Connecting the “Dots”: From Free Radical Lipid Autoxidation to Cell Pathology and Disease

Abstract

Our understanding of lipid peroxidation in biology and medicine is rapidly evolving, as it is increasingly implicated in various diseases but also recognized as a key part of normal cell function, signaling, and death (ferroptosis). Not surprisingly, the root and consequences of lipid peroxidation have garnered increasing attention from multiple disciplines in recent years. Here we “connect the dots” between the fundamental chemistry underpinning the cascade reactions of lipid peroxidation (enzymatic or free radical), the reactive nature of the products formed (lipid-derived electrophiles), and the biological targets and mechanisms associated with these products that culminate in cellular responses. We additionally bring light to the use of highly sensitive, fluorescence-based methodologies. Stemming from the foundational concepts in chemistry and biology, these methodologies enable visualizing and quantifying each reaction in the cascade in a cellular and ultimately tissue context, toward deciphering the connections between the chemistry and physiology of lipid peroxidation. The review offers a platform in which the chemistry and biomedical research communities can access a comprehensive summary of fundamental concepts regarding lipid peroxidation, experimental tools for the study of such processes, as well as the recent discoveries by leading investigators with an emphasis on significant open questions.

Lipid peroxidation derived reactive carbonyl species in free and conjugated forms as an index of lipid peroxidation: limits and perspectives

“…From an analytical point of view, the measurement of oxidative stress is quite complex due to the fact that the oxidant species causing oxidative stress are very reactive and unstable and so are short lived species [ 8 , 9 ]. A direct measurement of these species can be performed in the presence of radical spin trappers for the radical species (ESR experiments) [ 10 ] or using suitable fluorescence probes which form a fluorophore when undergoing oxidation [ 2 ]. These techniques are mainly performed in in vitro conditions because their measurement requires that the spin trapper/fluorescent probe is added concomitantly to the oxidant formation.…”

“…The general process of LPO consists of three stages: initiation, propagation, and termination [ 2 ]. Hydroxyl and hydroperoxyl radicals are the most powerful initiators of LPO.…”

“…The LOOH thus formed can be cleaved by reduced metals, such as Fe 2+ , producing lipid alkoxyl radicals (LO • ) which further stimulate the chain reaction of LPO by abstracting additional hydrogen atoms or decomposes forming RCS [ 14 ]. Termination of the chain reaction occurs when two LOO • s encounter one another to yield nonradical products or when the LOO • abstracts an H atom from radical trapping antioxidants such as α-tocopherol [ 2 ].

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“…ROS and RNS can then be classified as free radicals (including hydroxyl radicals, HO • ; peroxyl radicals, ROO • ; alkoxyl radicals RO • ; superoxide anions O 2 •- and nitric oxide NO • ) and non-radical oxidizing species (H 2 O 2 , ROOH, ONOOH). ROS/RNS are able to react with and oxidize any biological molecules, such as proteins, lipids, and nucleic acids, causing structural and functional changes [ 1 , 2 ]. In physiological conditions, such oxidant events/reactions are prevented by the antioxidant defense mediated by enzymatic and non-enzymatic antioxidants which compete with the oxidizable substrates thus significantly delaying or inhibiting their oxidation.…”

Iron-doxorubicin prodrug loaded liposome nanogenerator programs multimodal ferroptosis for efficient cancer therapy

“…Fortunately, iron could also cause ferroptosis via other pathways expect for Fenton chemistry, such as iron redox couple-catalyzed oxidation of unsaturated lipids [9 , [13] , [14] – 15] . Several studies have reported iron-induced oxidation in liposomes and iron loaded liposome triggered lipid peroxide for ferroptosis therapy [15 – 17] .…”