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

Area of Science:

• Biochemistry
• Neuroscience
• Toxicology

Background:

• Alzheimer disease is associated with increased lipid peroxidation in the brain.
• Lipid aldehydes, products of lipid peroxidation, are implicated as pathological effectors.
• The toxicity and disposition of these aldehydes depend on their chemical structure and interactions.

Purpose of the Study:

• To perform a structure-function analysis of 4-hydroxy/oxoalkenals on mitochondrial endpoints.
• To test if 4-oxo-2-nonenal (4-ONE) is more toxic than 4-hydroxy-2-nonenal (HNE) due to its reactivity.
• To determine if HNE toxicity is enantioselective in brain mitochondria.

Main Methods:

• Studied freshly isolated brain mitochondria.
• Assessed mitochondrial endpoints including respiration, swelling, and enzyme activities (ALDH2, ALDH5A).
• Utilized quantum mechanical calculations to understand reactivity differences.

Main Results:

• HNE enantioselectivity had minimal effect on mitochondrial endpoints.
• 4-ONE demonstrated greater toxicity than HNE in the mitochondrial environment (4-ONE > HNE).
• 4-ONE uncoupled mitochondrial respiration (5μM) and inhibited ALDH2 (IC50 ≈ 0.5μM).

Conclusions:

• 4-ONE is a potent effector of lipid peroxidation within mitochondria.
• The study highlights 4-ONE's significant role in mitochondrial dysfunction relevant to neurodegeneration.
• Thiol-based scavengers, but not amine-based ones, protected against 4-ONE's effects on respiration.