bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2024–11–17
seventeen papers selected by
Lakesh Kumar, BITS Pilani
  1. An endoplasmic reticulum localized acetyl-CoA transporter is required for efficient fatty acid synthesis in Toxoplasma gondii.
  2. Architecture of the Toxoplasma gondii apical polar ring and its role in gliding motility and invasion.
  3. A bioinformatic approach for the prediction and functional classification of Toxoplasma gondii long non-coding RNAs.
  4. Cap-independent translation directs stress-induced differentiation of the protozoan parasite Toxoplasma gondii.
  5. Designing a multi-epitope subunit vaccine against Toxoplasma gondii through reverse vaccinology approach.
  6. Sec14 proteins in the apicomplexan parasites Plasmodium and Toxoplasma.
  7. When more sugar is better-a GPI side chain modification results in a less virulent phenotype during a protozoan infection.
  8. Bioluminescence assay of lysine deacylase sirtuin activity.
  9. Toxoplasma gondii Infection of BALB/c Mice Perturbs Host Neurochemistry.
  10. Pharmacophore-guided in-silico discovery of SIRT1 inhibitors for targeted cancer therapy.
  11. Iron‑sulfur cluster biogenesis and function in Apicomplexa parasites.
  12. Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
  13. The Intestinal Barrier Protective Effect of Indole Aldehyde Derivatives on Acute Toxoplasma gondii Infection.
  14. Dissecting the epigenetic orchestra of HDAC isoforms in breast cancer development: a review.
  15. A two-way relationship between histone acetylation and metabolism.
  16. Elucidating the spatiotemporal dynamics of glucose metabolism with genetically encoded fluorescent biosensors.
  17. Nuclear localization of MTHFD2 is required for correct mitosis progression.
  1. Open Biol. 2024 Nov;14(11): 240184
    An endoplasmic reticulum localized acetyl-CoA transporter is required for efficient fatty acid synthesis in Toxoplasma gondii.
    Biyun Qin, Bolin Fan, Yazhou Li, Yidan Wang, Bang Shen, Ningbo Xia.
      Toxoplasma gondii is an obligate intracellular parasite that can infect humans and diverse animals. Fatty acids are critical for the growth and proliferation of T. gondii, which has at least two pathways to synthesize fatty acids, including the type II de novo synthesis pathway in the apicoplast and the elongation pathway in the endoplasmic reticulum (ER). Acetyl-CoA is the key substrate for both fatty acid synthesis pathways. In the apicoplast, acetyl-CoA is mainly provided by the pyruvate dehydrogenase complex. However, how the ER acquires acetyl-CoA is not fully understood. Here, we identified a putative acetyl-CoA transporter (TgAT1) that localized to the ER of T. gondii. Deletion of TgAT1 impaired parasite growth and invasion in vitro and attenuated tachyzoite virulence in vivo. Metabolic tracing using 13C-acetate found that loss of TgAT1 reduced the incorporation of 13C into certain fatty acids, suggesting reduced activities of elongation. Truncation of AT1 was previously reported to confer resistance to the antimalarial compound GNF179 in Plasmodium falciparum. Interestingly, GNF179 had much weaker inhibitory effect on Toxoplasma than on Plasmodium. In addition, deletion of AT1 did not affect the susceptibility of Toxoplasma to GNF179, suggesting that this compound might be taken up differently or has different inhibitory mechanisms in these parasites. Together, our data show that TgAT1 has important roles for parasite growth and fatty acid synthesis, but its disruption does not confer GNF179 resistance in T. gondii.
    Keywords:  apicomplexan; apicoplast; drug resistance; fatty acids; malaria
    DOI:  https://doi.org/10.1098/rsob.240184
  2. Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2416602121
    Architecture of the Toxoplasma gondii apical polar ring and its role in gliding motility and invasion.
    Bingjian Ren, Romuald Haase, Sharon Patray, Quynh Nguyen, Bohumil Maco, Nicolas Dos Santos Pacheco, Yi-Wei Chang, Dominique Soldati-Favre.
