Glycation Interferes with the Expression of Sialyltransferases in Meningiomas

Meningiomas are the most common non-malignant intracranial tumors and prefer, like most tumors, anaerobic glycolysis for energy production (Warburg effect). This anaerobic glycolysis leads to an increased synthesis of the metabolite methylglyoxal (MGO) or glyoxal (GO), which is known to react with amino groups of proteins. This reaction is called glycation, thereby building advanced glycation end products (AGEs). In this study, we investigated the influence of glycation on sialylation in two meningioma cell lines, representing the WHO grade I (BEN-MEN-1) and the WHO grade III (IOMM-Lee). In the benign meningioma cell line, glycation led to differences in expression of sialyltransferases (ST3GAL1/2/3/5/6, ST6GAL1/2, ST6GALNAC2/6, and ST8SIA1/2), which are known to play a role in tumor progression. We could show that glycation of BEN-MEN-1 cells led to decreased expression of ST3Gal5. This resulted in decreased synthesis of the ganglioside GM3, the product of ST3Gal5. In the malignant meningioma cell line, we observed changes in expression of sialyltransferases (ST3GAL1/2/3, ST6GALNAC5, and ST8SIA1) after glycation, which correlates with less aggressive behavior.

CXCR4 Drives Lympho-Myeloid Fate of Hematopoietic Progenitors Via mTOR and Mitochondrial Metabolic Pathways

Blood production is a tightly regulated process that starts with hematopoietic stem cells (HSCs). In adults, HSCs are unique in their capacity to self-renew and replenish the entire blood system through production of a series of increasingly committed progenitor cells within the bone marrow (BM) microenvironment. HSCs form a rare, quiescent population that displays a metabolism skewed towards anaerobic glycolysis at the expense of mitochondrial oxidative phosphorylation (OXPHOS) to preserve its quiescent state and long-term reconstitution capacity. However, when HSCs differentiate, they undergo a metabolic switch from anaerobic glycolysis to mitochondrial OXPHOS, a process that is in part mediated by the metabolic sensor mTOR. It is well-established that HSCs in the BM adapt the production of myeloid and lymphoid cells depending on the needs of the body and that metabolic plasticity is a critical driver of HSC fate decisions. This has never been assessed for multipotent progenitors (MPPs) which constitute the stage at which the major divergence of lymphoid and myeloid lineages occurs. In mice, common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs) are generated from phenotypically and functionally distinct subpopulations of lineage-biased MPPs, i.e. MPP2 and MPP3 are reported as distinct myeloid-biased MPP subsets that operate together with lymphoid-primed MPP4 to control blood leukocyte production. This question is thus of paramount importance to understand how the lympho-myeloid specification process is regulated. Signaling by the G protein-coupled receptor CXCR4 on MPPs in response to stimulation by its natural ligand, the chemokine CXCL12, produced by BM perivascular stromal cells constitutes a key pathway through which the niches and MPPs communicate. However, the mechanisms whereby CXCR4 signaling regulates MPP specification are still unknown. We addressed this point using BM samples of patients with WHIM Syndrome (WS), a rare immunodeficiency caused by inherited heterozygous autosomal gain-of-CXCR4-function mutations affecting desensitization of CXCR4 and characterized by chronic lympho-neutropenia, as well as a unique WS mouse model which phenocopies severe pan-leukopenia. We unraveled myeloid skewing of the hematopoietic stem and progenitor cell (HSPC) compartment in BM of patients with WS and of WS mice. This relied on CXCR4 signaling strength that controls the output of the lymphoid and myeloid lineages by coordinating the composition and molecular identity of the MPP compartment. The fate of the lymphoid-biased MPP4 subset was central in such a process. Indeed, CXCR4 signaling termination was required for efficient generation and maintenance of the MPP4 pool, while regulating intrinsically their cell cycle status and lymphoid-myeloid gene landscape. In fact, we demonstrated for the first time that enhanced mTOR signaling, accumulation of damaged mitochondria and overactive OXPHOS-driven metabolism promoted cell-autonomous molecular changes that reprogram mutant MPP4 away from lymphoid differentiation. Consistent with this, in vivo chronic treatment with the CXCR4 antagonist AMD3100/Plerixafor or the mTOR inhibitor Rapamycin normalized mitochondrial metabolism and MPP4 differentiation. Thus, our study shows that CXCR4 signaling acts through the mTOR pathway as an essential gatekeeper for integrity of the mitochondrial machinery, which in turn controls lymphoid potential of MPP4. Disclosures No relevant conflicts of interest to declare.

