bims-toxgon 2025-06-01 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–06–01
seventeen papers selected by
Lakesh Kumar, BITS Pilani

Inhibition of GPX4 by Toxoplasma gondii Promotes Ferroptosis and Enhances Its Proliferation in Acute and Chronic Infection.
Molecular interactions of Toxoplasma gondii dense granule 23 (GRA23) with host proteins PEX3 and TRAP1.
Structural basis for sirtuin 2 activity and modulation: current state and opportunities.
Indoleamine 2,3-Dioxygenase and Tryptophan Catabolism: Key Players in Immunosuppression and Intracellular Parasite Survival Mechanisms.
Defining neuronal responses to the neurotropic parasite Toxoplasma gondii.
Calcium-dependent protein kinases 2A involved in the growth of both asexual and sexual stages of Cryptosporidium parvum.
New Perspectives on Postmenopausal Osteoporosis: Mechanisms and Potential Therapeutic Strategies of Sirtuins and Oxidative Stress.
Lysine acetylation modulates s-OPA1 GTPase activity and oligomerization in mitochondrial membrane remodeling.
Structural Insights Into centSIRT6: Bioinformatic Analysis of N308K and A313S Substitution Effects.
Sorbate induces lysine sorbylation through noncanonical activities of class I HDACs to regulate the expression of inflammation genes.
Effects of latent infection of Toxoplasma gondii strains with different genotypes on mouse behavior and brain transcripts.
P5CS deacetylation mediated by SIRT2 facilitates tumor growth by enhancing mitochondrial respiration in hepatocellular carcinoma.
Nuclear-localized metabolic enzymes: emerging key players in tumor epigenetic regulation.
Mechanisms of heme transport in the mitochondria.
Reliable protein-protein docking with AlphaFold, Rosetta, and replica exchange.
Actin in mitochondrial regulation and mechanometabolic crosstalk.
Post-translational modifications and the reprogramming of tumor metabolism.

Cells. 2025 05 21. pii: 756. [Epub ahead of print]14(10):

Inhibition of GPX4 by Toxoplasma gondii Promotes Ferroptosis and Enhances Its Proliferation in Acute and Chronic Infection.

Yanlong Gu, Zhipeng Niu, Hui-Hong Lu, Si-Ang Li, Dong-Hui Zhou.

  Toxoplasma gondii (T. gondii) is an intracellular parasite that extensively infects warm-blooded animals, causing toxoplasmosis and posing a significant threat to global public health. In this study, we investigated the association between T. gondii infection and ferroptosis in host cells, as well as the regulatory role of glutathione peroxidase 4 (GPX4). Our findings revealed that mice infected with RH and PRU strains of T. gondii exhibited significantly elevated levels of reactive oxygen species and malondialdehyde in brain and liver tissues. Concurrently, the expression of GPX4, a critical negative regulator of ferroptosis, was downregulated, which correlated with the elevated parasite burden. In Vero cells, T. gondii infection similarly inhibited GPX4 expression, whereas GPX4 overexpression suppressed T. gondii proliferation. These results indicate that T. gondii infection can promote ferroptosis in host cells and that GPX4 plays a pivotal role in regulating infection and proliferation. This study provides novel insights into the pathogenic mechanisms of T. gondii and identifies GPX4 as a regulatory factor that constrains parasite proliferation, offering new approaches for toxoplasmosis prevention and control.

Keywords:  Toxoplasma gondii; ferroptosis; glutathione peroxidase 4 (GPX4); lipid peroxidation; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/cells14100756
Front Vet Sci. 2025 ;12 1585261

Molecular interactions of Toxoplasma gondii dense granule 23 (GRA23) with host proteins PEX3 and TRAP1.

Xuewei Fan, Nan Zhang, Xichen Zhang, Shudong Li, Jiangming Fu, Min Sun, Xiaoxiao Ma, Muhammad Zahoor Khan, Xin Jiang.

