bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2022–03–13
two papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. A non-canonical tricarboxylic acid cycle underlies cellular identity.
  2. Metabolic dynamics instructs CD8+ T cell differentiation and functions.
  1. Nature. 2022 Mar 09.
    A non-canonical tricarboxylic acid cycle underlies cellular identity.
    Paige K Arnold, Benjamin T Jackson, Katrina I Paras, Julia S Brunner, Madeleine L Hart, Oliver J Newsom, Sydney P Alibeckoff, Jennifer Endress, Esther Drill, Lucas B Sullivan, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents for energy production and critical metabolites for biosynthetic reactions. Despite the importance of the products of the TCA cycle for cell viability and proliferation, mammalian cells display diversity in TCA-cycle activity1,2. How this diversity is achieved, and whether it is critical for establishing cell fate, remains poorly understood. Here we identify a non-canonical TCA cycle that is required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes that is sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially derived citrate exported to the cytoplasm is metabolized by ATP citrate lyase, ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating the expression of ATP citrate lyase or the canonical TCA-cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells revealed that changes in the configuration of the TCA cycle accompany cell fate transitions. During exit from pluripotency, embryonic stem cells switch from canonical to non-canonical TCA-cycle metabolism. Accordingly, blocking the non-canonical TCA cycle prevents cells from exiting pluripotency. These results establish a context-dependent alternative to the traditional TCA cycle and reveal that appropriate TCA-cycle engagement is required for changes in cell state.
    DOI:  https://doi.org/10.1038/s41586-022-04475-w
  2. Eur J Immunol. 2022 Mar 06.
    Metabolic dynamics instructs CD8+ T cell differentiation and functions.
    Alessio Bevilacqua, Zhiyu Li, Ping-Chih Ho.
      Cytotoxic CD8+ T cells are a key element of the adaptative immune system to protect the organism against infections and malignant cells. During their activation and response T cells undergo different metabolic pathways to support their energetic needs according to their localization and function. However, it has also been recently appreciated that this metabolic reprogramming also directly supports T cells lineage differentiation. Accordingly, metabolic deficiencies and prolonged stress exposure can impact T cell differentiation and skew them into exhausted state. Here, we review how metabolism defines CD8+ T cells differentiation and function. Moreover, we cover the principal metabolic dysregulation that promotes the exhausted phenotype under tumor or chronic virus condition. Finally, we summarize recent strategies to reprogram impaired metabolic pathways to promote CD8+ T cells effector function and survival. This article is protected by copyright. All rights reserved.
    Keywords:  T cell differentiation; T cell exhaustion; T cells; infection; metabolism
    DOI:  https://doi.org/10.1002/eji.202149486
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