bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–09–07
23 papers selected by
Marc Segarra Mondejar
  1. Purine metabolism in tumorigenesis and its clinical implications.
  2. Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood-brain barrier dysfunction, metabolic reprogramming and increased inflammation in the aging brain.
  3. Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
  4. Saccharomyces cerevisiae malate dehydrogenase Mdh1p lacking mitochondrial targeting signal can be re-localized to peroxisomes.
  5. Glutamate utilization fuels rapid production of mitochondrial ROS in dendritic cells and drives systemic inflammation during tularemia.
  6. In situ metabolomics reveals intra-islet metabolite changes upon in vivo stimulation of insulin secretion.
  7. Biliverdin reductase-A is a key modulator in insulin signaling and metabolism.
  8. Exploiting metabolic vulnerabilities to improve cancer therapeutics.
  9. Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
  10. Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.
  11. Evidence that mitochondria in macrophages are destroyed by microautophagy.
  12. Flubendazole inhibits cervical carcinoma by targeting DHODH to induce ferroptosis and mitophagy.
  13. Quantification of Endothelial Fatty Acid Uptake using Fluorescent Fatty Acid Analogs.
  14. Understanding the Changes in Mitochondrial Morphology through Dynamic and Three-dimensional Fluorescence Micrographs.
  15. FOXO1- mediated argininosuccinate lyase transcription inhibits ammonia metabolism and breast cancer cell metastasis.
  16. Activation of WNK1 signaling through Piezo1.
  17. Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
  18. Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
  19. Uridine 5'-monophosphate (UMP) synthesis connects nucleotide metabolism to programmed cell death in C. elegans.
  20. Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
  21. β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
  22. Rewiring of cortical glucose metabolism fuels human brain cancer growth.
  23. A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression.
  1. Semin Oncol. 2025 Sep 02. pii: S0093-7754(25)00101-0. [Epub ahead of print]52(6): 152409
    Purine metabolism in tumorigenesis and its clinical implications.
    Zerui Lu, Jiayi Li, Ying Liu, Hui Li, Ying Sun, Rui Geng, Jiahang Song, Jinhui Liu.
      Metabolic reprogramming constitutes a hallmark of malignant neoplasms. Purine metabolism emerges as a pivotal regulator in cellular metabolic networks through multiple mechanisms, including dysregulation of de novo biosynthesis/salvage pathway coordination, adenosine-mediated immunosuppressive microenvironment formation, and collective contributions to tumorigenesis and malignant progression. During metastatic progression, purine metabolism reinforces tumor cell plasticity through mitochondrial energy regulation and modulation of cell cycle checkpoints (eg, G1/S transition). These mechanistic revelations have positioned purine metabolism-targeting strategies as promising oncotherapeutic candidates. This review methodically analyzes (1) purine metabolic pathways and their regulatory dynamics, (2) adenosine-mediated pathophysiological interactions, and (3) the synergistic impacts of these pathways in malignant transformation. We propose a unified mechanistic framework that clarifies oncogenic purine metabolic rewiring while evaluating translational potential through three clinical dimensions: pathogenesis elucidation, diagnostic biomarker discovery, and targeted therapeutic development. This comprehensive synthesis aims to advance precision oncology through mechanistic insights and therapeutic innovation.
    Keywords:  Immune evasion; Metabolic reprogramming; Purine metabolism; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.seminoncol.2025.152409
  2. bioRxiv. 2025 Aug 28. pii: 2025.08.22.671845. [Epub ahead of print]
    Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood-brain barrier dysfunction, metabolic reprogramming and increased inflammation in the aging brain.
    Sarah Otu-Boakye, Duraipandy Natarajan, Bhuvana Plakkot, Ilakiya Raghavendiran, Tamas Kiss, Madhan Subramanian, Priya Balasubramanian.
      Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood-brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis, and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo . Collectively, our findings indicate that lipid accumulation drives structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.
    DOI:  https://doi.org/10.1101/2025.08.22.671845
  3. bioRxiv. 2025 Aug 27. pii: 2025.08.27.672715. [Epub ahead of print]
    Mitochondria structurally remodel near synapses to fuel the sustained energy demands of plasticity.
    Monil Shah, Ilika Ghosh, Luca Pishos, Valentina Villani, Tristano Pancani, Ryohei Yasuda, Chao Sun, Naomi Kamasawa, Vidhya Rangaraju.
