bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2024–09–01
nine papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program.
  2. The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
  3. Propionyl-CoA metabolism links chromatin acylation to cardiac transcription.
  4. Osteoclasts control endochondral ossification via regulating acetyl-CoA availability.
  5. Citrate Promotes Nitric Oxide Production during Human Sperm Capacitation.
  6. Sodium Acetate Enhances Neutrophil Extracellular Trap Formation via Histone Acetylation Pathway in Neutrophil-like HL-60 Cells.
  7. NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
  8. Lactate helps cancer cells resist chemotherapy.
  9. Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.
  1. Nat Cardiovasc Res. 2024 Jul;3(7): 869-882
    Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program.
    Michael P Lazaropoulos, Andrew A Gibb, Douglas J Chapski, Abheya A Nair, Allison N Reiter, Rajika Roy, Deborah M Eaton, Kenneth C Bedi, Kenneth B Margulies, Kathryn E Wellen, Conchi Estarás, Thomas M Vondriska, John W Elrod.
      Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFβ stimulation enhances ACLY nuclear localization and ACLY-SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis.
    DOI:  https://doi.org/10.1038/s44161-024-00502-3
  2. Cell Rep. 2024 Aug 27. pii: S2211-1247(24)01039-8. [Epub ahead of print]43(9): 114688
    The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
    Caroline Stanton, Chavin Buasakdi, Jie Sun, Ian Levitan, Prerona Bora, Sergei Kutseikin, R Luke Wiseman, Michael J Bollong.
      The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity is not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for the pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells. We find that methylglyoxal inactivates NLRP3 via a non-enzymatic, covalent-crosslinking-based mechanism, promoting inter- and intraprotein MICA (methyl imidazole crosslink between cysteine and arginine) posttranslational linkages within NLRP3. This work establishes NLRP3 as capable of sensing a host of electrophilic chemicals, both exogenous small molecules and endogenous reactive metabolites, and suggests a mechanism by which glycolytic flux can moderate the activation status of a central inflammatory signaling pathway.
    Keywords:  CP: Immunology; CP: Metabolism; MICA modification; NLRP3; PGK1; covalent; glycolysis; inflammasome; inflammation; methylglyoxal
    DOI:  https://doi.org/10.1016/j.celrep.2024.114688
  3. Nat Cardiovasc Res. 2023 Dec;2(12): 1109-1111
    Propionyl-CoA metabolism links chromatin acylation to cardiac transcription.
    Christina Demetriadou, Andrew A Gibb, John W Elrod, Nathaniel W Snyder.
      The molecular mechanisms that link propionyl-CoA metabolism and epigenetic regulation of gene expression are unclear, as are the implications for heart function. Now, new insights into the modulation of chromatin acylation and transcription by aberrant oxidation of propionyl-CoA are revealed in the dysfunctional hearts of mice with propionic acidemia.
    DOI:  https://doi.org/10.1038/s44161-023-00381-0
  4. Bone Res. 2024 Aug 28. 12(1): 49
    Osteoclasts control endochondral ossification via regulating acetyl-CoA availability.
    Daizhao Deng, Xianming Liu, Wenlan Huang, Sirui Yuan, Genming Liu, Shanshan Ai, Yijie Fu, Haokun Xu, Xinyi Zhang, Shihai Li, Song Xu, Xiaochun Bai, Yue Zhang.
      Osteoclast is critical in skeletal development and fracture healing, yet the impact and underlying mechanisms of their metabolic state on these processes remain unclear. Here, by using osteoclast-specific small GTPase Rheb1-knockout mice, we reveal that mitochondrial respiration, rather than glycolysis, is essential for cathepsin K (CTSK) production in osteoclasts and is regulated by Rheb1 in a mechanistic target of rapamycin complex 1 (mTORC1)-independent manner. Mechanistically, we find that Rheb1 coordinates with mitochondrial acetyl-CoA generation to fuel CTSK, and acetyl-CoA availability in osteoclasts is the central to elevating CTSK. Importantly, our findings demonstrate that the regulation of CTSK by acetyl-CoA availability is critical and may confer a risk for abnormal endochondral ossification, which may be the main cause of poor fracture healing on alcohol consumption, targeting Rheb1 could successfully against the process. These findings uncover a pivotal role of mitochondria in osteoclasts and provide a potent therapeutic opportunity in bone disorders.
    DOI:  https://doi.org/10.1038/s41413-024-00360-6
  5. Antioxidants (Basel). 2024 Jul 23. pii: 885. [Epub ahead of print]13(8):
    Citrate Promotes Nitric Oxide Production during Human Sperm Capacitation.
    Diego Loggia, Cristian O'Flaherty.
