bims-toxgon 2024-07-14 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2024‒07‒14
sixteen papers selected by
Lakesh Kumar, BITS Pilani

Selective host autophagy is induced during the intracellular parasite Toxoplasma gondii infection controlling amino acid levels.
CRISPR-based functional profiling of the Toxoplasma gondii genome during acute murine infection.
The Effects and Mechanism of ATM Kinase Inhibitors in Toxoplasma gondii.
Research Progress on the Association between Schizophrenia and Toxoplasma gondii Infection.
Seeing the unseen: illuminating Toxoplasma gondii's metabolic manipulation.
Metabolic changes in Toxoplasma gondii-infected host cells measured by autofluorescence imaging.
In vitro and in vivo activity evaluation and mode of action of broxaldine on Toxoplasma gondii.
4D label-free proteomic analysis reveals key potential pathways of Toxoplasma invasion into the central nervous system.
The Toxoplasma secreted effector TgWIP modulates dendritic cell motility by activating host tyrosine phosphatases Shp1 and Shp2.
The Toxoplasma secreted effector TgWIP modulates dendritic cell motility by activating host tyrosine phosphatases Shp1 and Shp2.
Targeting histone deacetylases: Emerging applications beyond cancer.
Mitochondrial sirtuin 3 and role of natural compounds: the effect of post-translational modifications on cellular metabolism.
The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases.
Acetylation, ADP-ribosylation and methylation of malate dehydrogenase.
Histone Deacetylases in Retinoblastoma.
Discovery and characterization of a new class of NAD+-independent SIRT1 activators.

mSphere. 2024 Jul 09. e0036924

Selective host autophagy is induced during the intracellular parasite Toxoplasma gondii infection controlling amino acid levels.

Matthew D White, Rajendra K Angara, Leticia Torres Dias, Dhananjay D Shinde, Vinai C Thomas, Leonardo Augusto.

  Toxoplasma gondii, a widespread parasite, has the ability to infect nearly any nucleated cell in warm-blooded vertebrates. It is estimated that around 2 billion people globally have been infected by this pathogen. Although most healthy individuals can effectively control parasite replication, certain parasites may evade the immune response, establishing cysts in the brain that are refractory to the immune system and resistant to available drugs. For its chronic persistence in the brain, the parasite relies on host cells' nutrients, particularly amino acids and lipids. Therefore, understanding how latent parasites persist in the brain is crucial for identifying potential drug targets against chronic forms. While shielded within parasitophorous vacuoles (PVs) or cysts, Toxoplasma exploits the host endoplasmic reticulum (ER) metabolism to sustain its persistence in the brain, resulting in host neurological alterations. In this study, we demonstrate that T. gondii disrupts the host ER homeostasis, resulting in the accumulation of unfolded protein within the host ER. The host counters this stress by initiating an autophagic pathway known as ER-phagy, which breaks down unfolded proteins into amino acids, promoting their recycling. Our findings unveil the underlying mechanisms employed by T. gondii to exploit host ER and lysosomal pathways, enhancing nutrient levels during infection. These insights provide new strategies for the treatment of toxoplasmosis.IMPORTANCE: Intracellular parasites employ several mechanisms to manipulate the cellular environment, enabling them to persist in the host. Toxoplasma gondii, a single-celled parasite, possesses the ability to infect virtually any nucleated cell of warm-blooded vertebrates, including nearly 2 billion people worldwide. Unfortunately, existing treatments and immune responses are not entirely effective in eliminating the chronic persisting forms of the parasite. This study reveals that T. gondii induces the host's autophagic pathway to boost amino acid levels in infected cells. The depletion of amino acids, in turn, influences the persistence of the parasite's chronic forms. Significantly, our investigation establishes the crucial role of host endoplasmic reticulum (ER)-phagy in the parasite's persistence within the host during latent infection.

Keywords:  ER-phagy; Toxoplasma gondii; amino acid; behavior; endoplasmic reticulum

DOI:  https://doi.org/10.1128/msphere.00369-24
Nat Microbiol. 2024 Jul 08.

CRISPR-based functional profiling of the Toxoplasma gondii genome during acute murine infection.

