Biology subjects

Meikle, P.

Publications and source records attributed to Meikle, P..

9 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↗

bioRxiv2026

Dual-Lipa: A sequential multi-omic subcellular landscape map of mouse heart

Spatial multi-omics can provide a unique understanding in molecular organisation and heterogeneity of organs including the heart. Heart function is dependent on the abundance and the spatial arrangement of proteins and lipids. Yet, an integrated multi-omics landscape of the heart at subcellular scale remains unknown. Here, we used a sequential lipid-proteomic analytical pipeline applied to the mouse heart to identify, map, and integrate lipid and protein features, revealing coordinated distinct molecular networks within defined subcellular niches. Here, we benchmark this dual extraction workflow for integrated global proteome-lipidome analyses to demonstrate its performance. We developed conserved subcellular proteome of mouse heart across 14 niches and applied the knowledge of subcellular proteome to spatially resolve the heart lipidome, identifying unique lipid features from different subcellular niches, including mitochondria (e.g., cardiolipin, LPC) and plasma membrane-enriched lipids (e.g., plasmalogens). We identified sex-dependent molecular differences in heart subcellular proteome between male and female, including RNA-protein complexes, mitochondrial calcium handling and immune regulatory pathways. We demonstrate that lipid-protein integrated multi-omics analysis of the heart by dual extraction workflow and mass spectrometry could enable previously unidentified discoveries in heart molecular composition and organisation and spatial cardiac biology. HighlightsO_LIResolved tissue-wide subcellular architecture of cardiac tissue through simultaneous high-resolution proteomics and lipidomics profiling. C_LIO_LISystematically evaluated MS-compatible dual extraction strategies for integrated proteome-lipidome recovery and performance. C_LIO_LIProteomics revealed major sex-dependent differences in mouse left ventricles, primarily involving cellular metabolism, immune regulation, detoxification pathways, and signalling responses. C_LIO_LILipidomics identified strong sex-specific lipid signatures, including differences in omega-3 vs omega-6 fatty-acid containing lipid species, triacylglycerides, and acylcarnitines. C_LIO_LIDeveloped supervised machine-learning models to classify 14 subcellular niches from tissue-wide fractionation proteomics and identified a conserved core subcellular proteome. C_LIO_LIApplied the tissue-wide subcellular proteome model to infer lipid subcellular localisation, revealing mitochondria-enriched lipids (e.g., cardiolipin, LPC) and plasma membrane-enriched lipids (e.g., plasmalogens) in the mouse left ventricle. C_LIO_LIMapped sex-specific subcellular distribution in the heart, highlighting pathways linked to RNA-protein complexes, mitochondrial calcium handling, and immune regulatory networks. C_LI

biochemistry↗

bioRxiv2026

Diet- and metabolic state-dependent remodeling of the mouse brain lipidome

The hypothalamus and brainstem are key hubs of metabolic control that undergo dynamic molecular adaptations in response to changes in energy availability. This remodeling is associated with changes in the expression and activity of enzymes linked to energy homeostasis but also importantly, lipid metabolism. Given that lipids account for [~]50% of the brains dry weight, it is likely that lipid metabolism is a major determinant of brain function. Therefore, understanding how the hypothalamic and brainstem lipidome adapts to metabolic perturbation is key to understanding tissue function and metabolic health. Here we characterize the remodeling of [~]750 lipid species in mouse hypothalamus and brainstem, as well as the cerebrospinal fluid and plasma, in response to a metabolic challenge (an Ad Libitum-Fasting-Refeeding cycle). We show that around 45% and 36% of lipids in the hypothalamus and brainstem respectively, exhibit reversible, nutritional state-dependent remodeling during this metabolic challenge, and that this remodeling is substantially impacted by long-term high fat diet intervention. Of note, targeted analysis of specific lipids revealed that certain fatty acids were affected by this intervention in the hypothalamus and brainstem, most strikingly defined by the reversible fasting-induced increase in linoleic acid (18:2)-containing phosphatidylcholines in both the hypothalamus and brainstem, an effect that is abolished by high fat diet intervention. Such precise and intervention-specific regulation of linoleic acid (18:2)-containing phosphatidylcholines provides a previously unrecognized role for this lipid in the physiological response to fasting. Thus, these findings demonstrate that the brain lipidome undergoes robust, nutritional state-dependent remodeling, and provide a comprehensive resource for investigating its role in regulating metabolic adaptations.

physiology↗

bioRxiv2025

Caspase-1 self-terminates protease activity to enforce homeostasis and prevent inflammasome-driven diseases

Signal shutdown mechanisms must exist to silence the potent inflammatory programs initiated by the caspase-1 (CASP1) protease, to allow inflammation to resolve and reinstate tissue homeostasis. It is unknown how CASP1 terminates its activity in vivo. Here, we use a knock-in mouse model in which the CASP1 CARD domain linker (CDL) is mutated to prevent self-cleavage (Casp1.CDL mice) to show that CASP1 CDL autoproteolysis terminates CASP1 activity in vivo. We examined these mice under homeostatic conditions and in response to major physiological challenges. In the brain, CASP1 CDL mutation caused anxiety-like behaviour under homeostatic conditions, and exacerbated hippocampal spatial learning deficits in the APP23 genetic model of amyloid-induced neurodegeneration. In the bone marrow, CASP1 CDL mutation promoted steady-state granulopoiesis. In a model of diet-induced liver disease, CASP1 CDL mutation accelerated liver steatosis and promoted liver immune cell infiltration, inflammation and damage. In a liver healing model, CASP1 CDL mutation delayed disease resolution, indicating that CASP1 autocleavage is required to restore homeostasis after a major challenge to organ function. Our data reveal that CASP1 CDL self-cleavage terminates CASP1 inflammatory programs in vivo to maintain homeostasis in steady-state, restore homeostasis after a major challenge to organ function, and suppress inflammasome-driven diseases. These data identify CASP1 as a prime anti-inflammatory drug target, as CASP1 inhibitors may enforce homeostasis and prevent inflammasome-driven diseases.

