Biology subjects

McNally, E.

Publications and source records attributed to McNally, E..

3 recordsLinked to original sources

bioRxiv2025

Succinate enhances mitochondrial metabolism and phagocytosis in human airspace monocytes

Airspace macrophages (AM) are crucial to host defence and to maintenance of lung homeostasis, with smoking drastically compromising these functions. Airspace monocytes, precursors of the differentiated AM, are found in increased numbers in the lungs of smokers yet little is known about their metabolic regulation and function. Here, we develop a click chemistry-based single cell analysis platform to characterise human airspace monocytes and AM ex vivo, identifying distinct metabolic profiles and a key role for oxidative phosphorylation in supporting phagocytic function. While blood and newly recruited CD93+ airspace monocytes show low mitochondrial dependency, AM rely heavily on oxidative phosphorylation. Acute succinate supplementation enhanced mitochondrial metabolism and phagocytosis in monocytes and promoted their differentiation into highly oxidative macrophages with enhanced function. Succinate emerges as a promising candidate to restore lung immune function, particularly in the smokers lung where airspace monocytes are enriched. Overall, we identify mitochondrial metabolism as a key modulator of lung immune function and a target for therapeutic intervention, with potential applications in systemic monocyte-targeted therapies and metabolic preconditioning for adoptive cell therapies. One Sentence Summary: Mitochondrial metabolism regulates phagocytic function in human lung monocytes and macrophages and can be targeted using succinate. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/659271v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@18c8716org.highwire.dtl.DTLVardef@f8f4b8org.highwire.dtl.DTLVardef@8a806forg.highwire.dtl.DTLVardef@f5f8b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Impaired lamin localization to the nuclear envelope is responsible for nuclear damage in LMNA mutant iPSC-derived cardiomyocytes

The LMNA gene encodes the nuclear envelope proteins Lamins A and C, which comprise a major part of the nuclear lamina, provide mechanical support to the nucleus, and participate in diverse intracellular signaling. LMNA mutations give rise to a collection of diseases called laminopathies, including dilated cardiomyopathy (LMNA-DCM) and muscular dystrophies. Although nuclear deformities are a hallmark of LMNA-DCM, the role of nuclear abnormalities in the pathogenesis of LMNA-DCM remains incompletely understood. Using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LMNA mutant patients and healthy controls, we show that LMNA mutant iPSC-CM nuclei have altered shape or increased size compared to healthy control iPSC-CM nuclei. The LMNA mutation exhibiting the most severe nuclear deformities, R249Q, additionally caused reduced nuclear stiffness and increased nuclear fragility. Importantly, for all cell lines, the degree of nuclear abnormalities corresponded to the degree of Lamin A/C and Lamin B1 mislocalization from the nuclear envelope. The mislocalization was likely due to altered assembly of Lamin A/C. Collectively, these results point to the importance of correct lamin assembly at the nuclear envelope in providing mechanical stability to the nucleus and suggest that defects in nuclear lamina organization may contribute to the nuclear and cellular dysfunction in LMNA-DCM.

cell biology↗

bioRxiv2020

Ocean acidification induces subtle shifts in gene expression and DNA methylation in mantle tissue of the Eastern oyster (Crassostrea virginica)

Early evidence suggests that DNA methylation can mediate phenotypic responses of marine calcifying species to ocean acidification (OA). Few studies, however, have explicitly studied DNA methylation in calcifying tissues through time. Here, we examined the phenotypic and molecular responses in the extrapallial fluid and mantle (fluid and tissue at the calcification site) in the Eastern oyster (Crassostrea virginica) exposed to experimental OA over 80 days. Oysters were reared under three experimental pCO2 treatments ( control, 580 atm; moderate OA, 1000 uatm; high OA, 2800 atm) and sampled at 6 time points (24 hours - 80 days). We found that high OA initially induced changes in the pH of the extrapallial fluid (pHEPF) relative to the external seawater, but the magnitude of this difference was highest at 9 days and diminished over time. Calcification rates were significantly lower in the high OA treatment compared to the other treatments. To explore how oysters regulate their extrapallial fluid, gene expression and DNA methylation were examined in the mantle-edge tissue of oysters from day 9 and 80 in the control and high OA treatments. Mantle tissue mounted a significant global molecular response (both in the transcriptome and methylome) to OA that shifted through time. Although we did not find individual genes that were significantly differentially expressed to OA, the pHEPF was correlated with the eigengene expression of several co-expressed gene clusters. A small number of OA-induced differentially methylated loci were discovered, which corresponded with a weak association between OA-induced changes in genome-wide gene body DNA methylation and gene expression. Gene body methylation, however, was not significantly correlated with the eigengene expression of pHEPF correlated gene clusters. These results suggest that in C. virginica, OA induces a subtle response in a large number of genes, but also indicates that plasticity at the molecular level may be limited. Our study highlights the need to re-assess the plasticity of tissue-specific molecular responses in marine calcifiers, as well as the role of DNA methylation and gene expression in mediating physiological and biomineralization responses to OA.

molecular biology↗