NAD(P)H Fluorescence Lifetime Imaging of Live Intestinal Nematodes Reveals Metabolic Crosstalk Between Parasite and Host

Infections with intestinal nematodes have an ambivalent impact: they represent a burden for human health and animal husbandry, but, at the same time, may ameliorate auto-immune diseases due to the immunomodulatory effect of the parasites. Thus, it is key to understand how intestinal nematodes arrive and persist in their luminal niche and interact with the host over long periods of time. The basic mechanism ruling over parasite and host cellular and tissue functions, the metabolism, was largely neglected in the study of intestinal nematode infections. Here we use NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate) fluorescence lifetime imaging of explanted murine duodenum infected with the natural nematode Heligmosomoides polygyrus and define the link between general metabolic and specific enzymatic activity in parasite and host tissue, during acute infection. In both healthy and infected host intestine, energy is effectively produced, mainly via oxidative phosphorylation. In contrast, the nematodes shift their energy production from balanced fast anaerobic glycolysis and effective oxidative phosphorylation, towards mainly anaerobic glycolysis, back to oxidative phosphorylation during the different life cycle phases in the submucosa versus the intestinal lumen. Additionally, we found an increased NADPH oxidase (NOX) enzymes-dependent oxidative burst in infected intestinal host tissue as compared to healthy tissue, which was mirrored by a similar defense reaction in the parasites. We expect that, the here presented application of in vivo NAD(P)H-FLIM constitutes a unique tool to study metabolic host-parasite crosstalk, in various parasitic intestinal infections.

An Explanation of Subsurface Optical Pathways through Food Myosystems and their Effect on Colorimetry

Light may pass along and across the long axes of muscle fibers in any food myosystem. Thus, incident light may be scattered in several ways before some of it reappears at the surface as diffuse reflectance. Pathways may be short if scattering is strong, or long if scattering is weak. Short pathways minimize selective absorbance by chromophores such as myoglobin, while long pathways maximize selective absorbance. Many food myosystems exhibit a post-mortem decrease in pH caused by anaerobic glycolysis with a series of microstructural changes – glycogen granules between myofibrils are lost, myofibrils shrink laterally as myofilaments move closer together, water moves from within myofibrils to the space between them, muscle fiber membranes leak and lose their electrical capacitance, and myoglobin is flushed into the fluid filled spaces between muscle fibers. These changes increase scattering of light passing across the long axes of muscle fibers. Scattering of light along muscle fibers is caused by sarcomere discs (A-bands). Interference from one or a small number of sarcomere discs may cause iridescence, but in most cases interference from numerous discs causes achromatic diffuse reflectance. Commission International de l’Éclairage (CIE) chromaticity coordinates were calculated for various subsurface optical pathways. Pathways across versus along muscle fibers had a strong effect on CIE y (r = 0.84, P < 0.01) and an even stronger effect on CIE Y% (r = 0.95, P < 0.005).

Endocrine Influence on Cardiac Metabolism in Development and Regeneration

Mammalian cardiomyocytes mostly utilize oxidation of fatty acids to generate ATP. The fetal heart, in stark contrast, mostly uses anaerobic glycolysis. During perinatal development, thyroid hormone drives extensive metabolic remodeling in the heart for adaptation to extrauterine life. These changes coincide with critical functional maturation and exit of the cell cycle, making the heart a post-mitotic organ. Here, we review the current understanding on the perinatal shift in metabolism, hormonal status, and proliferative potential in cardiomyocytes. Thyroid hormone and glucocorticoids have roles in adult cardiac metabolism, and both pathways have been implicated as regulators of myocardial regeneration. We discuss the evidence that suggests these processes could be inter-related and how this can help explain variation in cardiac regeneration across ontogeny and phylogeny, and what breakthroughs are still to be made.