Christopher J Giuliano, Kenneth J Wei, Faye M Harling, Benjamin S Waldman, Madeline A Farringer, Elizabeth A Boydston, Tammy C T Lan, Raina W Thomas, Alice L Herneisen, Allen G Sanderlin, Isabelle Coppens, Jeffrey D Dvorin, Sebastian Lourido.

Examining host-pathogen interactions in animals can capture aspects of infection that are obscured in cell culture. Using CRISPR-based screens, we functionally profile the entire genome of the apicomplexan parasite Toxoplasma gondii during murine infection. Barcoded gRNAs enabled bottleneck detection and mapping of population structures within parasite lineages. Over 300 genes with previously unknown roles in infection were found to modulate parasite fitness in mice. Candidates span multiple axes of host-parasite interaction. Rhoptry Apical Surface Protein 1 was characterized as a mediator of host-cell tropism that facilitates repeated invasion attempts. GTP cyclohydrolase I was also required for fitness in mice and druggable through a repurposed compound, 2,4-diamino-6-hydroxypyrimidine. This compound synergized with pyrimethamine against T. gondii and malaria-causing Plasmodium falciparum parasites. This work represents a complete survey of an apicomplexan genome during infection of an animal host and points to novel interfaces of host-parasite interaction.

DOI: https://doi.org/10.1038/s41564-024-01754-2
Int J Mol Sci. 2024 Jun 25. pii: 6947. [Epub ahead of print]25(13):

The Effects and Mechanism of ATM Kinase Inhibitors in Toxoplasma gondii.

Yangfei Xue, Zhu Ying, Fei Wang, Meng Yin, Yanqun Pei, Jing Liu, Qun Liu.

  Toxoplasma gondii, an important opportunistic pathogen, underscores the necessity of developing novel therapeutic drugs and identifying new drug targets. Our findings indicate that the half-maximal inhibitory concentrations (IC50) of KU60019 and CP466722 (abbreviated as KU and CP) against T. gondii are 0.522 μM and 0.702 μM, respectively, with selection indices (SI) of 68 and 10. Treatment with KU and CP affects the in vitro growth of T. gondii, inducing aberrant division in the daughter parasites. Transmission electron microscopy reveals that KU and CP prompt the anomalous division of T. gondii, accompanied by cellular enlargement, nuclear shrinkage, and an increased dense granule density, suggesting potential damage to parasite vesicle transport. Subsequent investigations unveil their ability to modulate the expression of certain secreted proteins and FAS II (type II fatty acid synthesis) in T. gondii, as well as including the dot-like aggregation of the autophagy-related protein ATG8 (autophagy-related protein 8), thereby expediting programmed death. Leveraging DARTS (drug affinity responsive target stability) in conjunction with 4D-Label-free quantitative proteomics technology, we identified seven target proteins binding to KU, implicated in pivotal biological processes such as the fatty acid metabolism, mitochondrial ATP transmission, microtubule formation, and Golgi proteins transport in T. gondii. Molecular docking predicts their good binding affinity. Furthermore, KU has a slight protective effect on mice infected with T. gondii. Elucidating the function of those target proteins and their mechanism of action with ATM kinase inhibitors may potentially enhance the treatment paradigm for toxoplasmosis.

Keywords:  ATM kinase inhibitors; Toxoplasma gondii; cell division; protein secretion

DOI:  https://doi.org/10.3390/ijms25136947
Biomed Environ Sci. 2024 Jun 20. 37(6): 647-660

Research Progress on the Association between Schizophrenia and Toxoplasma gondii Infection.

Yi Ting Zhu, Xiao Hui Yang, Miao Ru Chen, Yu Hu, Yun Feng Chang, Xiang Wu.

  Toxoplasma gondii( T. gondii or Tg), is an obligatory intracellular parasite with humans as its intermediate hosts. In recent years, significant correlations between T. gondii infection and schizophrenia have been reported, including the possible mediating mechanisms. Currently, mechanisms and hypotheses focus on central neurotransmitters, immunity, neuroinflammation, and epigenetics; however, the exact underlying mechanisms remain unclear. In this article, we review the studies related to T. gondii infection and schizophrenia, particularly the latest research progress. Research on dopamine (DA) and other neurotransmitters, the blood-brain barrier, inflammatory factors, disease heterogeneity, and other confounders is also discussed. In addition, we also summarized the results of some new epidemiological investigations.

