bims-toxgon 2025-05-18 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–05–18
eight papers selected by
Lakesh Kumar, BITS Pilani

AP2X-8 Is Important for Tachyzoite Growth and Bradyzoite Differentiation of Toxoplasma gondii.
Ubiquitin-activating enzyme1 (TgUAE1) acts as a key regulator of Toxoplasma gondii lytic cycle and homeostasis.
Unveiling the impact of cGMP-dependent protein kinase of Neospora caninum on calcium fluxes and egress functions through quantitative phosphoproteome analysis.
Therapeutic applications of exercise in neurodegenerative diseases: focusing on the mechanism of SIRT1.
Endocytic Activity by Apicomplexa Parasites.
Quality control of un-imported mitochondrial proteins at a glance.
Lysine demethylases and cancer.
The role of glutamate dehydrogenase in the ageing brain.

Animals (Basel). 2025 May 07. pii: 1349. [Epub ahead of print]15(9):

AP2X-8 Is Important for Tachyzoite Growth and Bradyzoite Differentiation of Toxoplasma gondii.

Li-Xiu Sun, Meng Wang, Hany M Elsheikha, Shi-Chen Xie, Bao-Quan Fu, Xing-Quan Zhu, Guo-Hua Liu.

  Toxoplasma gondii is a protozoan parasite capable of establishing chronic infections, with potential reactivation in immunocompromised individuals. However, the molecular mechanisms governing tachyzoite-to-bradyzoite differentiation remain incompletely understood. Previous studies have identified AP2 transcription factors as key regulators of this developmental switch. In this study, we investigated the role of the AP2 factor AP2X-8. Immunofluorescence analysis revealed that AP2X-8 is constitutively expressed in the nucleus of both tachyzoite and bradyzoite stages. Using CRISPR-Cas9-mediated homologous recombination, we successfully generated an ap2X-8 knockout strain. Phenotypic assays including plaque formation, invasion, replication, and egress, and bradyzoite differentiation assays, were then performed to assess the impact of ap2X-8 deletion. Our analyses showed that the loss of ap2X-8 significantly impaired plaque formation and intracellular replication, while invasion and egress were unaffected. Furthermore, ap2X-8 knockout enhanced bradyzoite differentiation in vitro. Despite these changes, deletion of ap2X-8 did not alter parasite virulence in a mouse infection model. These findings demonstrate that AP2X-8 is an important regulator of T. gondii tachyzoite growth and bradyzoite differentiation, offering new insights into the parasite's developmental regulation.

Keywords:  AP2 transcription factors; AP2X-8; Toxoplasma gondii; bradyzoite differentiation; tachyzoite growth; toxoplasmosis

DOI:  https://doi.org/10.3390/ani15091349
Commun Biol. 2025 May 10. 8(1): 728

Ubiquitin-activating enzyme1 (TgUAE1) acts as a key regulator of Toxoplasma gondii lytic cycle and homeostasis.

Qi-Xin Zhou, Dai-Qiang Lu, Si-Yu Tian, Yao Lv, Ming-Wei Chen, Xin Tian, Yan-Tao Wu, Fang-Jun Luo, Feng Tan, Ya-Ni Mou.

Ubiquitylation, regulated by the ubiquitin-proteasome system (UPS), is crucial for cell division and cycle transitions in Toxoplasma gondii. However, the primary E1 ubiquitin-activating enzyme (UAE1) in this process has been unclear. This study identified and characterized TGGT1_290290 (TgUAE1) as the canonical E1 enzyme in T. gondii. Through a combination of bioinformatics, biochemical, pharmacological, and genetic approaches, TgUAE1 was shown to exhibit typical E1 activity, particularly in forming K48- and K63-linked polyubiquitin chains. TAK-243, a UAE1 inhibitor, can effectively inhibit the ubiquitin pathway in T. gondii, as thermal stabilization experiments identified TgUAE1 as its intracellular target. Disruption of TgUAE1 severely impaired parasite homeostasis and suppressed the lytic cycle, highlighting its critical role in T. gondii fitness. Mutation of C634 in TgUAE1 confirmed that its enzymatic activity is essential for function. Transcriptomics and quantitative ubiquitin proteomics revealed TgUAE1 as a key regulator of the ubiquitination process and the broader gene expression network in T. gondii. These findings not only underscore the indispensable role of TgUAE1 in the life cycle of T. gondii but also offer valuable data that could inform future studies on parasite biology and the development of novel therapeutic strategies.

