Mapping the lipidome in mitochondria-associated membranes (MAMs) in an in vitro model of Alzheimer's disease

Tânia Fernandes; Tânia Melo; Tiago Conde; Bruna Neves; Pedro Domingues; Rosa Resende; Cláudia F Pereira; Paula I Moreira; Maria Rosário Domingues

doi:10.1111/jnc.16072

Mapping the lipidome in mitochondria-associated membranes (MAMs) in an in vitro model of Alzheimer's disease

J Neurochem. 2024 Feb 7. doi: 10.1111/jnc.16072. Online ahead of print.

Authors

Tânia Fernandes^{1

2

3

4}, Tânia Melo^{5

6}, Tiago Conde^{5

6}, Bruna Neves^{5

6}, Pedro Domingues^{5

6}, Rosa Resende^{1

2

3}, Cláudia F Pereira^{1

3

4}, Paula I Moreira^{1

3

4}, Maria Rosário Domingues^{5

6}

Affiliations

¹ CNC-Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
² IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
³ CACC-Clinical Academic Center of Coimbra, Coimbra, Portugal.
⁴ Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁵ Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal.
⁶ CESAM - Centre for Environmental and Marine Studies, Department of Chemistry, University of Aveiro, Aveiro, Portugal.

PMID: 38327008
DOI: 10.1111/jnc.16072

Abstract

The disruption of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) plays a relevant role in Alzheimer's disease (AD). MAMs have been implicated in neuronal dysfunction and death since it is associated with impairment of functions regulated in this subcellular domain, including lipid synthesis and trafficking, mitochondria dysfunction, ER stress-induced unfolded protein response (UPR), apoptosis, and inflammation. Since MAMs play an important role in lipid metabolism, in this study we characterized and investigated the lipidome alterations at MAMs in comparison with other subcellular fractions, namely microsomes and mitochondria, using an in vitro model of AD, namely the mouse neuroblastoma cell line (N2A) over-expressing the APP familial Swedish mutation (APPswe) and the respective control (WT) cells. Phospholipids (PLs) and fatty acids (FAs) were isolated from the different subcellular fractions and analyzed by HILIC-LC-MS/MS and GC-MS, respectively. In this in vitro AD model, we observed a down-regulation in relative abundance of some phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and lysophosphatidylethanolamine (LPE) species with PUFA and few PC with saturated and long-chain FA. We also found an up-regulation of CL, and antioxidant alkyl acyl PL. Moreover, multivariate analysis indicated that each organelle has a specific lipid profile adaptation in N2A APPswe cells. In the FAs profile, we found an up-regulation of C16:0 in all subcellular fractions, a decrease of C18:0 levels in total fraction (TF) and microsomes fraction, and a down-regulation of 9-C18:1 was also found in mitochondria fraction in the AD model. Together, these results suggest that the over-expression of the familial APP Swedish mutation affects lipid homeostasis in MAMs and other subcellular fractions and supports the important role of lipids in AD physiopathology.

Keywords: Alzheimer's disease; ER-mitochondria contacts; lipid dyshomeostasis; lipidomics; subcellular fractions.

Abstract

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