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Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis

ABSTRACT: RNA-sequencing was performed to look for transcriptional differences between wild-type and Mpc2-deficient granulocyte-macrophage progenitors immediately following the deletion of Mpc2. Paper abstract: Hematopoietic stem and progenitor cells likely engage specific metabolic pathways to promote homeostasis of downstream mature lineages. We examined hematopoiesis in mice conditionally deficient in genes required for long-chain fatty acid oxidation (Cpt2), glutaminolysis (Gls), or mitochondrial pyruvate import (Mpc2). Genetic ablation of Cpt2 or Gls minimally impacted most blood lineages. Deletion of Mpc2 led to a sharp decline in mature myeloid cells and a slower reduction in T cells, whereas other hematopoietic lineages were unaffected. Yet MPC2-deficient monocytes and neutrophils rapidly recovered due to a transient increase in proliferation of myeloid but not other progenitors. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was progenitor-intrinsic and accompanied by a metabolic switch to glutaminolysis. Myeloid recovery after loss of MPC2 or cyclophosphamide treatment was delayed in the absence of GLS. Reciprocally, MPC2 was not required for myeloid recovery after cyclophosphamide treatment. Thus, whereas mitochondrial pyruvate metabolism maintains myelopoiesis under steady-state conditions, rapid recovery from acute loss of myeloid cells requires a switch to glutaminolysis in progenitors.

ORGANISM(S): Mus musculus

PROVIDER: GSE225578 | GEO | 2023/02/22

REPOSITORIES: GEO

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Project description:Collombet2016 - Lymphoid and myeloid cell specification and transdifferentiation This model is described in the article: Logical modeling of lymphoid and myeloid cell specification and transdifferentiation Samuel Collombet, Chris van Oevelen, Jose Luis Sardina Ortega, Wassim Abou-Jaoudé, Bruno Di Stefano, Morgane Thomas-Chollier, Thomas Graf, and Denis Thieffry Proceedings of the National Academy of Sciences of the United States of America Abstract: Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors, and chromatin remodelers. Using public data and data from our own molecular genetic experiments (quantitative PCR, Western blot, EMSA) or genome-wide assays (RNA-sequencing, ChIP-sequencing), we have assembled a comprehensive regulatory network encompassing the main transcription factors and signaling components involved in myeloid and lymphoid development. Focusing on B-cell and macrophage development, we defined a qualitative dynamical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knockdowns, and the reprogramming of pre-B cells into macrophages induced by the ectopic expression of specific transcription factors. The resulting network model can be used as a template for the integration of new hematopoietic differentiation and transdifferentiation data to foster our understanding of lymphoid/myeloid cell-fate decisions. This model is hosted on BioModels Database and identified by: MODEL1610240000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Background: Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown. Methods: We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of 13C-glucose. Cardiac glycogen was measured biochemically and by transmission electron microscopy. Cardiac glucose uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the heart failure in CS-Mpc2-/- mice. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed either low-fat or ketogenic diet. Results: Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, suggesting their heart failure is not caused by energetic stress. These hearts displayed increased enrichment from 13C-glucose and increased glycolytic metabolite pool sizes. 13C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ~6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of the priming enzyme glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic 13C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet. Conclusions: Our results indicate that loss of MPC in the heart increases glycolytic metabolism and ultimately glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is dramatically reduced by consumption of a ketogenic diet.

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Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis

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