Phosphatidylethanolamine: Between Oxidative Stress And Uncoupling

Reactive aldehydes (RAs) have been implicated in the pathogenesis of many diseases. Understanding how RAs interact with biological molecules, in particular proteins, under oxidative stress is critical for the effective design of therapeutic approaches. Over the last few decades most studies focussed only on direct interactions of 4-hydroxy-2-nonenal (HNE) with proteins1. We hypothesized that the modification of membrane protein function under oxidative stress is mediated by the membrane lipid phosphatidylethanolamine (PE)2. Our results showed that (i) the interaction of HNE or ONE with the PE amino group led to the formation of four HNE-PE adducts or one ONE-PE (Schiff base) adduct. We revealed that (ii) only ONE-PE adduct caused the alteration of transport activity of mitochondrial uncoupling proteins 1 (UCP1), potassium carrier valinomycin and ionophore CCCP. In contrast, (iii) neither direct protein modification by RAs as previously shown for cytosolic proteins, nor RAs insertion into membrane bilayers without PE influenced the studied transporters. Interestingly, in the protein-free PE-containing membranes HNE (but not ONE!) increased the membrane permeability, P, for cations, in particular for sodium3. PNa, calculated in the presence of double HNE-PE adducts, was increased by three to four orders of magnitude when compared to PNain adduct - free membranes. Our results explain the diversity of RA action on cell proteins and open new perspectives in the investigation of PE-mediated effects of biologically important RAs on membrane transporters. 1. Malingriaux, E.A., Rupprecht, A., Gille, L., Jovanovic, O., Jezek P., Jaburek, M., Pohl, E.E. (2013) PLOS ONE 8(10): e77786. 2. Jovanovic, O., Pashkovskaya, A.A., Annibal, A., Vazdar, M., Burchardt, N., Sansone, A., Gille, L., Fedorova, M., Ferreri, C., Pohl, E.E. (2015) Free Radical Biol. Med., 89, 1067-1076. 3. Jovanović, O., Škulj, S., Pohl, E.E., Vazdar, M.(2019) Free Radical Biol. Med. 143, 433-440.