bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–01–25
twenty-six papers selected by
Marc Segarra Mondejar, AINA
  1. Cholesterol depletion activates trafficking-coupled sphingolipid synthesis.
  2. Acetyl-CoA as a metabolic switch for selective mitophagy.
  3. The pivotal role of endoplasmic reticulum in cancer glucose metabolism.
  4. NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
  5. A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.
  6. SLC25A45: a gatekeeper for methylated amino acid metabolism.
  7. Metabolic reprogramming in clear cell renal cell carcinoma: core pathways and targeted therapeutic strategies.
  8. Spatiotemporal regulation of energetic charge dictates T cell function.
  9. Glucose and Oxygen Metabolism Coordinate Human Cortical Developmental Decisions.
  10. Metabolic reprogramming in the post-metastatic tumor microenvironment: multi-omics insights into determinants of immunotherapy response.
  11. Targeting glycolysis in prostate cancer: Molecular mechanisms and therapeutic advances.
  12. Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.
  13. Modeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels.
  14. Metabolite accumulation mediates the shift between the High Oxygen Consumption and Low Oxygen Consumption phases in the Yeast Metabolic Cycle.
  15. Optical photothermal infrared imaging of fatty acid esterification in the ER of living cells.
  16. Deploying the high-throughput virtual screening (HTVS) approach for the identification of new lactate dehydrogenase (LDH) inhibitors with anticancer assets.
  17. Mammalian fatty acid synthase and O-GlcNAc transferase preferentially interact via their respective N-terminal regions.
  18. Targeting immunometabolism in cancer through pharmacological and lifestyle interventions.
  19. Nuclear MBL-1 modulates mitochondrial morphology through carnitine palmitoyltransferase in Caenorhabditis elegans with toxic trinucleotide repeats.
  20. TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
  21. Unraveling COPD pathogenesis: a multi-omics approach to identify metabolites and genetic links.
  22. Immunometabolism in obesity: Understanding the beneficial and detrimental roles of inflammation.
  23. A metabolic link between DNA synthesis and chromatin assembly.
  24. Mechanometabolism of cell adhesion: Vinculin regulates bioenergetics via RhoA-ROCK.
  25. Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.
  26. Basal level of ATF4 promotes T cell readiness for activation-induced proliferation.
  1. J Cell Biol. 2026 Apr 06. pii: e202502083. [Epub ahead of print]225(4):
    Cholesterol depletion activates trafficking-coupled sphingolipid synthesis.
    Yeongho Kim, Jan Parolek, Christopher G Burd.
      Homeostatic pathways maintain the lipid composition of organelle membranes, and mechanistic links between lipid sensing, synthesis, and trafficking are lacking. Acute depletion of cell cholesterol elicits an increase in the rate of very-long-chain (VLC) sphingomyelin synthesis in the Golgi apparatus, thereby promoting cholesterol retention in the plasma membrane. Stable isotope metabolic analyses and lipid trafficking assays showed that the increase in VLC-sphingomyelin results from an increase in the rate of coatomer II-dependent trafficking of VLC-ceramide from the endoplasmic reticulum to the Golgi apparatus. An integral membrane protein of the coatomer II network, cTAGE5, is required for endoplasmic reticulum-to-Golgi trafficking of ceramide and cTAGE5 overexpression caused herniations of the endoplasmic reticulum network that entrapped a synthetic ceramide analog to which cTAGE5 could be photochemically cross-linked. We propose that cTAGE5 is a ceramide sensor for export of VLC-ceramide from the endoplasmic reticulum exit site.
    DOI:  https://doi.org/10.1083/jcb.202502083
  2. Autophagy. 2026 Feb;22(2): 235-237
    Acetyl-CoA as a metabolic switch for selective mitophagy.
    Daolin Tang, Rui Kang, Daniel J Klionsky.
      A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.
    Keywords:  Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2593032
  3. iScience. 2026 Jan 16. 29(1): 114503
    The pivotal role of endoplasmic reticulum in cancer glucose metabolism.