   Background: Toxoplasma gondii, an obligate intracellular protozoan, utilizes dense granule proteins to modulate host cell processes. Dense granule protein 23 (GRA23) facilitates molecular trafficking between the parasitophorous vacuole and host cell cyto-plasm, though its specific host protein interactions remain poorly characterized.
Methods: This study employed pull-down assays coupled with mass spectrometry to identify host proteins interacting with GRA23.
Results: Among 35 proteins identified, peroxisomal biogenesis factor 3 (PEX3) and TNF receptor-associated protein 1 (TRAP1) were validated through bimolecular fluorescence complementation (BiFC) and co-immunoprecipitation (Co-IP) assays. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed significant enrichment of these interacting proteins in metabolic pathways and cellular processes related to reproduction, growth, and development.
Conclusion: The interaction between GRA23 and PEX3 suggests potential parasite modulation of peroxisomal functions, while its association with TRAP1 indicates possible exploitation of host chaperone mechanisms. This study provides the first evidence that GRA23 interacts with host proteins implicated in key cellular functions, offering novel insights into T. gondii pathogenesis and potential therapeutic targets for toxoplasmosis treatment.

Keywords:  BiFC; GRA23; PEX3; TRAP1; Toxoplasma gondii

DOI:  https://doi.org/10.3389/fvets.2025.1585261
J Biol Chem. 2025 May 22. pii: S0021-9258(25)02124-6. [Epub ahead of print] 110274

Structural basis for sirtuin 2 activity and modulation: current state and opportunities.

Samuel P Bernhard, Francesc X Ruiz, Stacy Remiszewski, Matthew J Todd, Thomas Shenk, John L Kulp, Lillian W Chiang.

Sirtuin 2 (SIRT2) is a ubiquitously expressed cellular enzyme that deacylates protein lysine residues using NAD+ as a cofactor. SIRT2-mediated post-translational modifications on a plethora of protein targets position the enzyme to exert a wide-ranging regulatory role in many physiological and pathological processes. More than 39 SIRT2 crystal structures in complex with substrates, products, mimetics of substrates and products, and modulators, have been reported. The Rossmann fold of the catalytic core presents inducible acyl and cofactor binding cavities that accommodate acyl chains of diverse lengths. These structures have provided information for the design of mechanism- and substrate-based inhibitors. Indeed, a specific SIRT2 selectivity pocket has been described and can be targeted by different chemotypes. Despite the determination of many crystal structures, numerous open questions remain, especially relating to the development of small molecule modulators, full or partial activation or inhibition, and relating these effects to different therapeutic applications. Additional questions include understanding the role of the disordered termini, and the role of potential quaternary states (monomer, dimer, and trimer). Deeper insight into these issues may facilitate the development of SIRT2 selective modulators that can be tailored to different pathological scenarios, such as viral infections and cancers, in which either activation or inhibition of SIRT2 may be of therapeutic benefit. This review covers the following topics: (1) primary to quaternary and catalytic structural biology; (2) structural insights into molecular modulation of SIRT2 (inhibition and selectivity by mechanism-based inhibitors, substrate-mimicking inhibitors, C pocket-binding inhibitors, and selectivity pocket binding inhibitors, including insights to activation; and (3) the impact of structural variations (mutations, post-translational modifications, polymorphs, protein interactions). Despite considerable progress, key knowledge gaps remain regarding the design of optimized SIRT2 modulators. Addressing these uncertainties, particularly within the realms of full/partial activation/inhibition, off-target effects, and tailoring modulators to specific pathologies, will require further investigation into the roles of the SIRT2 disordered termini, quaternary states, and post-translational modifications. Ultimately, unraveling these intricacies holds the key to unlocking the therapeutic potential of SIRT2 modulation.

DOI: https://doi.org/10.1016/j.jbc.2025.110274
Immunol Invest. 2025 May 30. 1-26

Indoleamine 2,3-Dioxygenase and Tryptophan Catabolism: Key Players in Immunosuppression and Intracellular Parasite Survival Mechanisms.

Lisset Torres-Martínez, Abraham U Morales-Primo, Jaime Zamora-Chimal.

   BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is a heme enzyme that catalyzes the oxidative degradation of L-tryptophan (L-Trp) through the kynurenine pathway (KP), generating metabolites that regulate immune responses. These byproducts, mainly kynurenines, contribute to immunosuppression and influence immune cell differentiation, promoting regulatory T cells (Tregs) and inducing apoptosis in inflammatory cells.
METHODS: We conducted a comprehensive literature review to examine the roles of IDO and KP metabolites in intracellular parasitic infections. Our analysis focused on studies involving Leishmania, Trypanosoma cruzi, Toxoplasma gondii, and Plasmodium species.
RESULTS: IDO has a dual role in parasitic diseases: L-Trp depletion can inhibit parasite growth, but also promotes an immunosuppressive microenvironment that may facilitate pathogen persistence. This balance between host defense and immune evasion is crucial in chronic infections. We discuss how IDO activity intersects with parasite immune evasion strategies and review potential therapeutic approaches targeting the IDO-KP axis.
CONCLUSION: IDO plays a complex and context-dependent role in the immunopathology of intracellular parasitic infections. While it may support host defense, its immunoregulatory effects can also favor chronic infection. Therapeutically targeting the IDO pathway is a promising strategy, but requires further investigation to optimize its clinical application.

Keywords:  Indoleamine-2,3-dioxygenas; Leishmania; Plasmodium; Toxoplasma; Trypanosoma

DOI:  https://doi.org/10.1080/08820139.2025.2511079
mSphere. 2025 May 30. e0021625

Defining neuronal responses to the neurotropic parasite Toxoplasma gondii.

Hannah J Johnson, Joshua A Kochanowsky, Sambamurthy Chandrasekaran, Christopher A Hunter, Daniel P Beiting, Anita A Koshy.

  A select group of pathogens infects neurons in the brain. Prior dogma held that neurons were "defenseless" against infecting microbes, but many studies suggest that neurons can mount anti-microbial defenses. However, a knowledge gap in understanding how neurons respond in vitro and in vivo to different classes of microorganisms remains. To address this gap, we compared a transcriptional data set derived from primary neuron cultures (PNCs) infected with the neurotropic intracellular parasite Toxoplasma gondii with a data set derived from neurons injected with T. gondii protein in vivo. These curated responses were then compared to the transcriptional responses of PNCs infected with the single-stranded RNA viruses, West Nile virus or Zika virus. These analyses highlighted a conserved response to infection associated with chemokines (Cxcl10, Ccl2) and cytokines (interferon signaling). However, T. gondii had diminished IFN-α signaling in vitro compared to the viral data sets and was uniquely associated with a decrease in neuron-specific genes (Snap25, Slc17a7, Prkcg). These data underscore that neurons participate in infection-induced neuroinflammation and illustrate that neurons possess both pathogen-specific and pathogen-conserved responses.IMPORTANCEThough neurons are commonly the target of pathogens that infect the central nervous system (CNS), few data sets assess the neuronal response to infection. This paucity of data is likely because neurons are perceived to have diminished immune capabilities. However, to understand the role of neurons in neuroinflammation and their immune capabilities, their responses must be investigated. Here, we analyzed publicly accessible, neuron-specific data sets to compare neuron responses to a eukaryotic pathogen vs two Orthoflaviviruses. A better understanding of neuron responses to different infections will allow us to develop methods for inhibiting pathways that lead to neuron dysfunction, enhancing those that limit pathogen survival, and mitigating infection-induced damage to the CNS.

Keywords:  RNA-seq; T. gondii; Toxoplasma gondii; central nervous system infections; host response; neurons; transcriptomics

DOI:  https://doi.org/10.1128/msphere.00216-25
PLoS Negl Trop Dis. 2025 May;19(5): e0013107

Calcium-dependent protein kinases 2A involved in the growth of both asexual and sexual stages of Cryptosporidium parvum.

Fanfan Shu, Yujin Huang, Fuxian Yang, Yaqiong Guo, Rui Xu, Lihua Xiao, Yaoyu Feng, Na Li.