      In Toxoplasma gondii, the conoid comprises a cone with spiraling tubulin fibers, preconoidal rings, and intraconoidal microtubules. This dynamic organelle undergoes extension and retraction through the apical polar ring (APR) during egress, gliding, and invasion. The forces involved in conoid extrusion are beginning to be understood, and its role in directing F-actin flux to the pellicular space, thereby controlling parasite motility, has been proposed. However, the contribution of the APR and its interactions with the conoid remain unclear. To gain insight into the APR architecture, ultrastructure expansion microscopy was applied to pinpoint known and newly identified APR proteins (APR2 to APR7). Our results revealed that the APR is constructed as a fixed multilayered structure. Notably, conditional depletion of APR2 resulted in significant impairments in motility and invasion. Electron microscopy and cryoelectron tomography revealed that depletion of APR2 alters APR integrity, affecting conoid extrusion and causing cytosolic leakage of F-actin. These findings implicate the APR structure in directing the apico-basal flux of F-actin to regulate parasite motility and invasion.
    Keywords:  Toxoplasma gondii; apical polar ring; apicomplexa; invasion; motility
    DOI:  https://doi.org/10.1073/pnas.2416602121
  3. Sci Rep. 2024 11 12. 14(1): 27687
    A bioinformatic approach for the prediction and functional classification of Toxoplasma gondii long non-coding RNAs.
    Laura Vanagas, Constanza Cristaldi, Gino La Bella, Agustina Ganuza, Sergio O Angel, Andrés M Alonso.
      Long non-coding RNAs (lncRNAs) have emerged as significant players in diverse cellular processes, including cell differentiation. Advancements in computational methodologies have facilitated the prediction of lncRNA functions, enabling insights even in non-model organisms like pathogenic parasites, in roles such as parasite development, antigenic variation, and epigenetics. In this work, we focus on the apicomplexan Toxoplasma gondii differentiation process, where the infective stage, tachyzoite, can develop into the cysted stage, bradyzoite, under stress conditions. Using a publicly available transcriptome dataset, we predicted putative lncRNA sequences associated with this differentiation process. Notably, a substantial proportion of these putative lncRNAs exhibited stage-specific expression, particularly at the bradyzoite stage. Furthermore, co-expression patterns between coding transcripts and putative TglncRNAs suggest their involvement in shared processes, such as bradyzoite development. Putative TglncRNA loci analysis revealed their potential influence on the expression of nearby coding genes, including subtelomeric genes unique to the T. gondii genome. Finally we propose a k-mer analysis approach to predict putative functional relationships between characterized lncRNAs from model organisms like Homo sapiens and the putative T. gondii lncRNAs. Our perspective led to predict putative T. gondii lncRNA that potentially could act mediating DNA damage repair pathways, opening a new study field to validate this kind of adaptive mechanisms of T. gondii in response to stress conditions.
    Keywords:   Toxoplasma gondii ; Differentiation; Non-coding RNAs; Stress response
    DOI:  https://doi.org/10.1038/s41598-024-79204-6
  4. J Biol Chem. 2024 Nov 12. pii: S0021-9258(24)02481-5. [Epub ahead of print] 107979
    Cap-independent translation directs stress-induced differentiation of the protozoan parasite Toxoplasma gondii.
    Vishakha Dey, Michael J Holmes, Matheus S Bastos, Ronald C Wek, William J Sullivan.