    Cecilia Marini, Maddalena Ghelardoni, Sonia Carta, Tiziana Bachetti, Silvia Bruno, Isotta Cainero, Silvia Ravera, Roberto Benelli, Marco Scotto, Francesca Vitale, Santina Bruzzone, Serena Losacco, Sabrina Chiesa, Matteo Bauckneht, Gabriele Tancreda, Matteo Raineri, Anna Maria Orengo, Andrea Benzi, Gianmario Sambuceti.
      The endoplasmic reticulum (ER) supports essential biosynthetic and quality control functions. These processes rely on sustained energy supply and precise redox control within the ER lumen. While ATP can be imported from mitochondria, pyridine nucleotides are impermeable to the ER membrane, necessitating compartment-specific mechanisms to regulate NAD(H) and NADP(H) pools. Here, we demonstrate that the ER-confined pentose phosphate pathway (ER-PPP), driven by hexose-6-phosphate dehydrogenase (H6PD), processes large amounts of glucose equivalents to preserve the local redox homeostasis in triple-negative breast cancer (TNBC) cells. H6PD silencing decreases the NADPH regeneration within the ER lumen. The consequent impairment of protein folding machinery accelerates lysosomes generation, up to disrupt the equivalence between the cell release of lactate and H+. Finally, the simultaneous impairment of glucose-6P (G6P) degradation (by H6PD silencing) and hydrolysis (by silencing glucose-6-phosphatase) eventually results in a measurable ER collapse documenting the high-rate nature of G6P flux across the reticular membrane.
    Keywords:  Cancer; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.114503
  4. JCI Insight. 2026 Jan 23. pii: e181812. [Epub ahead of print]11(2):
    NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
    Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro Tm Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B Orger, Philipp Gut.
      Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2-/- zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2-/- zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.
    Keywords:  Cell biology; Genetic diseases; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.181812
  5. Nat Commun. 2026 Jan 17.
    A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.
    Wenjing Yan, Daniel C Talley, Antara Syam, Carina Danchik, Yongwang Zhong, Xianzheng Zhang, Xiaoying Liu, Bolormaa Baljinnyam, Stephen C Kales, Matthew G Cyr, Yuhong Fang, Alexey V Zakharov, Xin Hu, Taylor Niehoff, Tuan Xu, Yanyan Qu, Allison Yang, Valentine V Courouble, Qin Yao, Anton Simeonov, Ruili Huang, Tatiana K Rostovtseva, Sergey M Bezrukov, Christopher A LeClair, Josephine M Egan, Hua Wang, Dingyin Tao, Ganesha Rai, Mark J Henderson, Shengyun Fang.
      Endoplasmic reticulum-associated degradation (ERAD) is a critical protein quality control mechanism that also regulates lipid metabolism and calcium homeostasis. Dysregulation of ERAD and unfolded protein response underlies diseases including cancer, neurodegenerative disorders, and metabolic syndromes. Small molecule modulators of ERAD could enable mechanistic discovery and therapeutic intervention, but few have been identified. Using a high-content screening, we discovered several ERAD-modulating compounds, including NCATS-SM0225, an ERAD inhibitor that unexpectedly binds all three isoforms of VDAC, outer mitochondrial membrane proteins enriched at mitochondria-associated membranes. This led us to discover an essential role for VDACs in ERAD and ER-phagy. NCATS-SM0225 elevates cytosolic, ER, and mitochondrial calcium through calcium influx and IP3R-MCU activity. This calcium imbalance strengthens VDAC1-IP3R coupling and activates PERK, which phosphorylates STIM1 and drives degradation of key ERAD regulators. Loss of these components amplifies PERK signaling and selectively kills cancer cells while sparing normal cells. These findings uncover a cancer-specific role of VDACs in ERAD regulation and calcium signaling, highlighting a therapeutically actionable vulnerability.
    DOI:  https://doi.org/10.1038/s41467-025-67816-z
  6. Trends Endocrinol Metab. 2026 Jan 22. pii: S1043-2760(25)00283-8. [Epub ahead of print]
    SLC25A45: a gatekeeper for methylated amino acid metabolism.