BACKGROUND: Cryptosporidium parvum is a protozoan pathogen that causes moderate to severe diarrhea in both humans and animals. Calcium-dependent protein kinases (CDPKs) are attractive drug targets against cryptosporidiosis given their critical role in the life cycle of Cryptosporidium spp. and their absence in human and animal hosts.
METHODOLOGY/PRINCIPAL FINDINGS: We used CRISPR-Cas9 technology to endogenously tag the CpCDPK2A gene in C. parvum IIdA20G1-HLJ strain with the hemagglutinin (HA) epitope and to delete the CpCDPK2A gene. An immunofluorescence assay was performed to localize the CpCDPK2A expression in the tagged strain and a luciferase assay was performed to compare growth rates of the tagged and deletion strains in vitro. Oocyst shedding, parasite load, villus length/crypt height ratio and survival of infected mice were used to evaluate the function of CpCDPK2A in vivo. The results revealed that CpCDPK2A was expressed in all the intracellular developmental stages, especially in the motile stages of sporozoites and merozoites. While CpCDPK2A is dispensable, deletion of the gene significantly reduced the growth of late asexual and sexual stages in vitro. In an interferon-γ knockout mouse model, gene deletion of CpCDPK2A reduced oocyst shedding by 25-fold and increased survival of infected mice.
CONCLUSIONS/SIGNIFICANCE: These observations suggest that CpCDPK2A may contribute to both asexual and sexual replication of C. parvum and may be a potential target to block the transmission of this important zoonotic pathogen.

DOI: https://doi.org/10.1371/journal.pntd.0013107
Antioxidants (Basel). 2025 May 17. pii: 605. [Epub ahead of print]14(5):

New Perspectives on Postmenopausal Osteoporosis: Mechanisms and Potential Therapeutic Strategies of Sirtuins and Oxidative Stress.

Huiying Zhao, Fan Yu, Wei Wu.

  Estrogen levels are the core factor influencing postmenopausal osteoporosis (PMOP). Estrogen can affect the progression of PMOP by regulating bone metabolism, influencing major signaling pathways related to bone metabolism, and modulating immune responses. When estrogen levels decline, the activity of Sirtuins (SIRTs) is reduced. SIRTs are enzymes that function as NAD+-dependent deacetylases. SIRTs can modulate osteocyte function, sustain mitochondrial homeostasis, and modulate relevant signaling pathways, thereby improving bone metabolic imbalances, reducing bone resorption, and promoting bone formation. In PMOP, SIRT1, SIRT3, and SIRT6 are primarily affected. Oxidative stress (OS) is a crucial factor in PMOP, as it generates excessive reactive oxygen species (ROS) that exacerbate PMOP. There is a certain interplay between SIRTs and OS. The reduced activity of SIRTs leads to intensified OS and the excessive accumulation of ROS. In return, ROS suppresses the AMPK signaling pathway and the synthesis of NAD+, which consequently diminishes the function of SIRTs. Natural SIRT activators and natural antioxidants, which are characterized by high safety, convenience, and minimal side effects, represent a potential therapeutic strategy for PMOP. This study aims to investigate the mechanisms of SIRTs and OS in PMOP and summarize potential therapeutic strategies to assist in the improvement of PMOP.

Keywords:  natural activator; natural antioxidant; oxidative stress; postmenopausal osteoporosis; sirtuins

DOI:  https://doi.org/10.3390/antiox14050605
Protein Sci. 2025 Jun;34(6): e70179

Lysine acetylation modulates s-OPA1 GTPase activity and oligomerization in mitochondrial membrane remodeling.

Javaid Jabbar, Bakht Afroze, Naomi X Y Ling, Jonathan S Oakhill, Isabelle Rouiller.