      The brain is a metabolically demanding organ as it orchestrates and stabilizes neuronal network activity through plasticity. This mechanism imposes enormous and prolonged energetic demands at synapses, yet it is unclear how these needs are met in a sustained manner. Mitochondria serve as a local energy supply for dendritic spines, providing instant and sustained energy during synaptic plasticity. However, it remains unclear whether dendritic mitochondria restructure their energy production unit to meet the sustained energy demands. We developed a correlative light and electron microscopy pipeline with deep-learning-based segmentations and 3D reconstructions to quantify mitochondrial remodeling at 2 nm pixel resolution during homeostatic plasticity. Using light microscopy, we observe global increases in dendritic mitochondrial length, as well as local increases in mitochondrial area near spines. Examining the mitochondria near spines using electron microscopy, we reveal increases in mitochondrial cristae surface area, cristae curvature, endoplasmic reticulum contacts, and ribosomal cluster recruitment, accompanied by increased ATP synthase clustering within mitochondria using single-molecule localization microscopy. Using mitochondria- and spine-targeted ATP reporters, we demonstrate that the local structural remodeling of mitochondria corresponds to increased mitochondrial ATP production and spine ATP levels. These findings suggest that mitochondrial structural remodeling is a key underlying mechanism for meeting the energy requirements of synaptic and network function.
    DOI:  https://doi.org/10.1101/2025.08.27.672715
  4. Biol Open. 2025 Sep 05. pii: bio.062199. [Epub ahead of print]
    Saccharomyces cerevisiae malate dehydrogenase Mdh1p lacking mitochondrial targeting signal can be re-localized to peroxisomes.
    Chutima Chan, Naraporn Sirinonthanawech, Brian K Sato, James E Wilhelm, Chalongrat Noree.
      Yeast mitochondrial malate dehydrogenase, Mdh1p, is known to form supramolecular complexes with other TCA cycle and mitochondrial dehydrogenase enzymes, including the aldehyde dehydrogenase, Ald4p. These complexes have been proposed to facilitate NADH channeling. Here, we demonstrate that in cells grown to saturation and stationary phases, the endogenous Mdh1p, expressed without its mitochondrial targeting signal (MTS), stays outside mitochondria, in both a diffuse cytoplasmic distribution as well as localized to distinct puncta. The puncta formed by MTS-lacking Mdh1p show no co-localization with the MTS-lacking Ald4p, suggesting that they do not co-assemble into a supramolecular complex in the cytoplasm. However, we found that the MTS-lacking Mdh1p does co-localize with its cytoplasmic counterpart, Mdh2p, in puncta. Interestingly, Mdh2p has recently been reported to form heterocomplexes with the peroxisomal Mdh3p and to be transported into peroxisomes to assist in the glyoxylate cycle. We also show that the MTS-lacking Mdh1p co-localizes with a fluorescent peroxisome marker, Pex3p. Our findings suggest that different malate dehydrogenases can enter peroxisomes, potentially as a means to make the glyoxylate pathway more efficient.
    Keywords:  Malate dehydrogenase; Mitochondria; Peroxisome; Supramolecular assembly; Yeast
    DOI:  https://doi.org/10.1242/bio.062199
  5. Sci Adv. 2025 Aug 29. 11(35): eadu6271
    Glutamate utilization fuels rapid production of mitochondrial ROS in dendritic cells and drives systemic inflammation during tularemia.
    Ivo Fabrik, Petra Spidlova, Lukas Prchal, Daniela Fabrikova, Ina Viduka, Valentina Marecic, Vlada Filimonenko, Radek Sleha, Marie Vajrychova, Rudolf Kupcik, Ondrej Soukup, Tomas Rousar, Anetta Härtlova, Marina Santic, Jiri Stulik.
      Dendritic cells (DCs) hijacked by intracellular bacteria contribute to pathogen dissemination and immunopathology. How bacteria achieve DC subversion remains largely unknown. Here, we describe the mechanism used by tularemia agent Francisella tularensis exploiting host mitochondrial anaplerosis. Shortly after internalization, Francisella associates with DC mitochondria, which leads to the rapid repurposing of their oxidative metabolism for production of mitochondrial reactive oxygen species (mtROS). Mitochondrial metabolic rewiring is orchestrated by the intramitochondrial signaling mediated by protein acetylation and involves switching to glutamate as the primary substrate for DC tricarboxylic acid cycle. Rather than killing the bacterium, glutamate-fueled mtROS production activates p38-dependent proinflammatory gene expression. Blocking of glutamate utilization prevents DC activation and bacterial dissemination and alleviates inflammation in vivo. Our findings underscore the importance of metabolic plasticity in antibacterial DC response and open up potential avenues for therapies targeting host metabolism.
