owing to the inhibition of complex III activity. In addition, complex II activity was reduced slightly. The lipophilicity and adduction characteristics of HNE were responsible for the effects of HNE on respiration. The inhibition of respiration was not prevented by N ‐acetylcysteine or aminoguanidine. Studies using mitochondria isolated from porcine cerebral cortex also demonstrated an inhibition of complex I‐ and complex II‐linked respiration. Thus, in neurodegenerative disease, oxidative stress may impair mitochondrial respiration through the production of HNE.