  Mitochondrial dynamics are regulated by coordinated fission and fusion events that rely on key proteins and lipids organized spatially within the mitochondria. The dynamin-related GTPase Optic Atrophy 1 (OPA1) is essential for inner mitochondrial membrane fusion and cristae structure maintenance. While post-translational modifications, particularly lysine acetylation, are emerging as critical regulators of mitochondrial protein function, their impact on OPA1 remains poorly characterized. In this study, we explored the effects of lysine acetylation on the short form of OPA1 (s-OPA1) using acetylation and deacetylation mimetic mutations. Through a combination of in silico analyses and functional assays, we identified lysine residues in s-OPA1 that are conserved across species and significantly influence protein stability, GTPase activity, and oligomeric assembly upon acetylation or deacetylation. Our findings reveal that acetylation at K328 and deacetylation at K342 within the G domain enhance the GTPase activity of s-OPA1 upon lipid membrane binding, whereas deacetylation at K772 abolishes membrane binding-induced GTPase activity. Negative-stain transmission electron microscopy indicated that while lysine acetylation does not alter the ability of s-OPA1 to bind and tubulate liposomes, it significantly impacts higher-order filament formation. These findings provide novel insights into how acetylation modulates s-OPA1 function, highlighting a potential mechanism for post-translational regulation of mitochondrial dynamics. Our study contributes to the understanding of how molecular changes influence broader cellular processes, with implications for mitochondrial function and related disorders.

Keywords:  GTPase activity; OPA1; acetylation; membrane remodeling; oligomeric assembly

DOI:  https://doi.org/10.1002/pro.70179
Bioinform Biol Insights. 2025 ;19 11779322251339698

Structural Insights Into centSIRT6: Bioinformatic Analysis of N308K and A313S Substitution Effects.

Francisco Alejandro Lagunas-Rangel.

  Sirtuin 6 (SIRT6), a member of the class III histone deacetylase (HDAC) family, is crucial for the maintenance of general health and is associated with increased life expectancy and resistance to age-related diseases such as cancer and metabolic disorders. A comparative analysis of the SIRT6 gene in Ashkenazi Jewish (AJ) centenarians and noncentenarian controls found a distinct allele, centSIRT6, enriched in the centenarian group. This allele features 2 linked substitutions, N308K and A313S, and exhibits enhanced functions, including more efficient suppression of LINE1 retrotransposons, improved repair of DNA double-strand breaks, and increased efficiency in cancer cell killing. Notably, centSIRT6 shows lower deacetylase activity but higher mono-adenosine diphosphate (ADP) ribosyl transferase activity compared with the wild-type enzyme. This study used several bioinformatics tools to explore the structural changes caused by the N308K and A313S substitutions in centSIRT6 and to elucidate how these alterations contribute to changes in the enzymatic activities of SIRT6. The results indicate that these mutations reduce the structural flexibility of centSIRT6, thus weakening its interactions with acetyl-lysine but strengthening its interactions with ADP-ribose. This research provides useful information for future experimental studies to further investigate the molecular mechanisms of centSIRT6.

Keywords:  Sirtuin; acetyl-lysine; active site; docking; substrate-enzyme complex energy

DOI:  https://doi.org/10.1177/11779322251339698
Sci Adv. 2025 May 30. 11(22): eadv1071

Sorbate induces lysine sorbylation through noncanonical activities of class I HDACs to regulate the expression of inflammation genes.

Yi-Cheng Sin, Breann Abernathy, Zuo-Fei Yuan, Jason L Heier, Justin E Gonzalez, Laurie L Parker, Douglas G Mashek, Yue Chen.

Environmental factors may affect gene expression through epigenetic modifications of histones and transcription factors. Here, we report that cellular uptake of sorbate, a common food preservative, induces lysine sorbylation (Ksor) in mammalian cells and tissue mediated by the noncanonical activities of class I histone deacetylases (HDAC1-3). We demonstrated that HDAC1-3 catalyze sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in cells. Sorbate uptake in mice livers significantly induced histone Ksor, correlating with decreased expressions of inflammation-response genes. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon lipopolysaccharide (LPS) stimulation dose-dependently down-regulated proinflammatory gene expressions and nitric oxide production. Proteomic profiling identified RelA, a component of the NF-κB complex, and its interacting proteins as bona fide Ksor targets and sorbate treatment significantly decreased NF-κB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Together, our study demonstrated a noncanonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.