Keywords:  Epigenetics; Immunity; Neuroinflammation; Neurotransmitters; Schizophrenia; Toxoplasma gondii

DOI:  https://doi.org/10.3967/bes2024.071
mBio. 2024 Jul 12. e0121124

Seeing the unseen: illuminating Toxoplasma gondii's metabolic manipulation.

Diego Huet, Victoria Jeffers.

  Intracellular infection by a pathogen induces significant rewiring of host cell signaling and biological processes. Understanding how an intracellular pathogen such as Toxoplasma gondii modulates host cell metabolism with single-cell resolution has been challenged by the variability of infection within cultures and difficulties in separating host and parasite metabolic processes. A new study from Gallego-Lopez and colleagues (G. M. Gallego-López, E. C. Guzman, D. E. Desa, L. J. Knoll, M. C. Skala, mBio e00727-24, 2024, https://doi.org/10.1128/mbio.00727-24) applies a quantitative imaging approach to evaluate the host cell metabolism during intracellular infection with Toxoplasma. This study provides important insights into host metabolic responses to Toxoplasma infection and offers a valuable tool to dissect the mechanisms underlying parasite infection and pathophysiology.

Keywords:  apicomplexan parasites; confocal microscopy; host-pathogen interactions; metabolism

DOI:  https://doi.org/10.1128/mbio.01211-24
mBio. 2024 Jul 08. e0072724

Metabolic changes in Toxoplasma gondii-infected host cells measured by autofluorescence imaging.

Gina M Gallego-López, Emmanuel Contreras Guzman, Danielle E Desa, Laura J Knoll, Melissa C Skala.

  Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular parasite that infects warm-blooded vertebrates across the world. In humans, seropositivity rates of T. gondii range from 10% to 90% across communities. Despite its prevalence, few studies address how T. gondii infection changes the metabolism of host cells. In this study, we investigate how T. gondii manipulates the host cell metabolic environment by monitoring the metabolic response over time using noninvasive autofluorescence lifetime imaging of single cells, metabolite analysis, extracellular flux analysis, and reactive oxygen species (ROS) production. Autofluorescence lifetime imaging indicates that infected host cells become more oxidized and have an increased proportion of bound NAD(P)H compared to uninfected controls. Over time, infected cells also show decreases in levels of intracellular glucose and lactate, increases in oxygen consumption, and variability in ROS production. We further examined changes associated with the pre-invasion "kiss and spit" process using autofluorescence lifetime imaging, which also showed a more oxidized host cell with an increased proportion of bound NAD(P)H over 48 hours compared to uninfected controls, suggesting that metabolic changes in host cells are induced by T. gondii kiss and spit even without invasion.IMPORTANCEThis study sheds light on previously unexplored changes in host cell metabolism induced by T. gondii infection using noninvasive, label-free autofluorescence imaging. In this study, we use optical metabolic imaging (OMI) to measure the optical redox ratio (ORR) in conjunction with fluorescence lifetime imaging microscopy (FLIM) to noninvasively monitor single host cell response to T. gondii infection over 48 hours. Collectively, our results affirm the value of using autofluorescence lifetime imaging to noninvasively monitor metabolic changes in host cells over the time course of a microbial infection. Understanding this metabolic relationship between the host cell and the parasite could uncover new treatment and prevention options for T. gondii infections worldwide.

Keywords:  NAD(P)H-binding enzymes; Toxoplasma gondii; host cell metabolism; optical metabolic imaging (OMI); reactive oxygen species; redox biology

DOI:  https://doi.org/10.1128/mbio.00727-24
Int J Parasitol Drugs Drug Resist. 2024 Jun 20. pii: S2211-3207(24)00033-2. [Epub ahead of print]25 100552

In vitro and in vivo activity evaluation and mode of action of broxaldine on Toxoplasma gondii.

Yanhua Qiu, Bintao Zhai, Yubin Bai, Hongling Lin, Lingyu Wu, Wei Luo, Mengyan Shi, Shulin Chen, Jiyu Zhang.