      Translational control mechanisms modulate microbial latency of eukaryotic pathogens, enabling them to evade immunity and drug treatments. The protozoan parasite Toxoplasma gondii persists in hosts by differentiating from proliferative tachyzoites to latent bradyzoites, which are housed inside tissue cysts. Transcriptional changes facilitating bradyzoite conversion are mediated by a Myb domain transcription factor called BFD1, whose mRNA is present in tachyzoites but not translated into protein until stress is applied to induce differentiation. We addressed the mechanisms by which translational control drives BFD1 synthesis in response to stress-induced parasite differentiation. Using biochemical and molecular approaches, we show that the 5'-leader of BFD1 mRNA is sufficient for preferential translation upon stress. The translational control of BFD1 mRNA is maintained when ribosome assembly near its 5'-cap is impaired by insertion of a 5'-proximal stem-loop and upon knockdown of the Toxoplasma cap-binding protein, eIF4E1. Moreover, we determined that a trans-acting RNA-binding protein called BFD2/ROCY1 is necessary for cap-independent translation of BFD1 through its binding to the 5'-leader. Translation of BFD2 mRNA is also suggested to be preferentially induced under stress, but by a cap-dependent mechanism. These results show that translational control and differentiation in Toxoplasma proceed through cap-independent mechanisms in addition to canonical cap-dependent translation. Our identification of cap-independent translation in protozoa underscores the antiquity of this mode of gene regulation in cellular evolution and its central role in stress-induced life-cycle events.
    Keywords:  Toxoplasma; gene expression; parasite; stress response; translation
    DOI:  https://doi.org/10.1016/j.jbc.2024.107979
  5. Mol Biochem Parasitol. 2024 Nov 07. pii: S0166-6851(24)00048-3. [Epub ahead of print]260 111655
    Designing a multi-epitope subunit vaccine against Toxoplasma gondii through reverse vaccinology approach.
    Nadim Ahmed, Nurul Amin Rani, Tanjin Barketullah Robin, Md Nafij Mashrur, Md Minhajul Islam Shovo, Anindita Ash Prome, Sadia Sultana, Mst Rubaiat Nazneen Akhand.
      The parasite Toxoplasma gondii, or T. gondii, is zoonotic that both individuals as well as animals can contract resulting in toxoplasmosis, a life-threatening illness. We used an immunoinformatic technique in our research to construct a vaccine with multi-epitopes so that it can decrease the devastating impact caused by this dangerous parasite. In order to construct the vaccine, GRA6 and MIC3 proteins were targeted, which are engaged in T. gondii identification, infection, and immune response. Novel epitopes for linear B lymphocytes (LBL), cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL) were found by epitope mapping, every anticipated epitope was assessed through rigorous screening to determine the top choices for epitopes which were entirely preserved, very antigenic in nature, nonallergenic, and nontoxic. 4 CTLs, 3 HTLs and 4 LBL epitopes were chosen and combined along with proper linkers and adjuvants to design a vaccine with several epitopes. Linkers as well as adjuvants were provided to make the vaccine more immunogenic, antigenic, and stable. The proposed vaccination was identified to possess the necessary biophysical properties, be soluble, extremely antigenic, and non-allergic. Reliability of the vaccine design was demonstrated by secondary along with tertiary structure prediction. It was anticipated that the vaccine's three-dimensional structure would likely link up with TLR-2 and TLR-4 via the investigation of molecular docking. TLR-2 and TLR-4 are crucial for the parasite's invasion and the body's response. In our docking investigation, both TLRs demonstrated strong binding affinities utilizing the vaccine structure. After that, the vaccine construct's elevated expression rate, which was observed in Escherichia coli strain K12, was confirmed by an investigation using in silico cloning and codon adaptation. The results of the research are really encouraging and some properties of the vaccine were found to be significantly better than existing the T. gondii multi-epitope vaccination based on the same proteins. Nonetheless, in vivo trials are strongly suggested for potential future studies.
    Keywords:  Antigenicity; Codon adaptation; GRA6 and MIC3 proteins; Immunoinformatic approach; In silico cloning; Molecular docking; Multi epitope peptide; Toxoplasma gondii
    DOI:  https://doi.org/10.1016/j.molbiopara.2024.111655
  6. Trends Parasitol. 2024 Nov 08. pii: S1471-4922(24)00307-6. [Epub ahead of print]
    Sec14 proteins in the apicomplexan parasites Plasmodium and Toxoplasma.
    Florian Lauruol, Dave Richard.
      Sec14 domain proteins are broadly conserved in eukaryotes and play essential roles in numerous cellular processes. Limited data on Sec14 proteins of apicomplexan parasites suggest that they could be important for their survival. The development of fungi-specific Sec14 inhibitors raises the tantalizing possibility that their apicomplexan counterparts might also be targeted.
