Mechanisms of Photosensitized Lipid Oxidation and Membrane Permeabilization

Abstract

Lipid oxidation encompasses chemical transformations affecting animals and plants in many ways, and light is one of the most common triggers of lipid oxidation in our habitat. Still, the molecular mechanisms and biological consequences of photoinduced lipid oxidation were only recently understood at the molecular level. In this review, we focus on the main mechanisms of photosensitized lipid oxidation and membrane permeabilization, dissecting the consequences of both singlet oxygen and contact-dependent pathways and discussing how these reactions contribute to chemical and biophysical changes in lipid membranes. We aim to enable scientists to develop novel and more efficient photosensitizers in photomedicine, as well as better strategies for sun protection.

Figure 1

Photosensitized oxidations have both detrimental and therapeutic effects. Detrimental effects occur in damage to skin cells and hair exposed to excessive sunlight and due to the presence of natural photosensitizers. In contrast, artificial light sources and synthetic photosensitizers are used in photodynamic therapy (PDT) to selectively inactivate cancer cells, bacteria, and fungi. Both detrimental and therapeutic effects share the same basic mechanism, which results in biomolecule oxidation and cytotoxicity.

Figure 2

Excited states of photosensitizers oxidize substrates by contact-dependent or contact-independent pathways. (A) The photoexcitation of a photosensitizer (PS) in the ground singlet state (S₀) results in an excited singlet state (S₁), which may undergo intersystem crossing (ISC) and originate an excited triplet state (T₁). In the contact-dependent pathway (B), the excited photosensitizer directly reacts with the target substrate. In contrast, in the contact-independent pathway (C), a mediator species is first formed by interaction or reaction with the excited photosensitizer. This mediator species, commonly singlet oxygen, may diffuse over hundreds of nanometers before reacting with the target substrate.

Figure 3

(A) Snapshots of a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) giant unilamellar vesicle irradiated with 4 μM methylene blue and observed by phase-contrast microscopy. Note that the initially tense vesicle first gains surface area, then recovers the tense state, and finally gets permeabilized. (B) Snapshots from molecular dynamics simulations of a single-component 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) hydroperoxide membrane, showing (i) lipids with oxidized groups highlighted in red (van der Waals spheres), with water molecules omitted for simplicity, and (ii) water molecules only, with lipids omitted. The molecular structure of the simulated lipid hydroperoxide is additionally provided. (C) Snapshots from molecular dynamics simulations of a single-component 1-palmitoyl-2-(9′-oxo-nonanoyl)-sn-glycero-3-phosphocholine (ALDOPC) membrane, showing (i) lipids with oxidized groups highlighted in red (van der Waals spheres), with water molecules omitted for simplicity, and (ii) water molecules only, with lipids omitted. The molecular structure of the simulated lipid aldehyde is additionally provided. Panels (B) and (C) were adapted with permission from Bacellar, I. O. L.; Oliveira, M. C.; Dantas, L. S.; Costa, E. B.; Junqueira, H. C.; Martins, W. K.; Durantini, A. M.; Cosa, G.; Di Mascio, P.; Wainwright, M; Miotto, R.; Cordeiro, R. M.; Miyamoto, S.; Baptista M. S. J. Am. Chem. Soc. 2018, 140 (30), 9606–9615. Copyright 2018 American Chemical Society.

Figure 4

Chemical pathways for photoinduced membrane permeabilization. The map distinguishes between contact-independent and contact-dependent processes, which rely on singlet oxygen or on direct reactions between PSs and lipids, respectively. PS(S₀), PS(T₁): PS ground and excited triplet states; ³O₂,¹O₂: ground and excited singlet states of oxygen; R^•: generic radical species; LH: nonoxidized lipid; L^•, LOO^•, LO^•: lipid-carbon-centered, peroxyl and alkoxyl radicals; LOOH, LOH, LO, LO*: lipid hydroperoxide, alcohol, ketone, and excited state ketone. A snapshot of a simulated aldehyde membrane, showing pore opening, is also provided. Reprinted with permission from Bacellar, I. O. L.; Oliveira, M. C.; Dantas, L. S.; Costa, E. B.; Junqueira, H. C.; Martins, W. K.; Durantini, A. M.; Cosa, G.; Di Mascio, P.; Wainwright, M; Miotto, R.; Cordeiro, R. M.; Miyamoto, S.; Baptista M. S. J. Am. Chem. Soc. 2018, 140 (30), 9606–9615. Copyright 2018 American Chemical Society.