    Yue Zhang, Yan Tian, Xianghui Fu.
      The metabolite substrates of numerous transporters remain largely elusive. Two recent studies by Khan et al. and Dias et al. identify SLC25A45 as a mitochondrial transporter of methylated amino acids that supports de novo carnitine synthesis, providing a valuable strategy for deorphanizing transporters and novel insights into cytoplasm-mitochondria communication and metabolic coordination.
    Keywords:  carnitine biosynthesis; fasting; machine learning; mitochondria; trimethyllysine
    DOI:  https://doi.org/10.1016/j.tem.2025.12.005
  7. Front Genet. 2025 ;16 1752384
    Metabolic reprogramming in clear cell renal cell carcinoma: core pathways and targeted therapeutic strategies.
    MingWei Zhan, BinBin Zhao, Haote Chen, Junjie Wu, Run Shi, Feng Gao, Lin Zhao, Jingyu Zhu.
      Clear cell renal cell carcinoma (ccRCC), rooted in VHL loss and dysregulated HIF signaling, is defined by a sweeping metabolic overhaul: intensified glycolysis, a "downshifted" TCA cycle, the buildup of lipid droplets and cholesteryl esters, and a pronounced dependence on glutamine and one-carbon metabolism-all tightly intertwined with an immunosuppressive microenvironment. Drawing on single-cell and spatial multi-omics, metabolomic and lipidomic profiling, and imaging-based evidence, this article maps the critical nodes of carbon, lipid, amino-acid, and one-carbon pathways, and their crosstalk with ferroptosis. It highlights how metabolic heterogeneity-exemplified by the DCCD spectrum-shapes prognosis and therapeutic response. The review further synthesizes how metabolic-immune coupling, including lipid metabolic rewiring in TAMs and MDSCs, and lactate/lipid stress in CD8+ T cells, contributes to immune-therapy resistance. On the translational front, HIF-2α inhibitors (such as belzutifan), strategies that suppress or oxidize lipids to trigger ferroptosis, and interventions targeting glutamine and one-carbon metabolism show promise when rationally combined with ICIs, TKIs, or anti-angiogenic therapies. We propose a stratified decision framework anchored in DCCD state, lipid-droplet/PLIN2 phenotype, ferroptosis sensitivity, and HIF activity, and discuss the emerging roles of radiopathomics (e.g., CT HU-PLIN2 coupling) and circulating metabolic fingerprints in companion diagnostics. Looking toward clinical deployment, advancing standardization within MSI/IBSI and FAIR data principles-and launching biomarker-enriched, prospective multicenter trials-will be essential to demonstrate the real-world value of precision metabolic oncology in the personalized treatment of ccRCC.
    Keywords:  DCCD; belzutifan; clear cell renal cell carcinoma (ccRCC); ferroptosis; glutamine metabolism; immunometabolism; lipid droplets/PLIN2; one-carbon metabolism
    DOI:  https://doi.org/10.3389/fgene.2025.1752384
  8. Nat Commun. 2026 Jan 21. 17(1): 770
    Spatiotemporal regulation of energetic charge dictates T cell function.
    Aleksandra S Chikina, Béatrice Corre, Fabrice Lemaître, Philippe Bousso.
      Immune cell functions are dictated by their differentiation state and regulated by transcriptional and epigenetic changes. Immune cell differentiation also controls the preferential metabolic pathways used for energy production. However, whether the energy charge of individual immune cells itself varies across time and space and regulates cell function remains to be fully understood. Here, we show that T cells harbor distinct energetic resources and function in different anatomical locations and times of the day. To monitor ATP: ADP ratio, an indicator of cellular energetic resources, we rely on SPICE-Met, a method that dissects energy metabolism in complex cell populations in vivo. We find that cells with the highest glycolytic capacity, including effector T cells and NK cells, exhibit the highest ATP: ADP ratio. Importantly, effector T cells but not naïve T cells display higher energetic charge when present in the blood compared to lymph nodes due to differential glucose availability. Energetic resources are also regulated in a circadian manner, being highest at the early rest phase. Importantly, differences in energetic charge are directly translated at the level of T cell function, impacting IFN-γ production. Thus, modulation of energetic charge and nutrient availability dictates immune cell function across time and space.