    Keywords:  Plasmodium: Toxoplasma; Sec14; apicomplexan; malaria; phosphoinositides
    DOI:  https://doi.org/10.1016/j.pt.2024.10.018
  7. mBio. 2024 Nov 13. e0274024
    When more sugar is better-a GPI side chain modification results in a less virulent phenotype during a protozoan infection.
    Frank Seeber.
      The assembly and function of side chain modifications of glycosylphosphatidylinositol (GPI) units (anchors or free forms) are poorly defined. In a recent study, two enzymes, PIGJ and PIGE, of the protozoan parasite Toxoplasma gondii were identified and shown to be involved in the assembly of such GPI side chains (J. A. Alvarez, E. Gas-Pascual, S. Malhi, J. C. Sánchez-Arcila, et al., mBio 15:e00527-24, 2024, https://doi.org/10.1128/mbio.00527-24). PIGJ adds N-acetylgalactosamine to the GPI core structure, while PIGE subsequently adds a terminal glucose. Deletion of PIGJ resulted in the loss of the side chain and, strikingly, increased mortality in infected mice, in contrast to PIGE knockouts. Absence of the side chain led to increased binding of the scavenger receptor CD36 to mutant parasites. In galectin-3 knockout mice, the virulent phenotype of side-chain-deficient parasites was largely lost. While the exact mechanisms remain to be elucidated by more experiments, these findings provide the first evidence for the importance of GPI side chains in parasite-host interactions in vivo.
    Keywords:  Toxoplasma gondii; glycobiology; parasitology
    DOI:  https://doi.org/10.1128/mbio.02740-24
  8. Cell Chem Biol. 2024 Nov 05. pii: S2451-9456(24)00441-0. [Epub ahead of print]
    Bioluminescence assay of lysine deacylase sirtuin activity.
    Alexandria N Van Scoyk, Orlando Antelope, Donald E Ayer, Randall T Peterson, Anthony D Pomicter, Shawn C Owen, Michael W Deininger.
      Lysine acylation can direct protein function, localization, and interactions. Sirtuins deacylate lysine toward maintaining cellular homeostasis, and their aberrant expression contributes to the pathogenesis of multiple conditions, including cancer. Measuring sirtuins' activity is essential to exploring their potential as therapeutic targets, but accurate quantification is challenging. We developed "SIRTify", a high-sensitivity assay for measuring sirtuin activity in vitro and in vivo. SIRTify is based on a split-version of the NanoLuc luciferase consisting of a truncated, catalytically inactive N-terminal moiety (LgBiT) that complements with a high-affinity C-terminal peptide (p86) to form active luciferase. Acylation of two lysines within p86 disrupts binding to LgBiT and abates luminescence. Deacylation by sirtuins reestablishes p86 and restores binding, generating a luminescence signal proportional to sirtuin activity. Measurements accurately reflect reported sirtuin specificity for lysine-acylations and confirm the effects of sirtuin modulators. SIRTify quantifies lysine deacylation dynamics and may be adaptable to monitoring additional post-translational modifications.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.10.006
  9. Parasite Immunol. 2024 Nov;46(11): e13073
    Toxoplasma gondii Infection of BALB/c Mice Perturbs Host Neurochemistry.
    Aisha A Abdelati Abdelsalam, Stuart Woods, Selina Henriquez, Lucy Curran, Gareth Westrop, Craig W Roberts.
      Toxoplasma gondii infection has been associated with psychoneurological disease in humans and behavioural changes in rodents. However, the mechanisms accounting for this have not been fully described and in some cases could be argued to reflect the severe neuropathology that some mice suffer during infection. Herein we employ a multi-omics approach to extensively examine BALB/c mice that are resistant to toxoplasmic encephalitis. Using a combination of LCMS (liquid chromatography-mass spectrometry) and RNAseq we demonstrate that infection alters the neurochemistry and the transcriptome of the brains of BALB/c mice. Notable changes to tryptophan, purine, arginine, nicotinamide and carnitine metabolism were observed in infected mice and this was accompanied with changes to the levels of a number of transcripts associated with enzymes these metabolic pathways. In addition, changes were seen in transcripts of many immunologically important genes known to contribute to immunity to T. gondii. Changes in the levels of additional transcripts during infection have previously been associated with psychoneurological diseases. The results demonstrate that the BALB/c mouse, with its relatively mild neurological disease, is a useful model for characterising the effects of T. gondii infection on murine neurochemistry. The results also implicate specific biochemical pathways in mediating these changes and should inform further mechanistic studies and suggest therapeutic targets.