    DOI:  https://doi.org/10.1126/sciadv.adu6271
  6. J Biol Chem. 2025 Sep 01. pii: S0021-9258(25)02513-X. [Epub ahead of print] 110661
    In situ metabolomics reveals intra-islet metabolite changes upon in vivo stimulation of insulin secretion.
    Yan Zhou, Nicolas Baez, Tingting Fu, Thierry Brun, Pierre Maechler.
      Upon glucose stimulation, metabolic pathways of pancreatic beta-cells promptly adapt metabolite levels inducing insulin secretion fine-tuned by mitochondrial glutamate dehydrogenase (GDH). Although well described in vitro, these responses cannot yet be captured in vivo due to the intrinsic nature of the islets scattered throughout the pancreas. Tested first in vitro, glutamate precursor glutamine enhanced glucose-stimulated insulin secretion without eliciting oxidative catabolism, as opposed to glucose. Then, to be as close as possible to the in vivo state, we collected the pancreas of mouse models in fasted versus fed states and at the peak of a glucose tolerance test, immediately followed by snap freezing before in situ analysis of metabolic pathways. On the same series of pancreatic cryosections, islets were identified by dithizone beta-cell staining for metabolic analyses combining spatial in situ redox enzymatic assay with targeted metabolomics using time-of-flight secondary ion MS high-resolution imaging. Direct measurements in cryopreserved pancreatic sections of control and beta-cell specific GDH knockout mice showed tight coupling between glycolysis and mitochondrial pathways favored by low lactate dehydrogenase activity and strong succinate dehydrogenase velocity. In response to regular feeding, intra-islet glutamate and glutamine levels were elevated, an effect dependent on beta-cell GDH. Acute in vivo glucose stimulation increased both alanine and glutamate intra-islet levels. Lack of beta-cell GDH abrogated the rise in glutamate and reduced insulin secretion without impacting alanine levels. Overall, the hallmark of in vivo beta-cell stimulation was a strong mitochondrial activity and GDH-dependent elevation of glutamate required for the full development of insulin secretion.
    Keywords:  beta-cell; glutamate dehydrogenase; insulin secretion; metabolomics; pancreatic islet
    DOI:  https://doi.org/10.1016/j.jbc.2025.110661
  7. Trends Endocrinol Metab. 2025 Sep 04. pii: S1043-2760(25)00176-6. [Epub ahead of print]
    Biliverdin reductase-A is a key modulator in insulin signaling and metabolism.
    Antonella Tramutola, Fabio Di Domenico, Marzia Perluigi, Eugenio Barone.
      Biliverdin reductase-A (BVRA) is a pleiotropic enzyme traditionally known for its antioxidant role in the heme degradation pathway. Recent findings have redefined BVRA as a master regulator of insulin signaling, acting as a kinase, scaffold, and redox-sensitive integrator of metabolic cues. BVRA modulates key nodes of the insulin cascade and sustains mitochondrial and synaptic function. Notably, BVRA loss precedes the accumulation of canonical markers of insulin resistance both peripherally and in the brain. Here we discuss how BVRA could represent an early cross-tissue biomarker of metabolic vulnerability. Its dysfunction contributes to mitochondrial stress, impaired proteostasis, and cognitive decline, thus linking metabolic and neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; aging; biliverdin reductase-A; cell stress response; insulin signaling; mitochondrial metabolism; obesity; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.tem.2025.08.007
  8. Trends Endocrinol Metab. 2025 Aug 28. pii: S1043-2760(25)00171-7. [Epub ahead of print]
    Exploiting metabolic vulnerabilities to improve cancer therapeutics.
    Ibrahim H Ibrahim, Cheng-Han Lin, Ming Zhou, Jer-Yen Yang, Robert W Sobol, Ming Tan.
      Over the past decade, our understanding of cancer metabolism has advanced significantly, revealing a complex and dynamic landscape of metabolic reprogramming that facilitates tumor progression and promotes therapeutic resistance. To survive under stressful conditions, cancer cells undergo crucial metabolic adaptations while also creating vulnerabilities that can be exploited for therapeutic purposes. Here, we discuss the evolving understanding of cancer cell metabolic adaptation in the tumor environment and the recent advances in identifying potential therapeutic mechanisms, including synthetic lethality, post-translational modifications (PTMs), as well as the interplay between metabolism and epigenetics. Furthermore, we discuss the integration of metabolic targeting with immune-based therapies and provide insights underscoring the potential of metabolic interventions to resensitize drug-resistant cancers and enhance efficacy for cancer treatment.
