2. Academic Validation
  3. Lipidomic Profiling of Red Blood Cells in the Mitochondrial Fatty Acid β-oxidation Disorder MCADD Reveals Phospholipid and Sphingolipid Dysregulation

Lipidomic Profiling of Red Blood Cells in the Mitochondrial Fatty Acid β-oxidation Disorder MCADD Reveals Phospholipid and Sphingolipid Dysregulation

  • J Proteome Res. 2025 Sep 5;24(9):4631-4642. doi: 10.1021/acs.jproteome.5c00308.
Inês M S Guerra 1 2,  Helena B Ferreira 1,  Luísa Diogo 3 4,  Sónia Moreira 3 4,  Stefano Bonciarelli 5,  Laura Goracci 6,  Tânia Melo 1 2,  Pedro Domingues 1,  M Rosário Domingues 1 2,  Ana S P Moreira 1 2
Affiliations

Affiliations

  • 1 Mass Spectrometry Center, LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro 3810-193, Portugal.
  • 2 CESAM - Centre for Environmental and Marine Studies, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro 3810-193, Portugal.
  • 3 Centro de Referência de Doenças Hereditárias do Metabolismo, Unidade Local de Saúde de Coimbra, MetabERN, Coimbra3000-075,Portugal.
  • 4 Serviço de Bioquímica, Faculdade de Medicina da Universidade de Coimbra, Coimbra3004-531,Portugal.
  • 5 Molecular Discovery Ltd., HertfordshireWD6 4PJ, U.K.
  • 6 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy.
PMID: 40704861 DOI: 10.1021/acs.jproteome.5c00308
Abstract

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is characterized by the accumulation of medium-chain acylcarnitines. Despite the therapeutic approach, changes in lipid homeostasis have been reported in MCADD plasma samples. Compared to plasma lipidomics, red blood cell (RBC) profiling provides a more stable biomarker that is less influenced by dietary changes and reflects long-term metabolic alterations. In this study, we assessed the plasticity of the lipidomic profile of RBC from children with MCADD and controls using C18 liquid chromatography-mass spectrometry. The results revealed significant alterations in 240 lipid species in MCADD, highlighting an upregulation of sphingolipids (sphingomyelins and ceramides) and lysophospholipid species (lysophosphatidylcholines and lysophosphatidylethanolamines) alongside a downregulation of polyunsaturated and ether-linked phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs). Also, altered PC/PE and (PC + SM)/(PE + PS) ratios could be associated with alterations in RBC membranes properties, e.g., fluidity and asymmetry. The observed changes in the lipidome suggest compromised antioxidant defenses, enhanced oxidative stress, and an inflammatory state, with potential systemic implications in MCADD lipid metabolism and long-term complications in older age. This study underscores the utility of RBC lipidomics as a robust tool for understanding the pathophysiology of MCADD. It may prove to be a useful tool for monitoring disease progression in the near future.

Keywords

FAOD; erythrocytes; glycerophospholipids; lipidomics; lipids; mass spectrometry; medium-chain acyl-CoA dehydrogenase deficiency; plasmanyl; plasmenyl; sphingolipids.

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