Biology subjects

Warmoes, M. O.

Publications and source records attributed to Warmoes, M. O..

4 recordsLinked to original sources

bioRxiv2023

CLN3 deficiency leads to neurological and metabolic perturbations during early development

Juvenile Neuronal Ceroid Lipofuscinosis (or Batten disease) is an autosomal recessive, rare neurodegenerative disorder that affects mainly children above the age of 5 years and is most commonly caused by mutations in the highly conserved CLN3 gene. Here, we generated cln3 morphants and stable mutant lines in zebrafish. Although neither morphant nor mutant cln3 larvae showed any obvious developmental or morphological defects, behavioral phenotyping of the mutant larvae revealed higher basal activity, hyposensitivity to abrupt light changes and hypersensitivity to pro-convulsive drugs. Importantly, in-depth metabolomics and lipidomics analyses revealed significant accumulation of several glycerophosphodiesters (GPDs) and a global decrease of bis(monoacylglycero)phosphate (BMP) species, two classes of molecules previously proposed as potential biomarkers for CLN3 disease based on independent studies in other organisms. We could also demonstrate GPD accumulation in human-induced pluripotent stem cell-derived cerebral organoids carrying a pathogenic variant for CLN3. Our models revealed that GPDs accumulate at very early stages of life in the absence of functional CLN3 and highlight glycerophosphoinositol and BMP as promising biomarker candidates for pre-symptomatic CLN3 disease.

molecular biology↗

bioRxiv2021

Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment

Not all cancer patients with severe neutropenia develop fever, and the fecal microbiome may play a role. In neutropenic hematopoietic cell transplant patients (n=119), 63 (53%) developed a subsequent fever and had increased fecal Akkermansia muciniphila, a mucus-degrading bacteria (p=0.006, corrected for multiple comparisons). In mouse models, two therapies, irradiation and melphalan, similarly expanded A. muciniphila. Dietary restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Azithromycin treatment depleted A. muciniphila and preserved colonic mucus. Dietary restriction raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila with lower pH and increased propionate prevented utilization of mucin. Treating irradiated mice with azithromycin or propionate preserved the mucus layer, lessened hypothermia, and reduced inflammatory cytokines in the colon. These results suggest that diet, metabolites and colonic mucus link the microbiome to neutropenic fever, and could guide future microbiome-based preventive strategies.

microbiology↗

bioRxiv2019

Inosine is an alternative carbon supply that supports effector T cell proliferation and anti-tumor function under glucose restriction

T cells undergo a characteristic metabolic rewiring that fulfills the dramatically increased bioenergetic, biosynthetic, and redox demands following antigen stimulation. A robust adaptive immune system requires effector T cells to respond and adapt to fluctuations in environmental nutrient levels imposed by infectious and inflammatory sites in different tissues. Inevitably, such responsiveness and adaptation reflect metabolic plasticity, allowing T cells to elicit immune functions by using a wide range of nutrient substrates. Here, we show that effector T cells utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase (PNP). Using Stable Isotope-Resolved Metabolomics (SIRM), we demonstrated that ribose moiety of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors. Accordingly, the dependence of T cells on extracellular glucose for growth and effector functions can be relieved by inosine. On the other hand, cancer cells display diverse capacity to utilize inosine as a carbon resource. Moreover, the supplement of inosine enhances the anti-tumor efficacy of immune-checkpoint blockade or adoptive T cell transfer, reflecting the capability of inosine in relieving tumor-imposed metabolic restrictions on T cells in vivo.

immunology↗

bioRxiv2018

Acetate is generated de novo from glucose metabolism in mammals and is coupled to central carbon metabolism

In cases of nutritional excess, there is incomplete catabolism of a nutritional source and secretion of a waste product (overflow metabolism), such as the conversion of glucose to lactate (the Warburg Effect) in tumors. Here we report that excess glucose metabolism generates acetate, a key nutrient whose source has been unclear. Conversion of pyruvate, the product of glycolysis, to acetate occurs through two mechanisms: 1) coupling to reactive oxygen species (ROS), and 2) a neomorphic enzyme activity from keto acid dehydrogenases that enable it to function as a pyruvate decarboxylase. Furthermore, we demonstrate that glucose-derived acetate is sufficient to maintain acetyl-coenzyme A (Ac-CoA) pools and cell proliferation in certain limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. Thus, de novo acetate production is coupled to the activity of central carbon metabolism providing possible regulatory mechanisms and links to pathophysiology.

biochemistry↗