Biology subjects

Morgan, P. K.

Publications and source records attributed to Morgan, P. K..

3 recordsLinked to original sources

bioRxiv2026

A diet enriched in highly poly-unsaturated fatty acids alters immune cell lipid composition and ferroptosis susceptibility

Ferroptosis is a regulated form of cell death that is dependent upon the peroxidation of phospholipids containing poly-unsaturated fatty acids (PL-PUFAs), particularly those with 4 or more double bonds. PL-PUFA content is dramatically different between immune cell types which directly influences their sensitivity to ferroptosis. Modulating the PL-PUFA content of various cells is becoming an attractive approach to increase the efficacy of therapies designed to target ferroptosis. In this study we aimed to determine whether a diet enriched in highly unsaturated PUFAs alters immune cell lipid composition and, consequently, the susceptibility to ferroptosis. To address this, mice were fed either a diet enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (High PUFA diet) or a standard control diet (Control diet) for eight weeks. Immune cells were then isolated from the bone marrow, blood, and lymph nodes for lipidomic analysis and sensitivity to ferroptosis. The High PUFA diet resulted in the widespread incorporation of EPA and DHA into multiple PL species across all immune cell types. However, the magnitude of incorporation differed between cell populations, with B cells exhibiting the greatest enrichment in PL-PUFA-EPA and PL-PUFA-DHA species, followed by monocytes and neutrophils, while T cells showed the lowest degree of enrichment. Importantly, these compositional changes were associated with increased susceptibility to ferroptosis in a cell and location specific manner. Collectively, these findings demonstrate that a diet enriched in highly unsaturated PUFAs increases PL-PUFAs in immune cells and broadly enhances immune cell susceptibility to ferroptosis. Therefore, altering dietary fatty acid composition may represent a strategy to influence ferroptosis sensitivity in conditions where either inducing or inhibiting ferroptosis is therapeutically desirable.

cell biology↗

bioRxiv2023

Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36

Lipids contribute to hematopoiesis and membrane properties and dynamics, however, little is known about the role of lipids in megakaryopoiesis. Here, a lipidomic analysis of megakaryocyte progenitors, megakaryocytes, and platelets revealed a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake and de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in thrombocytopenia. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production, and that changes in dietary fatty acids may be a novel and viable target to modulate platelet counts.

cell biology↗

bioRxiv2023

An immune cell lipid atlas reveals the basis of susceptibility to ferroptosis

The cellular lipidome is comprised of thousands of unique lipid species. This complexity underpins the many roles of lipids in cellular biology. How lipidome composition varies between cell types and how such differences contribute to cell-specific functionality is poorly understood. Here, using mass spectrometry-based targeted lipidomics, we have characterised the cellular lipid landscape of the human and mouse immune systems (www.cellularlipidatlas.com). We find that myeloid and lymphoid cell lineages have unique lipid compositions, notably in the usage of ester and ether bonds within glycerophospholipids (PLs) and PL acyl chain composition. To determine if immune cell-specific lipid phenotypes promote cell-specific functional properties we focused on differences in poly-unsaturated fatty acid (PUFA)-containing PL, the levels of which are markedly higher in lymphoid cells relative to myeloid cells. We firstly show that differences in PUFA-PL content provides a mechanistic basis for previously described differences in immune cell susceptibility to ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, and secondly, that the low PUFA-PL content of neutrophils restrains NADPH oxidase-driven ferroptosis. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.

cell biology↗