      Sperm capacitation is a complex process essential for the spermatozoon to recognize and fertilize the oocyte. For capacitation to occur, human spermatozoa require low levels of reactive oxygen species (ROS), increased protein tyrosine phosphorylation, and sufficient levels of energy metabolites such as citrate. Human spermatozoa are exposed to high concentrations of citrate from the seminal plasma, yet the role of citrate in sperm capacitation is largely unknown. We report that citrate can support capacitation in human spermatozoa incubated with no other energy metabolites in the capacitation medium. Reduced capacitation levels were observed in spermatozoa incubated with inhibitors of mitochondrial citrate transporter (CIC), cytosolic ATP-citrate lyase (ACLY), malic enzyme (ME), and nitric oxide synthase (NOS). The role of citrate metabolism in ROS production was further elucidated as citrate increased NO● production in capacitated spermatozoa, whereas inhibition of ACLY reduced NO● production. This research characterizes a novel metabolic pathway for citrate to produce NO● in the process of human sperm capacitation.
    Keywords:  citrate; male fertility; nitric oxide (NO●); reactive oxygen species (ROS); sperm capacitation
    DOI:  https://doi.org/10.3390/antiox13080885
  6. Int J Mol Sci. 2024 Aug 11. pii: 8757. [Epub ahead of print]25(16):
    Sodium Acetate Enhances Neutrophil Extracellular Trap Formation via Histone Acetylation Pathway in Neutrophil-like HL-60 Cells.
    Hiroyuki Yasuda, Yutaka Takishita, Akihiro Morita, Tomonari Tsutsumi, Naoya Nakagawa, Eisuke F Sato.
      Neutrophil extracellular trap formation has been identified as a new cell death mediator, termed NETosis, which is distinct from apoptosis and necrosis. NETs capture foreign substances, such as bacteria, by releasing DNA into the extracellular environment, and have been associated with inflammatory diseases and altered immune responses. Short-chain fatty acids, such as acetate, are produced by the gut microbiota and reportedly enhance innate immune responses; however, the underlying molecular mechanisms remain unclear. Here, we investigated the effects of sodium acetate, which has the highest SCFA concentration in the blood and gastrointestinal tract, on NETosis by focusing on the mechanisms associated with histone acetylation in neutrophil-like HL-60 cells. Sodium acetate enhanced NETosis, as shown by fluorescence staining with SYTOX green, and the effect was directly proportional to the treatment duration (16-24 h). Moreover, the addition of sodium acetate significantly enhanced the acetylation of Ace-H3, H3K9ace, and H3K14ace. Sodium acetate-induced histone acetylation rapidly decreased upon stimulation with the calcium ionophore A23187, whereas histone citrullination markedly increased. These results demonstrate that sodium acetate induces NETosis via histone acetylation in neutrophil-like HL-60 cells, providing new insights into the therapeutic effects based on the innate immunity-enhancing effect of dietary fiber.
    Keywords:  NETosis; acetate; histone acetylation; histone citrullination; immune response; neutrophil extracellular trap; peptidyl arginine deiminase 4
    DOI:  https://doi.org/10.3390/ijms25168757
  7. Nat Immunol. 2024 Aug 28.
    NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
    Caterina Scirgolea, Rosa Sottile, Marco De Luca, Alberto Susana, Silvia Carnevale, Simone Puccio, Valentina Ferrari, Veronica Lise, Giorgia Contarini, Alice Scarpa, Eloise Scamardella, Simona Feno, Chiara Camisaschi, Gabriele De Simone, Gianluca Basso, Desiree Giuliano, Emilia Maria Cristina Mazza, Luca Gattinoni, Rahul Roychoudhuri, Emanuele Voulaz, Diletta Di Mitri, Matteo Simonelli, Agnese Losurdo, Davide Pozzi, Carlson Tsui, Axel Kallies, Sara Timo, Giuseppe Martano, Elettra Barberis, Marcello Manfredi, Maria Rescigno, Sebastien Jaillon, Enrico Lugli.
      CD8+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-024-01923-9
  8. Nature. 2024 Aug 23.
    Lactate helps cancer cells resist chemotherapy.
      
    Keywords:  Cancer; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-02731-9
  9. Nat Cardiovasc Res. 2023 Aug;2(8): 746-763
    Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.
    Maria N Barrachina, Gerard Pernes, Isabelle C Becker, Isabelle Allaeys, Thomas I Hirsch, Dafna J Groeneveld, Abdullah O Khan, Daniela Freire, Karen Guo, Estelle Carminita, Pooranee K Morgan, Thomas J C Collins, Natalie A Mellett, Zimu Wei, Ibrahim Almazni, Joseph E Italiano, James Luyendyk, Peter J Meikle, Mark Puder, Neil V Morgan, Eric Boilard, Andrew J Murphy, Kellie R Machlus.
      Lipids contribute to hematopoiesis and membrane properties and dynamics; however, little is known about the role of lipids in megakaryopoiesis. Here we show that megakaryocyte progenitors, megakaryocytes and platelets present a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake as well as de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in low platelets. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production and that changes in dietary fatty acids may be a viable target to modulate platelet counts.
    DOI:  https://doi.org/10.1038/s44161-023-00305-y
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