DOI: https://doi.org/10.1038/s42003-025-08149-x
Commun Biol. 2025 May 13. 8(1): 744

Unveiling the impact of cGMP-dependent protein kinase of Neospora caninum on calcium fluxes and egress functions through quantitative phosphoproteome analysis.

Xianmei Wang, Kun Guo, Zhili Shan, Zhu Ying, Zifu Zhu, Shiman Yang, Na Yang, Qun Liu, Lifang Wang, Jing Liu.

Neospora caninum, a pathogen associated with abortion in pregnant cattle and motor nerve disorders in dogs, poses a substantial threat. Cyclic GMP-dependent protein kinase (PKG) functions as a central signal transduction hub in apicomplexan parasites. However, PKG has not been characterized in N. caninum, and its targets and pathways controlled by PKG remain unknown. Using a mini auxin-inducible degron system (mAID), we knocked down PKG in N. caninum, demonstrating its indispensable role in tachyzoite invasion and egress from host cells. PKG promotes microneme secretion and enhances tachyzoite gliding motility by elevating intracellular Ca2+ levels ([Ca2+]i). Phosphoproteomics identified 1125 proteins as potential downstream targets of PKG, showing significantly reduced phosphorylation after treatment with the PKG inhibitor MBP146-78. These proteins are involved in signal transduction, transcriptional regulation, lipid transport and metabolism, vesicle transport, and ion transport. Additionally, CACNAP, a calcium channel-associated protein that facilitates calcium influx at the plasma membrane, plays a supportive role in the egress process of N. caninum. These findings underscore the importance of PKG and its downstream molecules in regulating egress, offering novel insights into the mechanisms underlying the activation of [Ca2+]i.

DOI: https://doi.org/10.1038/s42003-025-08173-x
Mol Cell Biochem. 2025 May 13.

Therapeutic applications of exercise in neurodegenerative diseases: focusing on the mechanism of SIRT1.

Jingwen Li, Tingting Liu, Meiyan Xian, Jianshe Wei.

  Neurodegenerative diseases comprise a group of central nervous system disorders marked by progressive neuronal degeneration and dysfunction. Their pathogenesis is multifactorial, involving oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Recent research has highlighted the potential of exercise as a non-pharmacological intervention for both the prevention and treatment of these disorders. In particular, exercise has received growing attention for its capacity to upregulate the expression and activity of SIRT1, a critical mediator of neuroprotection via downstream signaling pathways. SIRT1, a key member of the Sirtuin family, is a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase. It plays an essential role in regulating cellular metabolism, energy homeostasis, gene expression, and cellular longevity. In the context of neurodegenerative diseases, SIRT1 confers neuroprotection by modulating multiple signaling cascades through deacetylation, suppressing neuronal apoptosis, and promoting neural repair and regeneration. Exercise enhances SIRT1 expression and activity by increasing NAD + synthesis and utilization, improving intracellular redox balance, alleviating oxidative stress-induced inhibition of SIRT1, and thereby promoting its activation. Moreover, exercise may indirectly modulate SIRT1 function by influencing interacting molecular networks. This review summarizes recent advances in the therapeutic application of exercise for neurodegenerative diseases, with a focus on SIRT1 as a central mechanism. It examines how exercise mediates neuroprotection through the regulation of SIRT1 and its associated molecular mechanisms and signaling pathways. Finally, the paper discusses the potential applications and challenges of integrating exercise and SIRT1-targeted strategies in the management of neurodegenerative diseases, offering novel perspectives for the development of innovative treatments and improvements in patients' quality of life.

Keywords:  Exercise; Neurodegenerative diseases; Neuroprotection; SIRT1

DOI:  https://doi.org/10.1007/s11010-025-05299-8
Acta Parasitol. 2025 May 16. 70(3): 108

Endocytic Activity by Apicomplexa Parasites.

Wanderley de Souza.

  Macromolecules are incorporated by eukaryotic cells through a process known as endocytosis, intensely analyzed in mammalian and yeast cells, but still lacking deep studies in pathogenic protists. Here we present what is presently known on endocytic activity carried out in some members of the Apicomplexa group (mainly concentrated in Plasmodium and Toxoplasma, but with references to Eimeria, Babesia, and Theileria). In most cells, endocytic activity takes place throughout the cell's surface. In apicomplexans, it is restricted to a special surface structure known as a micropore (also called cytostome). Recent studies indicate that several proteins are in the micropore, playing a role in macromolecule uptake from the medium via budding vesicles.

