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

• Grant number: 17/13804-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): October 01, 2017
• Effective date (End): September 30, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Sayuri Miyamoto
• Grantee: Alex Inague
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

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)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MIYAMOTO, SAYURI; LIMA, RODRIGO S.; INAGUE, ALEX; VIVIANI, LUCAS G.. Electrophilic oxysterols: generation, measurement and protein modification. Free Radical Research, JAN 2021. (13/07937-8, 17/13804-1)

DANTAS, LUCAS S.; VIVIANI, LUCAS G.; INAGUE, ALEX; PICCIRILLO, ERIKA; REZENDE, LEANDRO DE; RONSEIN, GRAZIELLA E.; AUGUSTO, OHARA; MEDEIROS, MARISA H. G.; AMARAL, ANTONIA T. DO; MIYAMOTO, SAYURI. Lipid aldehyde hydrophobicity affects apo-SOD1 modification and aggregation. Free Radical Biology and Medicine, v. 156, p. 157-167, AUG 20 2020. (14/07248-0, 12/06633-2, 13/07937-8, 17/13804-1)

INAGUE, ALEX; ALECRIM, LILIAN COSTA; MONTEIRO, JHONATAS SIRINO; YOSHINAGA, MARCOS YUKIO; SETUBAL, JOAO CARLOS; MIYAMOTO, SAYURI; GIORDANO, RICARDO JOSE. Oxygen-induced pathological angiogenesis promotes intense lipid synthesis and remodeling in the retina. ISCIENCE, v. 26, n. 6, p. 22-pg., 2023-06-16. (19/25828-8, 13/07937-8, 17/13804-1)

DOS SANTOS, ANCELY F.; INAGUE, ALEX; ARINI, GABRIEL S.; TERRA, LETICIA F.; WAILEMANN, ROSANGELA A. M.; PIMENTEL, ANDRE C.; YOSHINAGA, MARCOS Y.; SILVA, RICARDO R.; SEVERINO, DIVINOMAR; DE ALMEIDA, DARIA RAQUEL Q.; et al. Distinct photo-oxidation-induced cell death pathways lead to selective killing of human breast cancer cells. CELL DEATH & DISEASE, v. 11, n. 12, DEC 14 2020. (19/09517-2, 17/13804-1, 19/05026-4, 16/04676-7, 17/23914-9, 17/18922-2, 17/03618-6, 15/02654-3, 13/07937-8)

DE ALMEIDA, DARIA R. Q.; DOS SANTOS, ANCELY F.; WAILEMANN, ROSANGELA A. M.; TERRA, LETICIA F.; GOMES, VINICIUS M.; ARINI, GABRIEL S.; BERTOLDI, ESTER R. M.; REIS, EDUARDO M.; BAPTISTA, MAURICIO S.; LABRIOLA, LETICIA. Necroptosis activation is associated with greater methylene blue-photodynamic therapy-induced cytotoxicity in human pancreatic ductal adenocarcinoma cells. PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES, v. N/A, p. 16-pg., 2022-12-10. (17/18922-2, 17/13804-1, 19/05026-4, 15/02654-3, 16/04676-7, 17/03618-6, 19/09517-2, 13/07937-8)

MIYAMOTO, SAYURI; LIMA, RODRIGO S.; INAGUE, ALEX; VIVIANI, LUCAS G.. Electrophilic oxysterols: generation, measurement and protein modification. Free Radical Research, v. 55, n. 4, SI, p. 416-440, APR 3 2021. (13/07937-8, 17/13804-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

INAGUE, Alex. Elucidating mechanisms of ferroptosis regulation: the roles of peroxiredoxin 6 and cellular lipid composition. 2023. Doctoral Thesis - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.