    DOI:  https://doi.org/10.1038/s41467-026-68559-1
  9. bioRxiv. 2025 Dec 05. pii: 2025.12.02.691634. [Epub ahead of print]
    Glucose and Oxygen Metabolism Coordinate Human Cortical Developmental Decisions.
    Taylor R Pennington, Alexandria S M Morales, Ammar Mehdi, Sophia A Cerna, Gradi Bamfonga, Jinhua Chi, Alicia M Saarinen, Sierra Wilferd, Fabiha Firoz, Tran Nguyen, Lingjun Li, Haiwei Gu, Benjamin Bartelle, Christopher Plaisier, Clifford Folmes, Madeline G Andrews.
      Defining metabolic regulation of neurodevelopmental programs is essential to approach developmental disorders and injuries driven by alterations in metabolism. In vitro cultures are the only available method to temporally perturb and study living human brain cells throughout neurogenesis, however most culture systems use supraphysiologic conditions of essential nutrients, glucose and oxygen. We probed how environmental exposure to endogenous-like concentrations impact metabolic state and developmental progression of cortical cell types using organoids. Nutrient accessibility globally impacted metabolic state, yet developmental responses to metabolic changes were cell type-specific. Metabolomic and transcriptomic datasets reveal increased TCA metabolites and amino acids and oxidative phosphorylation (OXPHOS) genes, under physiologic glucose conditions. Oxygen level had a modest, yet specific, molecular impact on deep layer excitatory neurons. We assessed consequences of metabolic changes on fate and observed that physiologic glucose expanded the human-enriched population of cortical stem cells, outer radial glia, and their progeny, upper layer excitatory neurons. Alterations in oxygen, instead, affected production of neurogenic progenitors and neuronal differentiation, with higher oxygen availability supporting shifts toward mitochondrial metabolism necessary for maturing cell types. We functionally tested this transition by inhibiting glycolysis; total inhibition promoted neuronal differentiation, whereas inhibition of anaerobic glycolysis/lactate production led to oRG expansion. Lactate signaling was sufficient to suppress oRG development and promote self-renewal of neurogenic progenitors. These data suggest that refined metabolic switches and decreased reliance on glucose are required for transition from stem cell self-renewal to more mature, diversified progenitor subtypes, where switch from anaerobic to aerobic metabolism discretely impacts progenitor diversification.
    DOI:  https://doi.org/10.64898/2025.12.02.691634
  10. Front Immunol. 2025 ;16 1742855
    Metabolic reprogramming in the post-metastatic tumor microenvironment: multi-omics insights into determinants of immunotherapy response.
    Mengxi Li, Tingting Wang, Zhenwang Zhang, Yuxi Dongye.
      Metabolic reprogramming has emerged as a central determinant of immune modulation in the post-metastatic tumor immune microenvironment (TIME). Alterations in glycolysis and lactate accumulation, lipid metabolic rewiring, metal-dependent cell death pathways such as ferroptosis and cuproptosis, and the tryptophan-IDO1-kynurenine axis collectively contribute to an immunosuppressive niche that drives tumor progression and therapeutic resistance. These metabolic shifts are not isolated events but are intricately connected with immune-regulatory networks, profoundly influencing the efficacy of immunotherapy. Advances in multi-omics technologies-including metabolomics, proteomics, single-cell sequencing, and spatial omics-have provided unprecedented resolution to decode these complex interactions, enabling the identification of predictive biomarkers, delineation of metabolic-immune signatures, and discovery of therapeutic vulnerabilities. Integrating these multi-layered datasets has paved the way for precision medicine strategies that tailor immunotherapy to patient-specific metabolic and immune contexts. Therapeutically, combining metabolic inhibitors with immune checkpoint blockade, exploiting ferroptosis or cuproptosis to enhance tumor immunogenicity, or modulating amino acid metabolism to reverse immune tolerance are promising strategies to overcome resistance and expand patient benefit. Looking forward, the integration of multi-omics-guided biomarkers, AI-driven analytics, and advanced delivery systems such as nanoparticles and engineered exosomes will accelerate the translation of these insights into clinical practice. Decoding the metabolism-immunity crosstalk through multi-omics not only advances our understanding of metastatic cancer biology but also paves the way for next-generation personalized and adaptive therapies that promise to enhance immunotherapy efficacy, prolong survival, and improve the quality of life for patients with advanced cancers.