  Toxoplasma gondii (T. gondii) is a highly successful global parasite, infecting about one-third of the world's population and significantly affecting human life and the economy. However, current drugs for toxoplasmosis treatment have considerable side effects, and there is no specific drug to meet current needs. This study aims to evaluate the anti-T. gondii activity of broxaldine (BRO) in vitro and in vivo and explore its mechanism of action. Our results showed that compared to the control group, the invasion rate of tachyzoites in the 4 μg/mL BRO group was only 14.31%, and the proliferation rate of tachyzoites in host cells was only 1.23%. Furthermore, BRO disrupted the lytic cycle of T. gondii and reduced the size and number of cysts in vitro. A mouse model of acute toxoplasmosis reported a 41.5% survival rate after BRO treatment, with reduced parasite load in tissues and blood. The subcellular structure of T. gondii was observed, including disintegration of T. gondii, mitochondrial swelling, increased liposomes, and the presence of autophagic lysosomes. Further investigation revealed enhanced autophagy, increased neutral lipids, and decreased mitochondrial membrane potential in T. gondii treated with BRO. The results also showed a significant decrease in ATP levels. Overall, BRO demonstrates good anti-T. gondii activity in vitro and in vivo; therefore, it has the potential to be used as a lead compound for anti-T. gondii treatment.

Keywords:  Autophagy; Broxaldine; Mitochondrial dysfunction; Neutral lipid; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.ijpddr.2024.100552
Int Immunopharmacol. 2024 Jul 11. pii: S1567-5769(24)01139-1. [Epub ahead of print]138 112618

4D label-free proteomic analysis reveals key potential pathways of Toxoplasma invasion into the central nervous system.

Zhaowen Ren, Zipeng Yang, Hao Yuan, Yining Song, Houjing He, Linchong Nie, Xiaohu Wang, Zi-Guo Yuan, Xiu-Xiang Zhang.

  Toxoplasma gondii is a successful parasite capable of infecting a wide range of warm-blooded animals, including people, livestock, and wildlife. In individuals with intact immune function, T. gondii can invade the host brain tissue by altering the blood-brain barrier permeability, leading to chronic infection. Proteins play crucial regulatory roles in disease progression. By monitoring changes in proteins, a deeper understanding of the molecular mechanisms underlying host resistance to infection and the potential pathogenic mechanisms of pathogens can be gained. This study analyzed differential protein expression and associated signaling pathways in mouse brain tissues during acute and chronic T. gondii infection using proteomic and bioinformatics methods. The results showed that during acute and chronic T. gondii infection stages, 74 and 498 differentially expressed proteins (DEPs) were identified in mouse brain tissue, respectively. Among them, 45 and 309 were up-regulated, while 29 and 189 were down-regulated. GO and KEGG analyses revealed that some of these DEPs were implicated in host immunity, pathogen immune evasion, and T. gondii invasion of the central nervous system, particularly interleukin production and secretion, complement system activation, and alterations in tight junction pathways. Notably, the upregulation of Rab13 was identified as a potential molecular mechanism for T. gondii to regulate blood-brain barrier permeability and facilitate central nervous system invasion. Our findings provided fundamental data for understanding host control of Toxoplasmosis infection and offered new insights into parasite immune evasion and invasion mechanisms within the central nervous system. These insights are crucial for developing strategies to prevent the establishment of chronic T. gondii infection.

Keywords:  4D label-free; Brain proteome; Pathogen-host interaction; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.intimp.2024.112618
Cell Mol Life Sci. 2024 Jul 09. 81(1): 294

The Toxoplasma secreted effector TgWIP modulates dendritic cell motility by activating host tyrosine phosphatases Shp1 and Shp2.

Pavel Morales, Abbigale J Brown, Lamba Omar Sangaré, Sheng Yang, Simon V N P Kuihon, Baoyu Chen, Jeroen P J Saeij.