Keywords:   Babesia ; Plasmodium ; Theileria ; Toxoplasma ; Apicomplexa; Electron microscopy; Endocytosis; Protozoan

DOI:  https://doi.org/10.1007/s11686-025-01038-7
J Cell Sci. 2025 May 01. pii: jcs263757. [Epub ahead of print]138(9):

Quality control of un-imported mitochondrial proteins at a glance.

Megan Balzarini, John Kim, Hilla Weidberg.

  Mitochondria are metabolic hubs that are essential for cellular homeostasis. Most mitochondrial proteins are translated in the cytosol and imported into the organelle. However, import machineries can become overwhelmed or disrupted by physiological demands, mitochondrial damage or diseases, such as metabolic and neurodegenerative disorders. Impaired import affects mitochondrial function and causes un-imported pre-proteins to accumulate not only in the cytosol but also in other compartments, including the endoplasmic reticulum and nucleus. Quality control pathways have evolved to mitigate the accumulation of these mistargeted proteins and prevent proteotoxicity. In this Cell Science at a Glance article and the accompanying poster, we summarize the fate of un-imported mitochondrial proteins and the compartment-specific quality control pathways that regulate them.

Keywords:  Mitochondrial protein import; Mitochondrial stress; Protein quality control

DOI:  https://doi.org/10.1242/jcs.263757
Pathol Res Pract. 2025 May 13. pii: S0344-0338(25)00203-1. [Epub ahead of print]271 156011

Lysine demethylases and cancer.

Tomas Eckschlager, Ales Vicha, Daniela Frolikova.

  Epigenetic mechanisms are of pivotal importance in the normal development and maintenance of cell and tissue-specific gene expression patterns, and are fundamental to the genesis of cancer. One significant category of epigenetic modifications is histone methylation. Histone methylation plays a crucial role in the regulation of gene expression, and its dysregulation has been observed in various diseases, including cancer. The maintenance of the histone methylation state is dependent on two classes of enzymes: histone methyltransferases, which add methyl groups to arginine and lysine residues, and lysine demethylases, which remove methyl groups from lysine residues of histones. To date, eight subfamilies have been identified, comprising approximately 30 lysine demethylases. These enzymes are expressed differently across cells and tissues and exert a substantial impact on the development and progression of cancer. The diverse range of lysine demethylases influence a multitude of oncogenic pathways, either by promoting or inhibiting their activity. However, comprehensive data on the full spectrum expression of lysine demethylases in distinct cancer types remain scarce. Lysine demethylases have been demonstrated to play a role in drug resistance in numerous cancers. This is achieved by modulating the metabolic profile of cancer cells, enhancing the ratio of cancer stem cells, and elevating the expression of drug-tolerant genes. Additionally, they facilitate epithelial-mesenchymal transition and metastatic potential. The objective of this review is to synthesize recent data on the relationship between lysine demethylases and cancer, with a particular focus on cancer cell drug resistance.

Keywords:  Cancer; Cancer cell drug resistance; Histone methylation; Lysine demethylases

DOI:  https://doi.org/10.1016/j.prp.2025.156011
Front Pharmacol. 2025 ;16 1586655

The role of glutamate dehydrogenase in the ageing brain.

Tao Zhou, Haichuan Wang.

  The homeostasis of glutamate, the primary excitatory neurotransmitter in the brain and is crucial for normal brain function. The mitochondrial enzyme glutamate dehydrogenase (GDH) connects the multifunctional amino acid glutamate, which is intimately related to glutamate metabolism, to the Krebs cycle. As a result, GDH reglutes the synthesis and uptake of the chemical messenger glutamate in neuroendocrine cells, playing a crucial role in the metabolism of proteins and carbohydrates. Nonetheless, brain ageing and numerous neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, have been linked to GDH malfunction or dysregulation. In this review, we summarize the dynamics of GDH levels in the ageing brain and provide additional details about the role of GDH in the ageing brain. Understanding the metabolic mechanisms underlying glutamate homeostasis in the aging brain and how GDH regulates glutamate-dependent metabolic processes at synapses may lead to novel therapeutic approaches for neurodegenerative and psychiatric disorders, potentially slowing the aging process and promoting brain regeneration.

Keywords:  Alzheimer’s disease; Parkinson’s disease; ageing brain; glutamate dehydrogenase; glutamate metabolism

DOI:  https://doi.org/10.3389/fphar.2025.1586655