    Keywords:  cancer metabolism; immuno-metabolism; metabolic vulnerabilities; synthetic lethality; therapeutic resistance
    DOI:  https://doi.org/10.1016/j.tem.2025.08.002
  9. J Cell Biol. 2025 Oct 06. pii: e202410130. [Epub ahead of print]224(10):
    Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
    Maria Pia Rodriguez Salazar, Sprihaa Kolanukuduru, Valentina Ramirez, Boyu Lyu, Gracie Manigault, Gabrielle Sejourne, Hiromi Sesaki, Guoqiang Yu, Cagla Eroglu.
      Dysfunctional mitochondrial dynamics are a hallmark of devastating neurodevelopmental disorders such as childhood refractory epilepsy. However, the role of glial mitochondria in proper brain development is not well understood. We show that astrocyte mitochondria undergo extensive fission while populating astrocyte distal branches during postnatal cortical development. Loss of mitochondrial fission regulator, dynamin-related protein 1 (Drp1), decreases mitochondrial localization to distal astrocyte processes, and this mitochondrial mislocalization reduces astrocyte morphological complexity. Functionally, astrocyte-specific conditional deletion of Drp1 induces astrocyte reactivity and disrupts astrocyte organization in the cortex. These morphological and organizational deficits are accompanied by loss of perisynaptic astrocyte process (PAP) proteins such as gap junction protein connexin 43. These findings uncover a crucial role for mitochondrial fission in coordinating astrocytic morphogenesis and organization, revealing the regulation of astrocytic mitochondrial dynamics as a critical step in neurodevelopment.
    DOI:  https://doi.org/10.1083/jcb.202410130
  10. Front Cell Neurosci. 2025 ;19 1661231
    Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.
    Christos Chinopoulos.
      Considering that the aerobic energetic landscape of the brain is shaped by its mitochondria, Mosharov et al. generated an atlas of mitochondrial content and enzymatic OXPHOS activities at a resolution comparable to MRI by physically voxelizing frozen human brain tissue. However, astrocytes in the adult human brain lack expression of several TCA cycle and OXPHOS enzymes. Therefore, their formula expressing mitochondrial respiratory capacity (MRC) -defined as tissue respiratory capacity normalized to mitochondrial density- underestimates actual values by a factor proportional to the square root of the fraction of respiration-capable cells (primarily neurons) in gray matter voxels.
    Keywords:  MRI; OXPHOS; astrocytes; mitochondria; neurons; respiratory capacity
    DOI:  https://doi.org/10.3389/fncel.2025.1661231
  11. Nat Commun. 2025 Aug 30. 16(1): 8123
    Evidence that mitochondria in macrophages are destroyed by microautophagy.
    Shiou-Ling Lu, Siyu Chen, Kazuya Noda, Yangjie Li, Chao-Yuan Tsai, Hiroko Omori, Yumiko Kato, Zidi Zhang, Bohan Chen, Kanako Tokuda, Tongxin Zheng, Masahiro Wakita, Eiji Hara, Mitsunori Fukuda, Yoh Wada, Eiji Morita, Narikazu Uzawa, Shinya Murakami, Takeshi Noda.
      Microautophagy is an intracellular degradation process in which degradatory organelles, such as the lysosome, directly take up substrates by invagination and/or protrusion of their membranes. Here, we provide evidence that Rab32-positive, lysosome-related organelles in macrophages incorporate various other organelles, including endosomes and mitochondria. Our data indicates that, upon exposure to a mitochondria-damaging reagent, mitochondria can be directly engulfed by the lysosome-like organelles independently of macroautophagy or ESCRT machinery. Rab32 GTPase, phosphatidylinositol 3,5-bisphosphates, ubiquitination, and p62/SQSTM1 are crucial for this degradation. Furthermore, the degree of M1 polarization of macrophages, which is facilitated by metabolic reprogramming into increased glycolysis via mitochondrial elimination, is significantly reduced in Rab32/38 double-knockout macrophages. Thus, microautophagy plays a role in the physiological regulation of macrophages.
    DOI:  https://doi.org/10.1038/s41467-025-63531-x
  12. Biochem Pharmacol. 2025 Aug 28. pii: S0006-2952(25)00552-0. [Epub ahead of print]242(Pt 1): 117287
    Flubendazole inhibits cervical carcinoma by targeting DHODH to induce ferroptosis and mitophagy.
