Mechanisms of detoxification and repair of oxidized biological membranes involving the action of the enzyme peroxiredoxin 6

Abstract

Processes involving oxidation of lipids, such as cholesterol and polyunsaturated fatty acids, are associated with different pathological conditions (e.g. diabetes, cancer and neurodegenerative diseases). Lipids are major components of cell membranes, being essential to their structure and flexibility, besides functioning as barriers to the passage of ions and polar compounds as well as intermediates in cell signaling pathways. Changes in the structure of lipids via oxidation result in a series of biological dysfunctions, and therefore repair mechanisms become essential for the maintenance of physiological activities.In particular, antioxidant proteins, such as peroxiredoxins, which constitute a family of cysteine-dependent enzymes, are critical for the regulation of peroxide levels within cells. Peroxiredoxin 6 (Prdx6), specifically, represents a group of peroxiredoxins with three main enzymatic activities: peroxidase, phospholipase A2 and acyl transferase. Such activities provide a complete system for the detoxification of oxidizing species of lipids and thus for the repair of oxidized membranes. In this context, the biological significance of Prdx6 is highlighted by its evolutionary conservation, being present in archaea, bacteria and eukaryotes, including yeast, plants, insects, molluscs, amphibians, birds and mammals. Here, a functional study of Prdx6 is proposed, focusing on the following aspects: a) comparative characterization of the enzymatic activities of Prdx6 against different substrates, such as cholesterol and phospholipid hydroperoxides; b) analysis of the co-activity of Prdx6 with other antioxidant proteins, such as glutathione peroxidase 4 (GPx4), using different cell models under oxidative stress and c) determination of Prdx6's relevance in aging, using a transgenic mouse model, which does not code for Prdx6. In this project, we intend to further knowledge into Prdx6's activity in the repair of oxidized membrane lipids and its relevance in the maintenance of cellular levels of peroxides. For this purpose, different methodologies will be employed, including advanced lipidomic and oxy-lipidomic analyses through high-resolution mass spectrometry. (AU)