Trans-4-oxo-2-nonenal potently alters mitochondrial function

Alzheimer disease elevates lipid peroxidation in the brain and data indicate that the resulting lipid-aldehydes are pathological effectors of lipid peroxidation. The disposition of 4-substituted nonenals derived from arachidonate (20:4, n-6) and linoleate (18:2, n-6) oxidation is modulated by their protein adduction targets, their metabolism, and the nature of the 4-substitutent. Trans-4-oxo-2-nonenal (4-ONE) has a higher toxicity in some systems than the more commonly studied trans-4-hydroxy-2-nonenal (HNE). In this work, we performed a structure–function analysis of 4-hydroxy/oxoalkenal upon mitochondrial endpoints. We tested the hypotheses that 4-ONE, owing to a highly reactive nature, is more toxic than HNE and that HNE toxicity is enantioselective. We chose to study freshly isolated brain mitochondria because of the role of mitochondrial dysfunction in neurodegenerative disorders. Whereas there was little effect related to HNE chirality, our data indicate that in the mitochondrial environment, the order of toxic potency under most conditions was 4-ONE > HNE. 4-ONE uncoupled mitochondrial respiration at a concentration of 5 μM and inhibited aldehyde dehydrogenase 2 (ALDH2) activity with an IC50 of approximately 0.5 μM. The efficacy of altering mitochondrial endpoints was ALDH2 inhibition > respiration = mitochondrial swelling = ALDH5A inhibition > GSH depletion. Thiol-based alkenal scavengers, but not amine-based scavengers, were effective in blocking the effects of 4-ONE upon respiration. Quantum mechanical calculations provided insights into the basis for the elevated reactivity of 4-ONE > HNE. Our data demonstrate that 4-ONE is a potent effector of lipid peroxidation in the mitochondrial environment.