    Xiaokun Liu, Yuxuan Yang, Bingqiang Zhang, Xiao Gao, Di Yang, Yani Sun, Lianhui Li, Mingkang Yu, Lin Hou, Ning Li, Yuling Yang.
      Cervical carcinoma remains a major public health challenge due to its elevated incidence and mortality rates. Dihydroorotate dehydrogenase (DHODH) is a crucial enzyme in de novo pyrimidine biosynthesis and ferroptosis defense with a targetable susceptibility in cancer. However, effective inhibitors of DHODH and their potential application in cervical cancer therapy have not yet been explored. This study aims to evaluate the inhibitory effects of flubendazole, a benzimidazole anthelmintic, on cervical carcinoma and the mechanisms involved. This study demonstrated that flubendazole effectively inhibited cervical cancer cell proliferation and tumor growth by inducing ferroptosis and PINK1/Parkin-mediated mitophagy. Mechanistically, flubendazole targeted DHODH and promoted its degradation via direct binding. Overexpression of DHODH prevented flubendazole-induced ferroptosis and mitophagy and markedly attenuated its anti-cancer effects in cervical cancer cells. Additionally, flubendazole enhanced the sensitivity of cervical cancer cells to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition and showed a potent synergistic anti-tumor effect in combination with GPX4 inhibitor in xenograft mouse models. These findings highlight the promising potential of flubendazole as a repurposed drug for cervical cancer therapy by inducing ferroptosis through inhibition of DHODH.
    Keywords:  Cervical carcinoma; DHODH; Ferroptosis; Flubendazole; Mitophagy
    DOI:  https://doi.org/10.1016/j.bcp.2025.117287
  13. J Vis Exp. 2025 Aug 15.
    Quantification of Endothelial Fatty Acid Uptake using Fluorescent Fatty Acid Analogs.
    Ayon Ibrahim, Tanisha Choudhury, Boa Kim.
      Endothelial cells (ECs) play a central role in regulating fatty acid (FA) transport from the bloodstream into metabolic tissues, yet tools to quantify EC FA uptake in a reliable, scalable manner remain limited. Here, we present a rapid, quantitative, and cost-effective assay to measure FA uptake in ECs using fluorescent FA analogs (BODIPY-C12 and BODIPY-C16), which allow investigation of chain length-specific uptake dynamics in a 96-well plate format. The protocol incorporates positive (3-hydroxyisobutyrate, lactate) and negative (niclosamide) controls and is validated in both primary (HUVECs) and immortalized (EA.hy926) EC lines. The assay detects time- and dose-dependent FA uptake, with results normalized to cell number using Hoechst nuclear staining and corrected for background using appropriate controls. It can be adapted to a variety of cell types, imaging modalities, and experimental conditions, including live-cell imaging and pulse-chase formats. Compared to traditional lipid staining or radiolabeled tracers, this method offers improved safety, speed, and versatility while capturing dynamic FA uptake in live cells. This assay provides a robust platform for studying the regulation of endothelial lipid transport and its contribution to metabolic disease.
    DOI:  https://doi.org/10.3791/68859
  14. J Vis Exp. 2025 Aug 15.
    Understanding the Changes in Mitochondrial Morphology through Dynamic and Three-dimensional Fluorescence Micrographs.
    Sholto de Wet, Rensu Theart, Ben Loos, G Angus McQuibban.
      Mitochondria are highly dynamic organelles that are vital to the survival of any animal, undergoing regular fission and fusion events in response to the needs or stresses of the host, leading to the constant remodeling of the mitochondrial network. Because of this, being able to evaluate the mitochondrial network in three dimensions, as well as over time, offers a benefit in understanding how the system responds to factors such as stress or pharmaceutical intervention. Fluorescence imaging of the mitochondrial networks of cells enables the ability to visualize and monitor these changes. However, the mitochondrial network is often described as a two-dimensional and static structure that is defined by unstandardized metrics. Therefore, we set out to describe a pipeline that enables the user to prepare their images for the mitochondrial event localizer (MEL), an ImageJ plugin tool that detects fission and fusion events in the mitochondrial network over time and in a 3-dimensional manner, thus, offering insight into the dynamic changes that this network undergoes. Additionally, we describe the benefits of understanding fission and fusion in light of the changes in the mitochondrial count and morphological changes.
    DOI:  https://doi.org/10.3791/68478
  15. J Biol Chem. 2025 Sep 02. pii: S0021-9258(25)02529-3. [Epub ahead of print] 110677
    FOXO1- mediated argininosuccinate lyase transcription inhibits ammonia metabolism and breast cancer cell metastasis.