DOI: https://doi.org/10.1126/sciadv.adv1071
Parasit Vectors. 2025 May 26. 18(1): 190

Effects of latent infection of Toxoplasma gondii strains with different genotypes on mouse behavior and brain transcripts.

Bei-Bei Zhou, Hong-Jie Dong, Hang Sun, Xiao-Man Xie, Huan-Huan Xie, Wen-Ju Zhu, Ya-Nan Li, Chao Xu, Jian-Ping Cao, Gui-Hua Zhao, Kun Yin.

   BACKGROUND: Toxoplasma gondii can cause severe damage to immunodeficient hosts, and also compromise brain structure and function in immunocompetent hosts during latent infection. In China, the two different isolates, Chinese I (ToxoDB#9) and Chinese III are dominant epidemic strains widely spreading in humans and domestic animals and can lead to latent infection in host brain tissues, but the comparison of their manipulation patterns and mechanisms remains unclear.
METHODS: Tachyzoites of the TgWh6 (Wh6) strain and the TgCtLHG (LHG) strain were used for establishing in vitro infection models within mouse microglia BV2 cells, and the differences in their invasion and proliferation patterns were observed. C57BL/6 J mice were used to establish in vivo latent infection models. After behavioral tests, the differential expressed transcripts (DETs) of the infected and control animals' cerebral cortex were sequenced by Nanopore RNA-seq. Functional differences of DETs were analyzed by Gene Ontology enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes enrichment analysis (KEGG), and protein-protein interaction (PPI) and cluster analysis. Expression of the key candidates were verified by quantitative polymerase chain reaction (qPCR).
RESULTS: In our infection models, we found that Wh6 had more vigorous invasion and proliferation abilities in vitro, while LHG had a greater ability to form cysts in vivo. In the latent infection phase, behavioral changes, including spatial working memory, cognitive and motor abilities, and anxiety, were observed in both Wh6 and LHG infected mice; however, the LHG group showed more serious anxiety. Among DETs, genes related to major histocompatibility complex (MHC) class II molecules were significantly upregulated in the infected mice, while genes related to synaptic transmission and neurodegenerative diseases were downregulated in the infected groups. The downregulated DETs of Sept4, Kcng4, Unc13c, and Prkcg in the WH6 group, which are related to synaptic transmission, and Ndrg2 and Arc in the LHG group, which are related to neurodegenerative diseases, were selected to be the key candidates in the latent infection phase.
CONCLUSIONS: Compared with WH6, although LHG has a milder invasion ability, it can cause increased behavioral disorders in hosts. Genes related to synaptic transmission and neurodegenerative diseases may be the main causes of host mental and behavioral disorders.

Keywords:   Toxoplasma gondii ; Cerebral cysts; Differentially expressed transcripts; Mental and behavioral disorders; Nanopore RNA-seq

DOI:  https://doi.org/10.1186/s13071-025-06819-7
Oncogene. 2025 May 27.

P5CS deacetylation mediated by SIRT2 facilitates tumor growth by enhancing mitochondrial respiration in hepatocellular carcinoma.

Xiaofang Geng, Mengyao Li, Lu Zhang, Yihan Cai, Xin Chen, Xiayue Mu, Jie Wang, Bowen Liu.

Cancer cells typically exhibit enhanced mitochondrial metabolism to fulfill their energy and biosynthetic demands for growth. The mitochondrial response to fluctuations in cellular energy demand is essential for cellular adaptation and proper organ function. The mitochondrial delta-1-pyrroline-5-carboxylate synthase (P5CS) encoded by the ALDH18A1 gene, the key enzyme for proline synthesis, is frequently up-regulated during tumor development. However, the regulatory mechanisms governing P5CS activity in the occurrence and development of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we observe that P5CS is highly expressed in HCC tissues, and elevated levels of P5CS expression are associated with poor prognosis in HCC patients. Notably, the knockdown of P5CS inhibits the proliferation, migratory and invasive capabilities of HCC cells by reducing mitochondrial respiration. Furthermore, we demonstrate that SIRT2 interacts with P5CS and mediates the deacetylation of P5CS at lysines K311 and K347, thereby activating its enzymatic activity. Activated P5CS significantly enhances mitochondrial respiration, which supports the proliferation and tumorigenesis of HCC cells. In addition, SIRT2 knockdown inhibits the proliferation, migratory and invasive capabilities of HCC cells. These observations suggest that SIRT2-mediated P5CS deacetylation is a crucial signaling event through which cancer cells sustain mitochondrial respiration and promote HCC progression. This finding offers the potential for targeting SIRT2-mediated P5CS deacetylation as a therapeutic strategy for HCC.

