The molecular mechanism behind reactive aldehyde action on transmembrane translocations of proton and potassium ions 2

Membrane transporters are involved in enormous number of physiological and pathological processes.Under oxidative stress they become targets for reactive oxygen species and its derivatives which causeprotein damage and/or influence protein function(s). The molecular mechanisms of this interaction arepoorly understood. Here we describe a novel lipid-mediated mechanism by which biologically importantreactive aldehydes (RAs; 4-hydroxy-2-nonenal, 4-hydroxy-2-hexenal and 4-oxo-2-nonenal) modify theactivity of several membrane transporters. We revealed that investigated RAs covalently modify themembrane lipid phosphatidylethanolamine (PE), that lead to the formation of different membrane activeadducts. Molecular dynamic simulations suggested that anchoring of PE-RA adducts in the lipid headgroupregion is primarily responsible for changes in the lipid membrane properties, such as membraneorder parameter, boundary potential and membrane curvature. These caused the alteration of transportactivity of mitochondrial uncoupling protein 1, potassium carrier valinomycin and ionophore CCCP. Incontrast, neither direct protein modification by RAs as previously shown for cytosolic proteins, nor itsinsertion into membrane bilayers influenced the studied transporters. Our results explain the diversity ofaldehyde action on cell proteins and open a new field in the investigation of lipid-mediated effects ofbiologically important RAs on membrane receptors, channels and transporters.

"The molecular mechanism behind reactive aldehyde action on transmembrane translocations of proton and potassium ions", O. Jovanovic, A. A. Pashkovskaya, A. Annibal, M. Vazdar, N. Burchardt, A. Sansone, L. Gille, M. Fedorova, C. Ferreri, E. E. Pohl, Free Radic Biol Med 2015, 89, 1067-1076. DOI: 10.1016/j.freeradbiomed.2015.10.422.


Uni bern 2017/02