  The obligate intracellular parasite Toxoplasma gondii causes life-threatening toxoplasmosis to immunocompromised individuals. The pathogenesis of Toxoplasma relies on its swift dissemination to the central nervous system through a 'Trojan Horse' mechanism using infected leukocytes as carriers. Previous work found TgWIP, a protein secreted from Toxoplasma, played a role in altering the actin cytoskeleton and promoting cell migration in infected dendritic cells (DCs). However, the mechanism behind these changes was unknown. Here, we report that TgWIP harbors two SH2-binding motifs that interact with tyrosine phosphatases Shp1 and Shp2, leading to phosphatase activation. DCs infected with Toxoplasma exhibited hypermigration, accompanying enhanced F-actin stress fibers and increased membrane protrusions such as filopodia and pseudopodia. By contrast, these phenotypes were abrogated in DCs infected with Toxoplasma expressing a mutant TgWIP lacking the SH2-binding motifs. We further demonstrated that the Rho-associated kinase (Rock) is involved in the induction of these phenotypes, in a TgWIP-Shp1/2 dependent manner. Collectively, the data uncover a molecular mechanism by which TgWIP modulates the migration dynamics of infected DCs in vitro.

Keywords:   TgWIP; Toxoplasma ; Dendritic cells; Dissemination; Shp1; Shp2

DOI:  https://doi.org/10.1007/s00018-024-05283-3
Res Sq. 2024 Jun 26. pii: rs.3.rs-4539584. [Epub ahead of print]

The Toxoplasma secreted effector TgWIP modulates dendritic cell motility by activating host tyrosine phosphatases Shp1 and Shp2.

Pavel Morales, Abbigale J Brown, Lamba Omar Sangare, Sheng Yang, Simon Kuihon, Baoyu Chen, Jeroen Saeij.

The obligate intracellular parasite Toxoplasma gondii causes life-threatening toxoplasmosis to immunocompromised individuals. The pathogenesis of Toxoplasma relies on its swift dissemination to the central nervous system through a 'Trojan Horse' mechanism using infected leukocytes as carriers. Previous work found Tg WIP, a protein secreted from Toxoplasma , played a role in altering the actin cytoskeleton and promoting cell migration in infected dendritic cells (DCs). However, the mechanism behind these changes was unknown. Here, we report that Tg WIP harbors two SH2-binding motifs that interact with tyrosine phosphatases Shp1 and Shp2, leading to phosphatase activation. DCs infected with Toxoplasma exhibited hypermigration, accompanying enhanced F-actin stress fibers and increased membrane protrusions such as filopodia and pseudopodia. By contrast, these phenotypes were abrogated in DCs infected with Toxoplasma expressing a mutant Tg WIP lacking the SH2-binding motifs. We further demonstrated that the Rho-associated kinase (Rock) is involved in the induction of these phenotypes, in a Tg WIP-Shp1/2 dependent manner. Collectively, the data uncover a molecular mechanism by which Tg WIP modulates the migration dynamics of infected DCs in vitro .

DOI: https://doi.org/10.21203/rs.3.rs-4539584/v1
Drug Discov Today. 2024 Jul 10. pii: S1359-6446(24)00219-8. [Epub ahead of print] 104094

Targeting histone deacetylases: Emerging applications beyond cancer.

Yasir S Raouf.

  Histone deacetylases (HDACs) are a special class of hydrolase enzymes, which through epigenetic control of cellular acetylation, play regulatory roles in various processes including chromatin packing, cytokine signaling, and gene expression. Widespread influence on cell function has implicated dysregulated HDAC activity in human disease. While traditionally an oncology target, in the past decade, there has been a notable rise in inhibition strategies within several therapeutic areas beyond cancer. This review highlights advances in four of these indications, neurodegenerative disease, metabolic disorders, cardiovascular disease, and viral infections, focusing on the role of deacetylases in disease, small molecule drug discovery, and clinical progress.

Keywords:  cardiovascular disease; drug discovery; histone deacetylase inhibitors; metabolic disorders; neurodegenerative disease; posttranslational modifications; virology

DOI:  https://doi.org/10.1016/j.drudis.2024.104094
Crit Rev Biochem Mol Biol. 2024 Jul 11. 1-22

Mitochondrial sirtuin 3 and role of natural compounds: the effect of post-translational modifications on cellular metabolism.

Francesca Oppedisano, Salvatore Nesci, Anna Spagnoletta.