    Min Zhao, Dongdong Yuan, Mengmeng Wei, Jie Zhang, Wenjing Yang, Shaojie Qin, Le Li.
      Cancer cells exhibit altered and elevated metabolic processes to meet their increased bioenergetic and biosynthetic demands, leading to the production of ammonia as a byproduct. However, the mechanisms by which tumor cells manage excess ammonia remain poorly understood, despite its critical role in nitrogen metabolism. The urea cycle, a central pathway for ammonia detoxification, has been insufficiently explored in the context of cancer metabolism. In this study, we identify Forkhead box O1 (FOXO1), a transcription factor essential for tumorigenesis and progression, as a key regulator of the urea cycle in breast cancer cells. Specifically, FOXO1 inhibits argininosuccinate lyase (ASL) expression, a crucial enzyme in the urea cycle, leading to reduced ammonia detoxification. Mechanistic analyses reveal that ASL is a direct transcriptional target of FOXO1. Functionally, we demonstrate that FOXO1 modulates the migratory ability of breast cancer cells through the regulation of ASL and arginine metabolism. These findings unveil an unexpected role of FOXO1 in regulating the urea cycle in tumors and highlight a novel mechanism by which breast cancer cells exploit metabolic pathways to support their progression and metastasis. Our study provides valuable insights into cancer metabolism and identifies potential targets for therapeutic intervention.
    Keywords:  ASL; Breast cancer metastasis; FOXO1; Urea cycle
    DOI:  https://doi.org/10.1016/j.jbc.2025.110677
  16. Proc Natl Acad Sci U S A. 2025 Sep 02. 122(35): e2513155122
    Activation of WNK1 signaling through Piezo1.
    Ji-Ung Jung, Steve Stippec, Melanie H Cobb.
      With No lysine (K) 1 (WNK1) is essential for ion and volume homeostasis, sensing osmotic stress and activating pathways that regulate ion transport. Its response to osmotic stress shares similarities with the function of the mechanosensitive ion channel Piezo1. In this study, we show that Yoda1, a Piezo1 agonist, activates WNK1 downstream kinase targets oxidative stress-responsive 1 (OSR1) and STE20/SPS1-related serine, proline-, and alanine-rich kinase (SPAK) in endothelial cells within minutes. Ionophore-induced Ca2+ influx similarly triggers their activation. Comparable responses were observed in HDMEC, HUVEC, A549, MDA-MB-231, and HeLa cells. Hypotonic stress also enhances SPAK and OSR1 phosphorylation, which is attenuated by WNK1 inhibition or Piezo1 knockdown, whereas hypertonic stress-induced phosphorylation is not affected by Piezo1 knockdown. Chelating Ca2+ or depleting intracellular stores prevents their activation, while increasing intracellular Ca2+ via the Na+/Ca2+ exchanger or thapsigargin enhances it. ER-released Ca2+ is sufficient to activate SPAK and OSR1 even in the absence of extracellular Ca2+, and this effect is diminished by Piezo1 knockdown. Both Yoda1 and ionomycin promote phosphorylation of WNK1 at serine 382, a modification that increases its catalytic activity. These findings identify Piezo1 as an activator of WNK1, linking Ca2+ dynamics to WNK1-OSR1/SPAK signaling.
    Keywords:  OSR1; Piezo1; SPAK; WNK1; osmotic stress
    DOI:  https://doi.org/10.1073/pnas.2513155122
  17. EMBO Rep. 2025 Aug 29.
    Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
    Tak Shun Fung, Amrapali Ghosh, Maite R Zavala, Zuzana Nichtova, Dhavalkumar Shukal, Marco Tigano, Gyorgy Csordas, Henry N Higgs, Rajarshi Chakrabarti.
      Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.
    Keywords:  Actin; Arp2/3 Complex; ER; LC3; Parkin
    DOI:  https://doi.org/10.1038/s44319-025-00561-y
  18. EMBO Rep. 2025 Aug 29.
    Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
    Lin Luo, Ana Victoria Lechuga-Vieco, Clara Sattentau, Mariana Borsa, Anna Katharina Simon.
      Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.
    Keywords:  Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing
    DOI:  https://doi.org/10.1038/s44319-025-00536-z
  19. Cell Death Differ. 2025 Sep 03.
    Uridine 5'-monophosphate (UMP) synthesis connects nucleotide metabolism to programmed cell death in C. elegans.