    Keywords:  immunotherapy resistance; metabolic reprogramming; multi-omics integration; precision oncology; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1742855
  11. Biochim Biophys Acta Rev Cancer. 2026 Jan 16. pii: S0304-419X(26)00009-0. [Epub ahead of print]1881(2): 189537
    Targeting glycolysis in prostate cancer: Molecular mechanisms and therapeutic advances.
    Jiexiang Zhang, Tongtong Zhang, Dexin Song, Dongliang Xu.
      Prostate cancer (PCa) is the second most common cancer among men worldwide and poses a significant threat to male health. A key feature of tumor progression is metabolic reprogramming, which involves the abnormal activation of glycolysis. This metabolic process supports PCa proliferation, metastasis, and drug resistance through rapid energy production, the provision of biosynthetic precursors, and the remodeling of the tumor microenvironment (TME). Key enzymes such as hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase M2 (PKM2), glucose transporters (GLUTs), and lactate dehydrogenase A (LDHA) play pivotal roles in regulating aerobic glycolysis in PCa cells. Glycolytic enzymes are modulated by a variety of mechanisms, including the PI3K/AKT and AMPK signaling pathways, hypoxia-inducible factor 1α (HIF-1α), c-Myc, and non-coding RNAs. Current therapeutic strategies targeting glycolysis include natural products and small-molecule inhibitors. Targeting glycolysis presents novel opportunities to address existing limitations in PCa management. This review discusses the advances, challenges, and future research directions in glycolysis-focused PCa studies, providing a theoretical foundation for the development of precise metabolic interventions.
    Keywords:  Glycolysis; Metabolic reprogramming; Molecular mechanism; Prostate cancer; Therapeutic advance; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189537
  12. Cell Rep. 2026 Jan 19. pii: S2211-1247(25)01629-8. [Epub ahead of print]45(1): 116857
    Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.
    Sneha Shah, Daniel Barnes, Botao Liu, Tenzin Tseyang, Thang Do, Jodi L Bubenik, Suna Jung, Mina N Anadolu, Maria P Ivshina, Verónica Martínez-Cerdeño, Elizabeth Berry-Kravis, Maurice S Swanson, Jessica B Spinelli, Joel D Richter.
      Metabolic homeostasis gone awry is a contributor to, if not an underlying cause of, several neurologic disorders. Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in FMR1 and consequent loss of the encoded protein FMRP, which results in downstream molecular, neurologic, and mitochondrial deficits that are linked to cognitive impairment. In the human postmortem brain, many metabolites and solute carrier proteins are coordinately dysregulated, which also occurs during the differentiation of human induced pluripotent stem cells (iPSCs) into excitatory neurons. Metabolic tracing in FXS neurons demonstrates a dearth of glutamine deamidation to glutamate, which reduces anaplerosis into the TCA cycle, potentially hindering the bioenergetic and biosynthetic functions of mitochondria. Mechanistically, aberrant expression of glutaminase isoforms in FXS is responsible for reduced glutaminolysis, thereby altering glutamate levels, which may contribute to FXS.
    Keywords:  CP: metabolism; CP: neuroscience; Fragile X syndrome; glutamate transporters; glutaminase; human neurons; iPSC; metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116857
  13. Nat Commun. 2026 Jan 19.
    Modeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels.