DOI: https://doi.org/10.1038/s41388-025-03456-3
Mol Cell Biochem. 2025 May 28.

Nuclear-localized metabolic enzymes: emerging key players in tumor epigenetic regulation.

Limei Chen, Zhihui Wu, Weixi Yuan, Nan Chen, Peina Lin, Senyi Liao, Guopeng Xie.

  Advancements in tumor research have highlighted the potential of epigenetic therapies as a targeted approach to cancer treatment. However, the application of these therapies has faced challenges due to the issue of substrate availability since the discovery of epigenetic modifications. Interestingly, metabolic changes are closely associated with epigenetic changes, and notably, certain metabolic enzymes exhibit nuclear localization within epigenetically active cellular contexts. This suggests that nuclear localization of metabolic enzymes may provide a mechanistic foundation for addressing substrate availability issues in epigenetic regulation. To date, there has been limited progress in synthesizing this information systematically. In this study, we provide an overview of the interplay between metabolic enzymes and epigenetic mechanisms, highlighting their critical roles. Subsequently, we summarize recent advances regarding the nuclear localization of metabolic enzymes, shedding light on their emerging roles in epigenetic regulation and oncogenesis.

Keywords:  DNA demethylation; Epigenetic modifications; Histone modifications; Lactylation; Nuclear localization of metabolic enzymes

DOI:  https://doi.org/10.1007/s11010-025-05316-w
Biochem Soc Trans. 2025 May 29. pii: BST20253013. [Epub ahead of print]

Mechanisms of heme transport in the mitochondria.

Saieeda Fabia Ali, Adrianna E White, Amy Medlock, Oleh Khalimonchuk.

  Heme is a vital but highly reactive compound that is synthesized in mitochondria and subsequently distributed to a variety of subcellular compartments for utilization. The transport of heme is essential for normal cellular metabolism, growth, and development. Despite the vital importance of heme transport within the cell, data are lacking about how newly synthesized heme is shuttled within the mitochondrion or exported from the organelle. Here, we briefly summarize current knowledge about the process of mitochondrial heme distribution and discuss the current unresolved questions pertinent to this process.

Keywords:  heme; heme biosynthesis; hemoproteins; membrane transporters; mitochondria

DOI:  https://doi.org/10.1042/BST20253013
Elife. 2025 May 27. pii: RP94029. [Epub ahead of print]13

Reliable protein-protein docking with AlphaFold, Rosetta, and replica exchange.

Ameya Harmalkar, Sergey Lyskov, Jeffrey J Gray.

  Despite the recent breakthrough of AlphaFold (AF) in the field of protein sequence-to-structure prediction, modeling protein interfaces and predicting protein complex structures remains challenging, especially when there is a significant conformational change in one or both binding partners. Prior studies have demonstrated that AF-multimer (AFm) can predict accurate protein complexes in only up to 43% of cases (Yin et al., 2022). In this work, we combine AF as a structural template generator with a physics-based replica exchange docking algorithm to better sample conformational changes. Using a curated collection of 254 available protein targets with both unbound and bound structures, we first demonstrate that AF confidence measures (pLDDT) can be repurposed for estimating protein flexibility and docking accuracy for multimers. We incorporate these metrics within our ReplicaDock 2.0 protocol to complete a robust in silico pipeline for accurate protein complex structure prediction. AlphaRED (AlphaFold-initiated Replica Exchange Docking) successfully docks failed AF predictions, including 97 failure cases in Docking Benchmark Set 5.5. AlphaRED generates CAPRI acceptable-quality or better predictions for 63% of benchmark targets. Further, on a subset of antigen-antibody targets, which is challenging for AFm (20% success rate), AlphaRED demonstrates a success rate of 43%. This new strategy demonstrates the success possible by integrating deep learning-based architectures trained on evolutionary information with physics-based enhanced sampling. The pipeline is available at https://github.com/Graylab/AlphaRED.