    Hang-Shiang Jiang, Hsiao-Fen Han, Cheng-Yi Chen, Kuan-Lun Hsu, Hung-Tsai Kan, Wan-Ying Lin, Mei-Hsuan Wu, Su-Yi Tsai, Jui-Ching Wu, Yi-Chun Wu.
      Nucleotide metabolism is essential for fundamental cellular functions such as growth, repair and proliferation. Emerging evidence suggests that metabolic pathways also influence programmed cell death (PCD), though the underlying mechanisms remain poorly understood. One model organism that has provided key insights into the regulation of PCD is Caenorhabditis elegans (C. elegans). In this nematode, apoptosis is often initiated through asymmetric cell division (ACD), a process that unequally distributes fate determinants between daughter cells to produce a larger surviving cell and a smaller cell destined for apoptosis. Here, we demonstrate that the simultaneous disruption of PCD and ACD leads to aberrant cell survival and the formation of extra hypodermal cells. Through a genetic screen in the grp-1 ACD mutant background, we identified pyr-1 as a regulator of PCD. pyr-1 encodes the C. elegans carbamoyl-phosphate synthetase/aspartate transcarbamoylase/dihydroorotase (CAD) enzyme which catalyzes the rate-limiting step of de novo pyrimidine biosynthesis, producing uridine 5'-monophosphate (UMP). UMP is a critical metabolite for the synthesis of nucleotides, lipids and carbohydrates. Genetic analysis of UMP metabolic pathways, combined with exogenous nucleoside supplementation, confirms that UMP availability is essential for PYR-1-mediated PCD. Loss of grp-1 induces cellular stress by disrupting fate determinant partitioning during ACD, whereas pyr-1 mutations cause metabolic stress through UMP depletion. While both mutations independently activate autophagy, they function redundantly to upregulate the mitochondrial chaperone hsp-6. Knockdown of autophagy-related genes and hsp-6 reveals that these pathways serve as compensatory mechanisms to protect against cell death in the pyr-1; grp-1 double mutants. Collectively, our findings establish a direct link between metabolism and cell death, demonstrating how UMP availability and proper ACD coordinate apoptotic regulation and developmental outcomes. This study highlights the intricate interplay between metabolic homeostasis and PCD, providing new insights into the metabolic control of cell fate decisions.
    DOI:  https://doi.org/10.1038/s41418-025-01564-x
  20. Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01005-8. [Epub ahead of print]44(9): 116234
    Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
    Shuang Ma, Jianhua Qin, Yao Zhang, Jing Luan, Na Sun, Guoyuan Hou, Jiyuan He, Yang Xiao, Wei Zhang, Minghui Gao.
      Ferroptosis is a regulated necrosis driven by iron-dependent lipid peroxidation. Mitochondria play vital roles in ferroptosis. Mitochondrial dynamics is critical for the health of mitochondria and cells. But how this process regulates ferroptosis is not fully understood. Here, we found that mitochondrial fission is induced during ferroptosis. Disruption of mitochondrial dynamics by impeding the expression of the central players of mitochondrial dynamics control, dynamin-related protein 1 (DRP1) and Mitofusion1/2, or modifying the expression of optic atrophy 1 (OPA1) inhibits ferroptosis. Mechanistically, a defect in mitochondrial dynamics homeostasis increases the ratio of [AMP+ADP]/[ATP], thus activating AMP-activated protein kinase (AMPK), which further phosphorylates nuclear factor erythroid 2-related factor 2 (NRF2) and promotes NRF2 nuclear translocation. Subsequently, NRF2 triggers ferroptosis suppressor 1 (FSP1) upregulation, which renders the cells resistant to ferroptosis. Importantly, mitochondrial fusion promoter M1 can mitigate the chemotoxicity induced by doxorubicin without compromising its anti-cancer efficacy. Collectively, the results of this study demonstrate the crucial role of mitochondrial dynamics in ferroptosis and indicate a potential therapeutic protective approach for chemotoxicity.
    Keywords:  AMPK; CP: Immunology; CP: Metabolism; FSP1; NRF2; chemotoxicity; ferroptosis; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116234
  21. J Biol Chem. 2025 Aug 28. pii: S0021-9258(25)02488-3. [Epub ahead of print] 110636
    β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
    Xiujuan Wei, Chengkai Zhang, Xiaoguang Zheng, Kexin Pan, Xiaojun Ren, Xiaoting Lou, Zhengquan Yang, Ting Fu, Hezhi Fang, Jianxin Lu.
