The role of free and esterified cholesterol in the susceptibility of astrocytes to death by ferroptosis

• Grant number: 23/09712-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2023
• End date: July 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Sayuri Miyamoto
• Grantee: Maria Fernanda Valente Nolf
• 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

Ferroptosis is a type of non-apoptotic cell death characterized by iron-dependent lipid peroxidation. Recent studies show a close relationship between cholesterol metabolism, lipid droplet accumulation and sensitivity to ferroptosis, however, little is known about its impact on brain cells. This project aims to evaluate the role of lipids such as free and esterified cholesterol, in addition to their precursors such as 7-dehydrocholesterol (7-DHC) in the susceptibility to death by ferroptosis in astrocytes. The project builds on previous work by the group showing that modulation of the cholesterol pathway with 7-DHC accumulation protects cells against death induced by lipid peroxidation and that accumulation of lipid droplets is a common phenotype of several types of cancer and also in neurodegenerative diseases. In this study, we will evaluate the susceptibility to ferroptosis using a cell line with C6 astrocytic characteristic (rat glioma) with or without pharmacological inhibition of cholesterol synthesis pathways and respective esters. The mapping of lipid alterations will be measured using high performance chromatography coupled to high resolution mass spectrometry (UPLC-HRMS). The expected results include not only contributing to the understanding of how cholesterol metabolism affects ferroptosis, but also identifying potential targets for the development of therapeutic strategies.