  Sirtuins (SIRTs) are a family of proteins with enzymatic activity. In particular, they are a family of class III NAD+-dependent histone deacetylases and ADP-ribosyltransferases. NAD+-dependent deac(et)ylase activities catalyzed by sirtuin include ac(et)ylation, propionylation, butyrylation, crotonylation, manylation, and succinylation. Specifically, human SIRT3 is a 399 amino acid protein with two functional domains: a large Rossmann folding motif and NAD+ binding, and a small complex helix and zinc-binding motif. SIRT3 is widely expressed in mitochondria-rich tissues and is involved in maintaining mitochondrial integrity, homeostasis, and function. Moreover, SIRT3 regulates related diseases, such as aging, hepatic, kidney, neurodegenerative and cardiovascular disease, metabolic diseases, and cancer development. In particular, one of the most significant and damaging post-translational modifications is irreversible protein oxidation, i.e. carbonylation. This process is induced explicitly by increased ROS production due to mitochondrial dysfunction. SIRT3 is carbonylated by 4-hydroxynonenal at the level of Cys280. The carbonylation induces conformational changes in the active site, resulting in allosteric inhibition of SIRT3 activity and loss of the ability to deacetylate and regulate antioxidant enzyme activity. Phytochemicals and, in particular, polyphenols, thanks to their strong antioxidant activity, are natural compounds with a positive regulatory action on SIRT3 in various pathologies. Indeed, the enzymatic SIRT3 activity is modulated, for example, by different natural polyphenol classes, including resveratrol and the bergamot polyphenolic fraction. Thus, this review aims to elucidate the mechanisms by which phytochemicals can interact with SIRT3, resulting in post-translational modifications that regulate cellular metabolism.

Keywords:  Sirtuins; diseases; health; mitochondria; phytochemical compounds; post-translational modification

DOI:  https://doi.org/10.1080/10409238.2024.2377094
Int J Mol Sci. 2024 Jun 25. pii: 6936. [Epub ahead of print]25(13):

The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases.

Florian Juszczak, Thierry Arnould, Anne-Emilie Declèves.

  Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute kidney injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding a large amount of ATP. They are composed of highly specialized cell types in the glomerulus and subsequent tubular compartments which fine-tune metabolism to meet their numerous and diverse functions. Defective renal cell metabolism, including altered fatty acid oxidation or glycolysis, has been linked to both AKI and CKD. Mitochondria play a vital role in renal metabolism, and emerging research has identified mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) as key regulators of renal cell metabolic adaptation, especially SIRT3. Sirtuins belong to an evolutionarily conserved family of mainly NAD+-dependent deacetylases, deacylases, and ADP-ribosyl transferases. Their dependence on NAD+, used as a co-substrate, directly links their enzymatic activity to the metabolic status of the cell. In the kidney, SIRT3 has been described to play crucial roles in the regulation of mitochondrial function, and the antioxidative and antifibrotic response. SIRT3 has been found to be constantly downregulated in renal diseases. Genetic or pharmacologic upregulation of SIRT3 has also been associated with beneficial renal outcomes. Importantly, experimental pieces of evidence suggest that SIRT3 may act as an important energy sensor in renal cells by regulating the activity of key enzymes involved in metabolic adaptation. Activation of SIRT3 may thus represent an interesting strategy to ameliorate renal cell energetics. In this review, we discuss the roles of SIRT3 in lipid and glucose metabolism and in mediating a metabolic switch in a physiological and pathological context. Moreover, we highlight the emerging significance of other mitochondrial sirtuins, SIRT4 and SIRT5, in renal metabolism. Understanding the role of mitochondrial sirtuins in kidney diseases may also open new avenues for innovative and efficient therapeutic interventions and ultimately improve the management of renal injuries.

Keywords:  SIRT3; SIRT4; SIRT5; glucose metabolism; kidney disease; lipid metabolism; lipotoxicity; metabolic switch; mitochondrial homeostasis; sirtuins

DOI:  https://doi.org/10.3390/ijms25136936
Essays Biochem. 2024 Jul 12. pii: EBC20230080. [Epub ahead of print]

Acetylation, ADP-ribosylation and methylation of malate dehydrogenase.

Misty L Kuhn, John F Rakus, Delphine Quenet.