    DOI:  https://doi.org/10.1111/pim.13073
  10. Comput Biol Chem. 2024 Nov 09. pii: S1476-9271(24)00263-9. [Epub ahead of print]113 108275
    Pharmacophore-guided in-silico discovery of SIRT1 inhibitors for targeted cancer therapy.
    Deepak Sharma, Rajiniraja Muniyan.
      Epigenetic modifier, Sirtuin (SIRTs) is a family of seven isoforms (SIRT1-7) and nicotinamide adenine dinucleotide (NAD+) dependent class III histone deacetylase (HDACs) protein. SIRT1 in association with the p53 protein can regulate crucial cell processes such as glucose metabolism, lipid metabolism, mitochondrial biogenesis, DNA repair, oxidative stress, apoptosis, and inflammation through the process of deacetylation. When SIRT1 deacetylates p53, it loses its tumor suppression property. To promote apoptosis and decrease cell proliferation by inhibiting SIRT1 protein and ultimately raising the acetylation of p53 to regain its tumor suppressor function. Though we have many SIRT1 protein inhibitors, they exhibited off-target effects and inefficiency at the clinical trial stage. This study has been executed to identify more potentially effective and reliable SIRT1 inhibitors that can perform better than the existing options. To do so, pharmacophore-based screening of compound libraries followed by virtual screening, pharmacokinetic, drug-likeness, and toxicity studies were conducted which gave 42 compounds to evaluate further. Subsequently, exhaustive molecular docking and molecular dynamics simulation predicted four potential hits to inhibit the SIRT1 protein better than the reference compound. Further studies such as principal components analysis, free energy landscape, and estimation of binding free energy were done which concluded Hit4 (PubChem ID: 55753455) to be a novel and potent SIRT1 small molecule inhibitor among the others. The total binding free energy for Hit4 was found to be -44.68 kcal/mol much better than the reference complex i.e., -29.38 kcal/mol.
    Keywords:  Anticancer; Deacetylation; Epigenetic modification; Molecular docking; Molecular dynamics simulation; Sirtuin
    DOI:  https://doi.org/10.1016/j.compbiolchem.2024.108275
  11. Biochim Biophys Acta Mol Cell Res. 2024 Nov 13. pii: S0167-4889(24)00219-2. [Epub ahead of print] 119876
    Iron‑sulfur cluster biogenesis and function in Apicomplexa parasites.
    Eléa Renaud, Ambre Maupin, Sébastien Besteiro.
      Iron‑sulfur cluster are ubiquitous and ancient protein cofactors that support a wide array of essential cellular functions. In eukaryotes, their assembly requires specific and dedicated machineries in each subcellular compartment. Apicomplexans are parasitic protists that are collectively responsible for a significant burden on the health of humans and other animals, and most of them harbor two organelles of endosymbiotic origin: a mitochondrion, and a plastid of high metabolic importance called the apicoplast. Consequently, apicomplexan parasites have distinct iron‑sulfur cluster assembly machineries located to their endosymbiotic organelles, as well as a cytosolic pathway. Recent findings have not only shown the importance of iron‑sulfur cluster assembly for the fitness of these parasites, but also highlighted parasite-specific features that may be promising for the development of targeted anti-parasitic strategies.
    Keywords:  Drug target; Iron‑sulfur cluster; Metabolism; Plasmodium; Toxoplasma
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119876
  12. Sci Adv. 2024 Nov 15. 10(46): eadp7423
    Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
    Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I Stunault, Hao Zhang, Xiangfeng Niu, Marissa A Laramie, Jasmin Sponagel, Leah P Shriver, Gary J Patti, Vitaly A Klyachko, Ghazaleh Ashrafi.
      Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval-functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.
    DOI:  https://doi.org/10.1126/sciadv.adp7423
  13. Molecules. 2024 Oct 24. pii: 5024. [Epub ahead of print]29(21):
    The Intestinal Barrier Protective Effect of Indole Aldehyde Derivatives on Acute Toxoplasma gondii Infection.
    Jieqiong Wang, Weifeng Yan, Xu Cheng, Yonggang Tong, Sihong Wang, Chunmei Jin.
      Toxoplasmosis, a zoonotic infection caused by Toxoplasma gondii (T. gondii), poses a significant risk to human health and public safety. Despite the availability of clinical treatments, none effectively mitigate the intestinal barrier damage, which is the primary defense against T. gondii invasion. This study introduced aldehyde groups into the indole scaffold of a peptide-like structure to investigate the protective effects of these indole aldehyde derivatives on the intestinal barrier in mice with acute T. gondii infection. This approach leveraged the propensity of peptides and aldehyde groups to form hydrogen bonds. We synthesized a range of indole derivatives using the Vilsmeier-Haack reaction and evaluated their intestinal barrier protective effects both in vitro and in vivo. Our findings revealed that indole derivatives A1 (1-Formyl-1H-indole-3-acetonitrile), A3 (Indole-3-carboxaldehyde), A5 (2-Chloro-1H-indole-3-carboxaldehyde), A8 (1-Methyl-indole-3-carboxaldehyde), and A9 (1-Methyl-2-phenyl-1H-indole-3-carboxaldehyde) demonstrated a higher selectivity index compared to the positive control, spiramycin. These derivatives enhanced gastrointestinal motility, increased glutathione (GSH) levels in the small intestine, and reduced malondialdehyde (MDA) and nitric oxide (NO) levels in the small intestine tissue and diamine oxidase (DAO) and NO levels in the serum of infected mice. Notably, A3 exhibited comparable anti-T. gondii tachyzoites activity in the peritoneal cavity. Molecular docking studies indicated that the aldehyde group on the indole scaffold not only formed a hydrogen bond with NTPase-II but also interacted with TgCDPK1 through hydrogen bonding. Among the derivatives, A3 showed promising intestinal barrier protective effects in mice with acute T. gondii infection. This research suggests that indole derivatives could serve as a potential therapeutic strategy for intestinal diseases induced by T. gondii, offering a novel direction for treating intestinal barrier damage and providing valuable insights for the chemical modification of drugs targeting T. gondii. Furthermore, it contributes to the advancement of therapeutic approaches for toxoplasmosis.
    Keywords:  Vilsmeier–Haack reaction; anti-T. gondii; indole derivatives; intestinal barrier protective effect
    DOI:  https://doi.org/10.3390/molecules29215024
  14. Med Oncol. 2024 Nov 12. 42(1): 1
    Dissecting the epigenetic orchestra of HDAC isoforms in breast cancer development: a review.
    Maria Debbarma, Kakali Sarkar, Samir Kumar Sil.
      Epigenetic modulators have recently emerged as potential targets in cancer therapy. Breast cancer, the second leading cause of cancer-related deaths among women globally and the most common cancer in India, continues to have a low survival rate despite available treatments. This underscores the urgent need for more effective therapeutic strategies. Histone deacetylases (HDACs), a prominent class of epigenetic modulators, are frequently overexpressed in various cancers, including breast cancer, making them and their downstream pathways, a focus of current research, aiming to develop more effective and less invasive treatments that could help overcome chemoresistance and enhance patient outcomes. Despite the growing body of evidences, a comprehensive and consolidated review on molecular intricacy behind the HDAC-mediated epigenetic regulation of breast cancer is conspicuously absent. Therefore, this review aims to open doors for future research by exploring the evolving role of HDACs, their molecular mechanisms, and their potential as therapeutic targets in breast cancer treatment.