immunology↗

bioRxiv2024

Skeletal Muscle Specific PolG Dysfunction Activates the Integrated Stress Response and Promotes a Cachexia like Phenotype

During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is specifically activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for this activation remain elusive. A gene often associated with mtDNA mutations/deletions is Polg1, which encodes the mitochondrial DNA Polymerase {gamma} (PolG). Here, we describe what is to our knowledge the first conditional muscle specific model of PolG mutation, and demonstrate a rapid development of mitochondrial dysfunction and cachexia in these animals from [~]5 months of age. Detailed molecular profiling of muscles demonstrated robust activation of the mtISR, likely mediated upstream by the HRI/DELE1 stress pathway. This was accompanied by striking alterations to the mitochondrial folate cycle and its metabolites, strongly implying imbalanced folate intermediates as a previously unrecognised pathology driving the mtISR in mitochondrial disease.

physiology↗

bioRxiv2024

Multi-omics discovery of hallmark protein and lipid features of circulating small extracellular vesicles in humans

Extracellular vesicles (EVs) are now being increasingly recognized as an essential signaling entity in human plasma, linking them to health and various diseases. Still, their core protein and lipid componentry, which lie at the center of EV form and function, remain poorly defined. Achieving this unmet milestone remains greatly hindered by abundant non-vesicular extracellular plasma components (non-EVs) in mass spectrometry-based analyses. Here, we performed high-resolution density gradient fractionation of over 140 human plasma samples to isolate circulating EVs, and systematically construct their quantitative proteome (4500 proteins) and lipidome (829 lipids) landscapes. This led to the discovery of a highly conserved panel of 182 proteins (ADAM10, STEAP23, STX7) and 52 lipids (PS, PIPs, Hex2Cer, PAs), providing a deep survey of hallmark molecular features and biological pathways intrinsic to circulating EVs. We also mapped the surfaceome diversity, identifying 151 proteins on the EV surface. We further establish a set of 42 proteins and 114 lipids features that served as hallmark features of non-EV particles in plasma. We submit ADAM10 and PS(36:1) as conserved EV biological markers that precisely differentiate between EV and non-EV particles. Our findings, which can be explored via an open-source Shiny web tool (evmap.shinyapps.io/evmap/) will serve as a valuable repository to the research community for a clearer understanding of circulating EV biology.

cell biology↗

bioRxiv2023

Deep multi-omic profiling reveals extensive mitochondrial remodeling driven by glycemia in early diabetic kidney disease

Changes in mitochondrial energy metabolism are thought to be central to the development of diabetic kidney disease (DKD); however, whether this response is explicitly driven by systemic glucose concentrations remains unknown. Here, we show that titrating blood glucose concentrations in vivo directly impacts mitochondrial morphology and bioenergetics and remodels the mitochondrial proteome in the kidney in early DKD. Mitoproteomic analysis revealed profound metabolic disturbances induced by severe hyperglycemia, including upregulation of enzymes involved in the TCA cycle and fatty acid metabolism, enhanced ketogenesis as well as dysregulation of the mitochondrial SLC25 carrier family. Untargeted metabolomics and lipidomics confirmed the enrichment of TCA cycle metabolites, an increase in triglyceride concentrations, and extensive and specific cardiolipin remodeling. Lowering blood glucose to moderate hyperglycemia stabilized all three omic landscapes, partially prevented changes in mitochondrial morphology and bioenergetics, and improved kidney injury. This study demonstrates altered substrate utilization and energy generation in the kidney early in diabetes, during moderate and severe hyperglycemia and provides new insights into kidney metabolism, which has implications for therapeutic strategies aiming at the reinvigoration of mitochondrial function and signaling in diabetes.

cell biology↗

bioRxiv2022

Class IIa HDACs reprogram mitochondrial metabolism to inhibit apoptosis and ferroptosis in response to lipotoxicity

Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.

cell biology↗

bioRxiv2021

Developmental and Intergenerational Landscape of Human Circulatory Lipidome and its Association with Obesity Risk

Lipids play a vital role in human health and development, but changes to their circulatory levels during gestation and in early life are poorly understood. Here we present the first developmental and intergenerational landscape of the human circulatory lipidome, derived by profiling of 480 lipid species representing 25 lipid classes, in mothers and their offspring (n=2491). Levels of 66% of the profiled lipids increased in maternal circulation during gestation, while cord blood had higher concentrations of acylcarnitines and lysophospholipids. The offspring lipidome at age six years revealed striking similarities with postnatal maternal lipidome (adult) in its lipid composition and concentrations. Comparison of lipids associated with child and maternal adiposity identified a 92% overlap, implying intergenerational similarities in the lipid signatures of obesity risk. We also catalogued lipid signatures linked with maternal adiposity during gestation and offspring birthweight, and validated (>70% overlap) the findings in an independent birth-cohort (n=1935).

systems biology↗