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

Abstract

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 cause protein damage and/or influence protein function(s). The molecular mechanisms of this interaction are poorly understood. Here we describe a novel lipid-mediated mechanism by which biologically important reactive aldehydes (RAs; 4-hydroxy-2-nonenal, 4-hydroxy-2-hexenal and 4-oxo-2-nonenal) modify the activity of several membrane transporters. We revealed that investigated RAs covalently modify the membrane lipid phosphatidylethanolamine (PE), that lead to the formation of different membrane active adducts. Molecular dynamic simulations suggested that anchoring of PE-RA adducts in the lipid headgroup region is primarily responsible for changes in the lipid membrane properties, such as membrane order parameter, boundary potential and membrane curvature. These caused the alteration of transport activity of mitochondrial uncoupling protein 1, potassium carrier valinomycin and ionophore CCCP. In contrast, neither direct protein modification by RAs as previously shown for cytosolic proteins, nor its insertion into membrane bilayers influenced the studied transporters. Our results explain the diversity of aldehyde action on cell proteins and open a new field in the investigation of lipid-mediated effects of biologically important RAs on membrane receptors, channels and transporters.

Biophysical Approaches Toward Understanding the Molecular Mechanism of Action of the Mitochondrial Therapeutic SS-31 (Elamipretide)

“…Although the activity for most saponins (e.g. digitonin, a-hederin) is usually attributed to their interactions with membrane Chol, our recent publication showed that Chol, contrary to SM, delays the cytotoxicity of the saponin ginsenoside Rh2 in human cancer cell lines (A549, THP-1, and U937) [1], renewing the idea that saponin activity is only ascribed to an interaction with Chol. In this study, we elucidated the respective importance of Chol and SM in the membranerelated effects of Rh2 using a large panel of biophysical approaches while carefully modulating their lipid compositions, i.e.…”

“…To the best of our knowledge, this study is the first to reveal the critical role of SM in membrane-related effects induced by a saponin reconsidering the theory that Chol is the only responsible for the activity of saponins. [1] Toxicol Appl Pharmacol 352, 59-67(2018). Gramicidin A (formyl-L-Val-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D-Val-L-Trp 9 -D-Leu-L-Trp 11 -D-Leu-L-Trp 13 -D-Leu-L-Trp 15 -ethanolamine) functions as a membrane-spanning channel for monovalent cations.…”

“…However, without a detailed description of the biophysical interactions of pHLIP that lead to function, it will be difficult to design variants with increased targeting abilities. A recent study utilizing pH probes on cancerous cells has determined an increased radius of extracellular space is affected by acidosis [1], and therefore a peptide approaching the bilayer would experience an acidic environment before interacting with the membrane. With this in mind, we employed constant pH molecular dynamics (MD) simulations to determine potential changes in conformation of pHLIP as it transitions into the acidic extracellular space.…”

“…Our results provide a unique and essential perspective on the behavior of pHLIP as it transitions into acidic microenvironments such as the extracellular region of cancerous cells. [1] Luo (2018) Anal. Chem.…”

COST Action CM1201 “Biomimetic Radical Chemistry”: free radical chemistry successfully meets many disciplines

“…In fact, 4-HNE signaling stimulates the cell response for insulin production, after liberation of the precursor omega-6 fatty acid from cell membranes and transformation by peroxidation [89][90][91]. Another interesting molecular mechanism was discussed in the Working Group, determining that by the interaction of these aldehydes with amino-containing membrane phospholipids (phosphatidyl ethanolamine, PE) lipid adducts are formed, with consequences for the transmembrane translocation process of proton and potassium ions [92].…”