    Keywords:  Breast cancer; Epigenetics; Epitarget; Histone deacetylases; Mechanistic role
    DOI:  https://doi.org/10.1007/s12032-024-02553-9
  15. Trends Biochem Sci. 2024 Nov 07. pii: S0968-0004(24)00230-5. [Epub ahead of print]
    A two-way relationship between histone acetylation and metabolism.
    Evelina Charidemou, Antonis Kirmizis.
      A link between epigenetics and metabolism was initially recognized because the cellular metabolic state is communicated to the genome through the concentration of intermediary metabolites that are cofactors of chromatin-modifying enzymes. Recently, an additional interaction was postulated due to the capacity of the epigenome to store substantial amounts of metabolites that could become available again to cellular metabolite pools. Here, we focus on histone acetylation and review recent evidence illustrating this reciprocal relationship: in one direction, signaling-induced acetyl-coenzyme A (acetyl-CoA) changes influence histone acetylation levels to regulate genomic functions, and in the opposite direction histone acetylation acts as an acetate reservoir to directly affect downstream acetyl-CoA-mediated metabolism. This review highlights the current understanding, experimental challenges, and future perspectives of this bidirectional interplay.
    Keywords:  acetate reservoir; aging; epigenetics; genome function; hyperacetylated histones; metabolic disease
    DOI:  https://doi.org/10.1016/j.tibs.2024.10.005
  16. Cell Rep Methods. 2024 Nov 06. pii: S2667-2375(24)00294-7. [Epub ahead of print] 100904
    Elucidating the spatiotemporal dynamics of glucose metabolism with genetically encoded fluorescent biosensors.
    Xie Li, Xueyi Wen, Weitao Tang, Chengnuo Wang, Yaqiong Chen, Yi Yang, Zhuo Zhang, Yuzheng Zhao.
      Glucose metabolism has been well understood for many years, but some intriguing questions remain regarding the subcellular distribution, transport, and functions of glycolytic metabolites. To address these issues, a living cell metabolic monitoring technology with high spatiotemporal resolution is needed. Genetically encoded fluorescent sensors can achieve specific, sensitive, and spatiotemporally resolved metabolic monitoring in living cells and in vivo, and dozens of glucose metabolite sensors have been developed recently. Here, we highlight the importance of tracking specific intermediate metabolites of glycolysis and glycolytic flux measurements, monitoring the spatiotemporal dynamics, and quantifying metabolite abundance. We then describe the working principles of fluorescent protein sensors and summarize the existing biosensors and their application in understanding glucose metabolism. Finally, we analyze the remaining challenges in developing high-quality biosensors and the huge potential of biosensor-based metabolic monitoring at multiple spatiotemporal scales.
    Keywords:  CP: Metabolism
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100904
  17. Nat Commun. 2024 Nov 12. 15(1): 9529
    Nuclear localization of MTHFD2 is required for correct mitosis progression.
    Natalia Pardo-Lorente, Anestis Gkanogiannis, Luca Cozzuto, Antoni Gañez Zapater, Lorena Espinar, Ritobrata Ghose, Jacqueline Severino, Laura García-López, Rabia Gül Aydin, Laura Martin, Maria Victoria Neguembor, Evangelia Darai, Maria Pia Cosma, Laura Batlle-Morera, Julia Ponomarenko, Sara Sdelci.
      Subcellular compartmentalization of metabolic enzymes establishes a unique metabolic environment that elicits specific cellular functions. Indeed, the nuclear translocation of certain metabolic enzymes is required for epigenetic regulation and gene expression control. Here, we show that the nuclear localization of the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) ensures mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability, including the methyltransferases KMT5A and DNMT3B. Loss of MTHFD2 induces severe methylation defects and impedes correct mitosis completion. MTHFD2 deficient cells display chromosome congression and segregation defects and accumulate chromosomal aberrations. Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, whereas restricting MTHFD2 to the nucleus is sufficient to ensure correct mitotic progression. Our discovery uncovers a nuclear role for MTHFD2, supporting the notion that translocation of metabolic enzymes to the nucleus is required to meet precise chromatin needs.
    DOI:  https://doi.org/10.1038/s41467-024-51847-z
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