Deciphering the age-related lipidome of the nuclear envelope and potential molecular players in healthy ageing

• Autor(a) principal: Silva, Maria Inês Pinto Coelho da
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/138617
• topic: Ageing; HGPS; Nuclear Envelope; Lipids; Lipidomics; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Ageing composes a major risk factor for disease, physical decline, and death. At a time when people are living longer than ever before, it becomes urgent that solutions are found to help prevent disease and alleviate their symptoms, other than simply postponing death. Changes in nuclear mechanics are known to accompany ageing at the cellular level, with consequences ranging from mild to severe phenotypes (classical and premature ageing). The Hutchinson- Gilford Progeria Syndrome (HGPS) recapitulates some features of ageing in an accelerated manner, through the production of progerin, a mutated form of lamin A. Progerin abnormally associates to the inner nuclear membrane, where it accumulates, compromising nuclear integrity and stability. However, the lipidic component of this protein-lipid interaction has been mainly overlooked until now. This project aimed to study the lipid composition of the nuclear envelope through ageing. To that end, nuclei were isolated from primary fibroblasts of healthy young and aged individuals, and from HGPS patients. Nuclei isolation was confirmed by transmission electron microscopy, histology, atomic force microscopy and confocal microscopy. Upon lipid extraction from the isolated nuclei, lipidomics analysis was performed using liquid and gas chromatography coupled to mass spectrometry. Phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins were found to be the major components of the nuclear lipid extracts, with other classes being present in lesser amounts. It was also observed that ether-linked lipids are among the most significantly altered species between young and aged individuals, with phosphatidylcholine ethers being significantly decreased in the aged group. Ether-linked lipids are known endogenous antioxidants, protecting membranes from oxidative conditions. Our results suggest that ether-linked lipids are altered with age, with the nuclear membranes of elder individuals being potentially more vulnerable to distinct stimuli, such as oxidative stress.