Biology subjects

Mellett, N. A.

Publications and source records attributed to Mellett, N. A..

3 recordsLinked to original sources

bioRxiv2026

Ablation of GM3 Gangliosides in cardiomyocytes modestly impacts heart size but does not protect the murine heart against ischemia reperfusion injury

Advances in mass spectrometry have seen the identification of hundreds of new lipid species, some of which have been found to be associated with adverse cardiac remodeling. Key among these are GM3 gangliosides, which have been associated with metabolic disease, and more recently, adverse cardiac remodeling. Whether GM3s have a direct pathophysiological effect in the heart remains unclear. The present study investigated the effects of cardiomyocyte-specific knockout of GM3 synthase (GM3S, enzyme responsible for the synthesis of GM3) in the heart under basal settings and in response to ischemia-reperfusion (I/R) injury. A new cardiomyocyte-specific GM3S knockout (KO) model was generated, with knockout confirmed via lipidomic profiling. Under basal conditions, male GM3SKO mice exhibited reduced heart weight to tibia length (HW/TL) ratios with no evidence of pathological remodeling, while female mice showed no significant morphological differences. Male GM3SKO mice subjected to 1 hour ischemia and 4 weeks reperfusion demonstrated reduced HW/TL ratio compared to control mice subjected to I/R. However, no significant differences were observed in cardiac function, heart failure and fibrotic markers. Lipidomic profiling (49 classes, [~]850 species) revealed significant accumulation of dihexosylceramide, a metabolic precursor of GM3 in the male heart under basal and post-I/R conditions. In male GM3SKO I/R hearts, GM3 reduction was associated with decreases in odd- and branch-chained phospholipids, together with distinct changes in circulating ether lipid species. Collectively, cardiomyocyte-specific GM3 depletion contributed to sphingolipid remodeling but did not confer protection against I/R-mediated injury. These findings suggest that elevated GM3 levels observed in settings of cardiac pathology are not cardiomyocyte driven, highlighting the importance of understanding cell-type specific contributions to adverse cardiac remodeling.

physiology↗

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↗

bioRxiv2021

Multi-omics reveal intricate network of mitochondrial adaptations to training in human skeletal muscle

Mitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible and inexpensive therapeutic intervention improving mitochondrial bioenergetics and quality of life. By combining a multi-omics approach with biochemical and in silico normalization, we removed the bias arising from the training-induced increase in human skeletal muscle mitochondrial content to unearth an intricate and previously undemonstrated network of differentially prioritized mitochondrial adaptations. We show that changes in hundreds of transcripts, proteins, and lipids are not stoichiometrically linked to the increase in mitochondrial content. We demonstrate that enhancing electron flow to oxidative phosphorylation (OXPHOS) is more important to improve ATP generation than increasing the abundance of the OXPHOS machinery, and that training-induced supercomplex formation does not confer enhancements in mitochondrial bioenergetics. Our study provides a new analytical approach allowing unbiased and in-depth investigations of training-induced mitochondrial adaptations, challenging our current understanding and calling for careful reinterpretation of previous findings.

cell biology↗