The SRCAP chromatin remodeling complex promotes oxidative metabolism during prenatal heart development

ABSTRACT Mammalian heart development relies on cardiomyocyte mitochondrial maturation and metabolism. Embryonic cardiomyocytes make a metabolic shift from anaerobic glycolysis to oxidative metabolism by mid-gestation. VHL-HIF signaling favors anaerobic glycolysis but this process subsides by E14.5. Meanwhile, oxidative metabolism becomes activated but its regulation is largely elusive. Here, we first pinpointed a crucial temporal window for mitochondrial maturation and metabolic shift, and uncovered the pivotal role of the SRCAP chromatin remodeling complex in these processes in mouse. Disruption of this complex massively suppressed the transcription of key genes required for the tricarboxylic acid cycle, fatty acid β-oxidation and ubiquinone biosynthesis, and destroyed respirasome stability. Furthermore, we found that the SRCAP complex functioned through H2A.Z deposition to activate transcription of metabolic genes. These findings have unveiled the important physiological functions of the SRCAP complex in regulating mitochondrial maturation and promoting oxidative metabolism during heart development, and shed new light on the transcriptional regulation of ubiquinone biosynthesis.

Remodeling of Cancer-Specific Metabolism under Hypoxia with Lactate Calcium Salt in Human Colorectal Cancer Cells

Hypoxic cancer cells meet their growing energy requirements by upregulating glycolysis, resulting in increased glucose consumption and lactate production. Herein, we used a unique approach to change in anaerobic glycolysis of cancer cells by lactate calcium salt (CaLac). Human colorectal cancer (CRC) cells were used for the study. Intracellular calcium and lactate influx was confirmed following 2.5 mM CaLac treatment. The enzymatic activation of lactate dehydrogenase B (LDHB) and pyruvate dehydrogenase (PDH) through substrate reaction of CaLac was investigated. Changes in the intermediates of the tricarboxylic acid (TCA) cycle were confirmed. The cell viability assay, tube formation, and wound-healing assay were performed as well as the confirmation of the expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). In vivo antitumor effects were evaluated using heterotopic and metastatic xenograft animal models with 20 mg/kg CaLac administration. Intracellular calcium and lactate levels were increased following CaLac treatment in CRC cells under hypoxia. Then, enzymatic activation of LDHB and PDH were increased. Upon PDH knockdown, α-ketoglutarate levels were similar between CaLac-treated and untreated cells, indicating that TCA cycle restoration was dependent on CaLac-mediated LDHB and PDH reactivation. CaLac-mediated remodeling of cancer-specific anaerobic glycolysis induced destabilization of HIF-1α and a decrease in VEGF expression, leading to the inhibition of the migration of CRC cells. The significant inhibition of CRC growth and liver metastasis by CaLac administration was confirmed. Our study highlights the potential utility of CaLac supplementation in CRC patients who display reduced therapeutic responses to conventional modes owing to the hypoxic tumor microenvironment.

Novel Insights Linking lncRNAs and Metabolism With Implications for Cardiac Regeneration

Heart disease is the leading cause of mortality in developed countries. The associated pathology is typically characterized by the loss of cardiomyocytes that leads, eventually, to heart failure. Although conventional treatments exist, novel regenerative procedures are warranted for improving cardiac regeneration and patients well fare. Whereas following injury the capacity for regeneration of adult mammalian heart is limited, the neonatal heart is capable of substantial regeneration but this capacity is lost at postnatal stages. Interestingly, this is accompanied by a shift in the metabolic pathways and energetic fuels preferentially used by cardiomyocytes from embryonic glucose-driven anaerobic glycolysis to adult oxidation of substrates in the mitochondria. Apart from energetic sources, metabolites are emerging as key regulators of gene expression and epigenetic programs which could impact cardiac regeneration. Long non-coding RNAs (lncRNAs) are known master regulators of cellular and organismal carbohydrate and lipid metabolism and play multifaceted functions in the cardiovascular system. Still, our understanding of the metabolic determinants and pathways that can promote cardiac regeneration in the injured hearth remains limited. Here, we will discuss the emerging concepts that provide evidence for a molecular interplay between lncRNAs and metabolic signaling in cardiovascular function and whether exploiting this axis could provide ground for improved regenerative strategies in the heart.