Keywords:  AlphaFold; RosettaDock; computational biology; molecular biophysics; none; protein docking; protein interactions; replica exchange; structural biology; structure prediction; systems biology

DOI:  https://doi.org/10.7554/eLife.94029
Curr Opin Cell Biol. 2025 May 26. pii: S0955-0674(25)00077-8. [Epub ahead of print]95 102539

Actin in mitochondrial regulation and mechanometabolic crosstalk.

Peng Shi, Yuhan Zhang, Congying Wu.

Mitochondria undergo dynamic adaptations to cellular energy demands, changing morphology and function, through active interactions with other cellular organelles and the cytoskeletons. With advances in light and electron microscopy, actin probes for live-cell imaging, as well as proximity labeling, subtle and transient actin structures associated with mitochondria have been resolved and examined, which opened a new era for the understanding of architectural and mechanical regulation of organelles and metabolism. Here, we first review the recent findings that elucidate the actin-mitochondrion interactions in regulating mitochondrial dynamics (including fission, fusion and trafficking), and cristae architecture. Further, we discuss the functional consequences accompanying these morphological changes, which link cellular metabolism to the cytoskeleton and mechanotransduction through direct or indirect organelle control. Moreover, we summarize the avant-garde techniques for probing mitochondrion-associated actin, including new ways to visualize mitochondria-actin interaction in the cytosol and within the mitochondria, methods to identify the molecular components mediating actin-mitochondria crosstalk, and techniques for reconstructing the 3D ultrastructure of actin-mitochondrion interaction. Finally, we conclude pressing issues in this exciting field, calling for interdisciplinary efforts in examine actin-mitochondrion interactions at micro and macro levels. The dynamics and structural integrity of mitochondria are essential for energy metabolism and signal transduction, while their abnormalities lead to mitochondrial dysfunction and severe disease. This review aims to provide a comprehensive perspective on the emerging roles of the actin cytoskeleton in shaping mitochondrial morphology, structure, and functions, providing new angles to understand mitochondria-related diseases.

DOI: https://doi.org/10.1016/j.ceb.2025.102539
Discov Oncol. 2025 May 26. 16(1): 929

Post-translational modifications and the reprogramming of tumor metabolism.

Yuqing Hu, Wenxia Xu, Lin Chen.

  Metabolic reprogramming occurs alongside tumor development. As cancers advance from precancerous lesions to locally invasive tumors and then to metastatic tumors, metabolic patterns exhibit distinct changes, including mutations in metabolic enzymes and modifications in the activity of metabolic regulatory proteins. Alterations in metabolic patterns can influence tumor evolution, either establishing or alleviating metabolic burdens and facilitating cancer growth. To fully understand how metabolic reprogramming helps tumors grow and find the metabolic activities that are most useful for treating tumors, we need to have a deeper understanding of how metabolic patterns are controlled as tumors grow. Post-translational modifications (PTMs), a critical mechanism in the regulation of protein function, can influence protein activity, stability, and interactions in several ways. In tumor cells, PTMs-mediated metabolic reprogramming is a crucial mechanism for adapting to the challenging microenvironment and sustaining fast growth. This article will deeply explore the intricate regulatory mechanism of PTMs on metabolic reprogramming and its role in tumor progression, with the expectation of providing new theoretical basis and potential targets for tumor treatment.

Keywords:  Cancer metabolic; Post-translational modifications; Tumor metabolic reprogramming

DOI:  https://doi.org/10.1007/s12672-025-02674-1