Oxidative stress and lipotoxicity

Abstract

The α,β polyunsaturated lipid aldehydes are potent lipid electrophiles that covalently modify lipids, proteins, and nucleic acids. Recent work highlights the critical role these lipids play under both physiological and pathological conditions. Protein carbonylation resulting from nucleophilic attack of lysine, histidine, and cysteine residues is a major outcome of oxidative stress and functions as a redox-sensitive signaling mechanism with roles in autophagy, cell proliferation, transcriptional control, and apoptosis. In addition, protein carbonylation is implicated as an initiating factor in mitochondrial dysfunction and endoplasmic reticulum stress, providing a mechanistic connection between oxidative stress and metabolic disease. In this review, we discuss the generation and metabolism of reactive lipid aldehydes, as well as their signaling roles.

Keywords: cardiolipin; lipids/peroxidation; oxidized lipids.

Fig. 1.

Generation and metabolism of reactive lipid aldehydes. Increased production of superoxide anion (^•O₂⁻) leads to the production of the hydroxyl radical (^•OH) and subsequent lipid peroxidation (LOOH). This eventually results in the generation of a variety of reactive lipid aldehydes that can covalently modify proteins in a process called protein carbonylation. Under normal conditions, these lipids are detoxified by phase I and phase II antioxidant enzymes. In metabolic disease, the antioxidant milieu is depressed leading to accumulation of reactive aldehydes and protein carbonylation. SOD, superoxide dismutase; AO, alkenal/one oxidoreductase; AKR, aldo-keto reductase.

Fig. 2.

Oxidative modification of CL. Representation of L₄CL oxidation by hydroxyl radicals (ROS) and subsequent production of α,β unsaturated lipid aldehydes as well as an CLox remnant. The head group of CL is drawn schematically to emphasize chemistry within the acyl chains. Unsaturated aldehydes lead to protein carbonylation, while CLox potentiates apoptosis, autophagy, or mitophagy leading to generalized mitochondrial dysfunction.

Fig. 3.

Cartoon representation of lipotoxic lipids and cellular responses. Peroxidation of CL (L₄CL) within the mitochondrial inner membrane leads to oxidized CL (CL_ox) with shortened acyl chains that may initiate an apoptotic response. In parallel, resultant lipid aldehydes modify mitochondrial proteins leading to dysfunction and potential induction of mitophagy. Aldehydes may diffuse from the mitochondrion and modify proteins within the cytoplasm, nuclear region, or ER affecting cellular homeostasis and signaling response.

Fig. 4.

Protein carbonylation and formation of protein-lipid adducts. Alkylation of the side chains of lysine, histidine, and cysteine are shown and the major affected mitochondrial pathways. For diagrammatic purposes, only the modification of amino acid side chains by 4-HNE is shown. Additional parallel modification reactions with other electrophiles occur.