      Ketone bodies are a key alternative energy source during carbohydrate deficiency. In addition to their metabolic function, they regulate essential cellular processes, including metabolism, signal transduction, and protein post-translational modifications (PTMs). However, the role of ketone body metabolism in tumorigenesis remains poorly understood. Here, we demonstrate that ketone body synthesis metabolism is activated in pancreatic cancer, while exogenous ketone supplementation does not affect PDAC cell proliferation. Moreover, we observe a significant upregulation of β-Hydroxybutyrate dehydrogenase (BDH1), a key enzyme in ketone body metabolism, in human pancreatic ductal adenocarcinoma (PDAC) tissues compared to adjacent normal pancreatic tissues. BDH1 promotes PDAC cell proliferation by maintaining mitochondrial acetylation levels through regulation of the intracellular NAD+/NADH ratio. These findings underscore the importance of ketone body metabolism in pancreatic cancer progression and highlight the regulatory role of BDH1 in maintaining cellular NAD+/NADH balance and mitochondrial acetylation.
    Keywords:  BDH1; Ketone body; NAD(+)/NADH; Pancreatic Cancer; mitochondrial acetylation
    DOI:  https://doi.org/10.1016/j.jbc.2025.110636
  22. Nature. 2025 Sep 03.
    Rewiring of cortical glucose metabolism fuels human brain cancer growth.
    Andrew J Scott, Anjali Mittal, Baharan Meghdadi, Alexandra O'Brien, Justine Bailleul, Palavalasa Sravya, Abhinav Achreja, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Ningning Liang, Ayesha U Kothari, Navyateja Korimerla, Donna M Edwards, Zhe Wu, Jiane Feng, Sophia Su, Li Zhang, Peter Sajjakulnukit, Anthony C Andren, Junyoung O Park, Johanna Ten Hoeve, Vijay Tarnal, Kimberly A Redic, Nathan R Qi, Joshua L Fischer, Ethan Yang, Michael S Regan, Sylwia A Stopka, Gerard Baquer, Krithika Suresh, Jann N Sarkaria, Theodore S Lawrence, Sriram Venneti, Nathalie Y R Agar, Erina Vlashi, Costas A Lyssiotis, Wajd N Al-Holou, Deepak Nagrath, Daniel R Wahl.
      The brain avidly consumes glucose to fuel neurophysiology1. Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue2. How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused 13C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.
    DOI:  https://doi.org/10.1038/s41586-025-09460-7
  23. Cancer Res. 2025 Sep 03.
    A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression.
    Justin Chak Ting Cheung, Lok Wan Ng, Zhongxu Zhu, Bonan Chen, Stephen Li, Mingjing Xu, Xiaofan Ding, Dandan Pu, Yi Hu, Yuqing Ren, Wei Kang, Ming Li, Jason Wing Hon Wong, Xin Wang, Yuen Kit Cheng, Wei Shen Aik, Ka Leung Wong, Simon Siu Man Ng, Nathalie Wong, Yujuan Dong.
      Metabolic reprogramming, notably alterations in the tricarboxylic acid (TCA) cycle, has emerged as a hallmark of cancer that supports tumor growth and metastasis. Despite the TCA cycle being a classical central metabolic pathway, further exploration is needed to fully elucidate the intricate manifestations and contributory mechanisms of TCA cycle rewiring in colorectal carcinogenesis. Herein, we identified a splicing isoform of citrate synthase (CS), CS-ΔEx4, and unveiled its role in TCA cycle dysregulation in colorectal cancer (CRC). CS-ΔEx4 was distinctly upregulated in CRC tumors compared with the canonical full-length (CS-FL) isoform. Clinical analyses established a strong correlation between elevated CS-ΔEx4 expression and cancer recurrence as well as inferior survival outcomes in patients with CRC. Functional experiments revealed the active contribution of CS-ΔEx4 to the aggressive phenotype of CRC cells both in vitro and in vivo. Mechanistically, CS-ΔEx4 formed a heterocomplex with CS-FL within the mitochondria that influenced the enzymatic function of canonical CS and accelerated TCA cycle flux, thereby promoting accumulation of the oncometabolite 2-hydroxyglutarate. The CS-ΔEx4-mediated metabolic alterations engendered epigenomic modulations that drove the upregulation of oncogenic gene signatures. In silico screening identified a small molecule with potent anti-proliferative effects in CRC cell line and organoid models that selectively antagonized the CS-ΔEx4 and CS-FL heterocomplex activity while sparing the CS-FL homodimers. Together, this study discovered the presence of a spliced CS isoform that promotes CRC progression and identified a molecule that holds potential for targeting the CS-ΔEx4 and CS-FL heterocomplex.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2355
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