Biology subjects

McCall, C. E.

Publications and source records attributed to McCall, C. E..

3 recordsLinked to original sources

bioRxiv2023

Glutathionylation of Pyruvate Dehydrogenase Complex E2 Protein During Acute Inflammation Is Magnified By Mitochondrial Oxidative Stress, Enhancing Cell Death

Lipopolysaccharide (LPS) is a known inducer of inflammatory signaling which triggers generation of reactive oxygen species (ROS) and cell death in responsive cells like THP-1 promonocytes and freshly isolated human monocytes. A key LPS-responsive metabolic pivot point is the 9 megadalton mitochondrial pyruvate dehydrogenase complex (PDC), which provides pyruvate dehydrogenase (E1), lipoamide-linked transacetylase (E2) and lipoamide dehydrogenase (E3) activities to produce acetyl-CoA from pyruvate. While phosphorylation-dependent decreases in PDC activity following LPS treatment or sepsis have been deeply investigated, redox-linked processes have received less attention. Data presented here demonstrate that LPS-induced reversible oxidation within PDC occurs in PDCE2 in both THP-1 cells and primary human monocytes. Knockout of PDCE2 by CRISPR and expression of FLAG-tagged PDCE2 in THP-1 cells demonstrated that LPS-induced glutathionylation is associated with wild type PDCE2 but not mutant protein lacking the lipoamide-linking lysine residues. Moreover, the mitochondrially-targeted electrophile MitoCDNB, which impairs both glutathione-and thioredoxin-based reductase systems, elevates ROS similar to LPS but does not cause PDCE2 glutathionylation. However, LPS and MitoCDNB together are highly synergistic for PDCE2 glutathionylation, ROS production, and cell death. Surprisingly, the two treatments together had differential effects on cytokine production; pro-inflammatory IL-1{beta} production was enhanced by the co-treatment, while IL-10, an important anti-inflammatory cytokine, dropped precipitously compared to LPS treatment alone. This new information may expand opportunities to understand and modulate PDC redox status and activity and improve the outcomes of pathological inflammation. HighlightsO_LIPDCE2 is glutathionylated (-SSG) during acute inflammation in monocytes C_LIO_LILipopolysaccharide-induced PDCE2-SSG occurs in THP1 cells and human monocytes. C_LIO_LILipoamide-deficient PDCE2 lowers LPS-induced PDCE2-SSG and ROS production. C_LIO_LIMitoCDNB leads to ROS production without PDCE2-SSG, but is synergistic with LPS C_LIO_LIMitoCDNB causes the LPS-stimulated cytokine profile to become more proinflammatory C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/525791v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@d509beorg.highwire.dtl.DTLVardef@72b40borg.highwire.dtl.DTLVardef@8a4596org.highwire.dtl.DTLVardef@1de8148_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Dichloroacetate improves hepatic and systemic energy metabolism during sepsis

Dramatic metabolic reprogramming between an anabolic resistance and catabolic tolerance state occurs within the immune system in response to systemic infection with the sepsis syndrome. While metabolic tissues such as the liver are subject to end-organ damage during sepsis and are the primary cause of sepsis death, how their metabolic and energy reprogramming during sepsis state ensures survival is unclear. Employing comprehensive metabolomic screening, targeted lipidomic screening, and transcriptional profiling in a mouse model of septic shock, we show that hepatocyte lipid metabolism, mitochondrial TCA energetics, and redox balance are significantly reprogramed after cecal ligation and puncture (CLP). We identify increases in TCA cycle metabolites citrate, cis-aconitate, and itaconate with reduced fumarate and triglyceride accumulation in septic hepatocytes. Transcription analysis of liver tissue supports and extends the hepatocyte findings. Strikingly, the administration of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) reverses dysregulated hepatocyte metabolism and mitochondrial dysfunction. Our data indicate sepsis promotes hepatic metabolic dysfunction. Furthermore, our data indicate that targeting the mitochondrial PDC/PDK energy home-ostat rebalances transcriptional and metabolic manifestations of sepsis within the liver.

immunology↗

bioRxiv2020

Divergent effects of Western and Mediterranean diets on behavior and monocyte polarization.

Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, which are major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an "evolutionary mismatch," between human physiology and modern nutritional environments. In support of this idea, Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to hunter-gatherer diets, such as a Mediterranean diet; however, the mechanisms linking dietary mismatch to inflammation and chronic disease are poorly understood. We used a macaque model and whole diet manipulations to evaluate one possible mechanism - inflammatory polarization of monocytes - that potentially leads to this evolutionary mismatch. After consuming a Western- or Mediterranean-like diet for 15 months, monocytes from Western diet consumers exhibited a more proinflammatory phenotype, with 40% of their genes differentially expressed (FDR<0.05). Compared to the Mediterranean diet, the Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered animal behavior. For example, Western-fed individuals were more anxious and less socially integrated compared to the Mediterranean-fed subjects. These behavioral changes were also associated with some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. The results of this study provide new insights into evolutionary mismatch at the molecular level and uncover new pathways through which Western diets generate inflammation and disease.

genomics↗