  Metabolism within an organism is regulated by various processes, including post-translational modifications (PTMs). These types of chemical modifications alter the molecular, biochemical, and cellular properties of proteins and allow the organism to respond quickly to different environments, energy states, and stresses. Malate dehydrogenase (MDH) is a metabolic enzyme that is conserved in all domains of life and is extensively modified post-translationally. Due to the central role of MDH, its modification can alter metabolic flux, including the Krebs cycle, glycolysis, and lipid and amino acid metabolism. Despite the importance of both MDH and its extensively post-translationally modified landscape, comprehensive characterization of MDH PTMs, and their effects on MDH structure, function, and metabolic flux remains underexplored. Here, we review three types of MDH PTMs - acetylation, ADP-ribosylation, and methylation - and explore what is known in the literature and how these PTMs potentially affect the 3D structure, enzymatic activity, and interactome of MDH. Finally, we briefly discuss the potential involvement of PTMs in the dynamics of metabolons that include MDH.

Keywords:  ADP-ribosylation; Acetylation; Malate Dehydrogenase; Metabolon; Methylation; Post-translational modifications

DOI:  https://doi.org/10.1042/EBC20230080
Int J Mol Sci. 2024 Jun 24. pii: 6910. [Epub ahead of print]25(13):

Histone Deacetylases in Retinoblastoma.

Malwina Lisek, Julia Tomczak, Julia Swiatek, Aleksandra Kaluza, Tomasz Boczek.

  Retinoblastoma, a pediatric ocular malignancy, presents significant challenges in comprehending its molecular underpinnings and targeted therapeutic approaches. The dysregulated activity of histone deacetylases (HDACs) has been associated with retinoblastoma pathogenesis, influencing critical cellular processes like cell cycle regulation or retinal ganglion cell apoptosis. Through their deacetylase activity, HDACs exert control over key tumor suppressors and oncogenes, influencing the delicate equilibrium between proliferation and cell death. Furthermore, the interplay between HDACs and the retinoblastoma protein pathway, a pivotal aspect of retinoblastoma etiology, reveals a complex network of interactions influencing the tumor microenvironment. The examination of HDAC inhibitors, encompassing both established and novel compounds, offers insights into potential approaches to restore acetylation balance and impede retinoblastoma progression. Moreover, the identification of specific HDAC isoforms exhibiting varying expression in retinoblastoma provides avenues for personalized therapeutic strategies, allowing for interventions tailored to individual patient profiles. This review focuses on the intricate interrelationship between HDACs and retinoblastoma, shedding light on epigenetic mechanisms that control tumor development and progression. The exploration of HDAC-targeted therapies underscores the potential for innovative treatment modalities in the pursuit of more efficacious and personalized management strategies for this disease.

Keywords:  cancer treatment therapies; chromatic remodeling; gene expression; histone deacetylase inhibitors; retinoblastoma

DOI:  https://doi.org/10.3390/ijms25136910
Pharmacol Res. 2024 Jul 04. pii: S1043-6618(24)00241-X. [Epub ahead of print] 107296

Discovery and characterization of a new class of NAD+-independent SIRT1 activators.

S Della Torre, G Dell'Omo, J Dellavedova, L Palazzolo, E Scanziani, Eberini, A Pinto, N Mitro, P Conti, A Villa, P Ciana.

  The activity of sirtuin 1 (SIRT1, a member of the NAD+-dependent deacetylases family) decreases during aging as NAD+ levels naturally decline, thus increasing the risk of several age-associated diseases. Several sirtuin-activating compounds (STACs) have been developed to counteract the age-associated reduction in SIRT1 activity, and some of them are currently under development in clinical trials. STACs induce SIRT1 activation, either through allosteric activation of the enzyme in the presence of NAD+, or by increasing NAD+ levels by inhibiting its degradation or by supplying a key precursor in biosynthesis. In this study, we have identified (E)-2'-des-methyl sulindac analogues as a novel class of STACs that act also in the absence of NAD+, a peculiar behavior demonstrated through enzymatic and mass spectrometry experiments, both in vitro and in cell lines. The activation of the SIRT1 pathway was confirmed in vivo through gene expression and metabolomics analysis. Our data suggest that these compounds could serve as candidate leads for a novel therapeutic strategy aimed at addressing a key metabolic deficiency that may contribute to metabolic and age-associated diseases.

Keywords:  NAD(+)-dependent deacetylases; ageing-associated diseases; metabolic diseases; sirtuin-activating compounds; sulindac analogues

DOI:  https://doi.org/10.1016/j.phrs.2024.107296