Biology subjects

Garcia-Canaveras, J. C.

Publications and source records attributed to Garcia-Canaveras, J. C..

4 recordsLinked to original sources

bioRxiv2023

GLUD1 dictates muscle stem cell differentiation by controlling mitochondrial glutamate levels

Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury. Upon activation MuSCs metabolically rewire to meet the changing demands of proliferation. Here we describe that primary changes in metabolism itself can dictate MuSC fate decisions to control differentiation and fusion. We found that glutamine anaplerosis into the TCA cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Genetic deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and imbalanced fusion combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation in proliferating MuSCs and inhibited the malate-aspartate shuttle (MAS). Restoring MAS activity by supplementation of alanine normalized differentiation. In conclusion, high GLUD1 activity in proliferating MuSCs prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS. It thereby acts as a compartment specific metabolic brake on MuSC differentiation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/560525v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@e3585dorg.highwire.dtl.DTLVardef@1be4a54org.highwire.dtl.DTLVardef@1f077org.highwire.dtl.DTLVardef@15220f1_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGlutamine is the major TCA cycle substrate in MuSCs with decreasing contribution upon differentiation. C_LIO_LILoss of Glud1 impairs MuSC self-renewal capacity and causes imbalanced fusion in vitro and in vivo. C_LIO_LIGlud1 deletion leads to mitochondrial glutamate trapping and malate-aspartate shuttle (MAS) dysfunction. C_LIO_LIRestoration of MAS activity in Glud1 deficient MuSCs reverses precocious differentiation and imbalanced fusion. C_LI

cell biology↗

bioRxiv2022

FAMetA: a mass isotopologue-based tool for the comprehensive analysis of fatty acid metabolism

The use of stable isotope tracers and mass spectrometry (MS) is the gold standard method for the analysis of fatty acids (FAs) metabolism. Yet current state-of-the-art tools provide limited and difficult to interpret information about FA biosynthetic routes. Here we present FAMetA, an R-package and a web-based application (www.fameta.es) that use 13C mass-isotopologue profiles to estimate FA import, de novo lipogenesis, elongation, and desaturation in a user-friendly platform. The FAMetA workflow covers all the functionalities needed for MS data analyses. To illustrate its utility, different in vitro and in vivo experimental settings are used in which FA metabolism is modified. Thanks to the comprehensive characterisation of FA biosynthesis and the easy-to-interpret graphical representations compared to previous tools, FAMetA discloses unnoticed insights into how cells reprogramme their FA metabolism and, when combined with FASN, SCD1 and FADS2 inhibitors, it enables the straightforward identification of new FAs by the metabolic reconstruction of their synthesis route.

systems biology↗

bioRxiv2022

LipidMS 3.0: an R-package and a web-based tool for LC-MS/MS data processing and lipid annotation

SummaryLipidMS was initially envisioned to use fragmentation rules and data-independent acquisition (DIA) for lipid annotation. However, data-dependent acquisition (DDA) remains the most widespread acquisition mode for untargeted LC-MS/MS-based lipidomics. Here we present LipidMS 3.0, an R package that not only adds DDA and new lipid classes to its pipeline, but also the required functionalities to cover the whole data analysis workflow from pre-processing (i.e., peak-peaking, alignment and grouping) to lipid annotation. We applied the new workflow in the data analysis of a commercial human serum pool spiked with 68 lipid standards acquired in the full scan, DDA and DIA modes. When focusing on the detected lipid standard features and total identified lipids, LipidMS 3.0 data pre-processing performance is similar to XCMS, whereas it complements the annotations provided by MS-DIAL, one of the most widely used tools in lipidomics. To extend and facilitate LipidMS 3.0 usage among less experienced R-programming users, the workflow was also implemented as a web-based application. Availability and ImplementationThe LipidMS R-package is freely available at https://CRAN.R-project.org/package=LipidMS and as a website at http://www.lipidms.com. Contactjuancarlos_garcia@iislafe.es, agustin.lahoz@uv.es

bioinformatics↗

bioRxiv2021

MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function

Antigenic stimulation promotes T cells metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme Methylenetetrahydrofolate Dehydrogenase-2 (MTHFD2) is highly expressed in inflammatory diseases and induced in activated T cells to promote proliferation and produce inflammatory cytokines. In pathogenic Th17 cells, MTHFD2 also prevented aberrant upregulation of FoxP3 and suppressive capacity. Conversely, MTHFD2-deficiency enhanced lineage stability of regulatory T (Treg) cells. Mechanistically, MTHFD2 maintained cellular 10-formyltetrahydrofolate for de novo purine synthesis and MTHFD2 inhibition led to accumulation of the intermediate 5-aminoimidazole carboxamide ribonucleotide that was associated with decreased mTORC1 signaling. MTHFD2 was also required for proper histone de-methylation in Th17 cells. Importantly, inhibiting MTHFD2 in vivo reduced disease severity in Experimental Autoimmune Encephalomyelitis and Delayed-Type Hypersensitivity. MTHFD2 induction is thus a metabolic checkpoint for pathogenic effector cells that suppresses anti-inflammatory Treg cells and is a potential therapeutic target within 1C metabolism.

immunology↗