    Sun Jin Moon, Yanhui Hu, Monika Dzieciatkowska, Ah-Ram Kim, John M Asara, Angelo D'Alessandro, Norbert Perrimon.
      Individual tissues perform highly specialized metabolic functions to maintain whole-body metabolic homeostasis. Although Drosophila serves as a powerful model for studying human metabolic diseases, modeling tissue-specific metabolism has been limited in this organism. To address this gap, we reconstruct 32 tissue-specific genome-scale metabolic models (GEMs) by integrating a curated Drosophila metabolic network with pseudo-bulk single-nuclei transcriptomics data, revealing distinct metabolic network structures and subsystem coverage across tissues. We validate enriched pathways identified through tissue-specific GEMs, particularly in muscle and fat body, using metabolomics and pathway analysis. Moreover, to demonstrate the utility in disease modeling, we apply muscle-GEM to investigate high sugar diet (HSD)-induced metabolic dysregulation. Constraint-based semi-quantitative flux and sensitivity analyses identify altered NAD(H)-dependent reactions and distributed control of glycolytic flux, including GAPDH. This prediction is further validated through in vivo 13C-glucose isotope tracing study. Notably, decreased glycolytic flux, including GAPDH, is linked to increased redox modifications. Finally, our pathway-level flux analyses identify dysregulation in fructose metabolism. Together, this work establishes a quantitative framework for tissue-specific metabolic modeling in Drosophila, demonstrating its utility for identifying dysregulated reactions and pathways in muscle in response to HSD.
    DOI:  https://doi.org/10.1038/s41467-026-68395-3
  14. bioRxiv. 2025 Dec 02. pii: 2025.12.01.691504. [Epub ahead of print]
    Metabolite accumulation mediates the shift between the High Oxygen Consumption and Low Oxygen Consumption phases in the Yeast Metabolic Cycle.
    Salvador Casani-Galdon, Shidong Xi, Jane Mellor, Sonia Tarazona, Ana Conesa.
      The Yeast Metabolic Cycle (YMC) is a molecular system that serves as a model to study the internal clock that maintains homeostasis in complex organisms. Traditionally, this ultradian rhythm has been studied in the three phases where mature mRNA transcripts show peak accumulation. However, recent studies have shown that the YMC can be interpreted as a two-phase cycle based on altered redox states, known as the high (HOC) and low oxygen consumption (LOC) phases. The length of the HOC phase is fixed and its frequency is nutrient dependent but the nature of the HOC to LOC transition is poorly defined. Here, we use multivariate statistics to integrate metabolic, chromatin and transcriptional changes across the YMC to study the levels of organization that connect them. Our model reveals that both the HOC-LOC and LOC-HOC phase transitions in the YMC are coordinated by accumulating metabolites, reflecting cellular energetics and redox state. We propose that the cycling behavior of chromatin states, transcription and transcripts is a consequence of accumulating metabolites at phase transitions, which function by modulating protein activity and coordinating biochemical pathways to maintain cellular homeostasis.
    DOI:  https://doi.org/10.64898/2025.12.01.691504
  15. bioRxiv. 2025 Dec 11. pii: 2025.12.09.693044. [Epub ahead of print]
    Optical photothermal infrared imaging of fatty acid esterification in the ER of living cells.
    Hannah B Castillo, Caitlin M Davis.
      Lipotoxicity is an accumulation of lipids that leads to cell death and metabolic disease. Saturated fatty acids are more likely to cause lipotoxicity, however, the mechanism remains unclear due to challenges visualizing reactions in live cells. Here, we use optical photothermal infrared (OPTIR) microspectroscopy to investigate palmitic acid (PA) metabolism in hepatocytes with sub-micron spatial resolution. Upon PA feeding, we discover a time-dependent ester carbonyl stretch localized to the ER and lipid droplet-ER contact sites of lipid droplets with abnormal morphology. This stretch is assigned to diacylglycerol intermediates in the glycerol-3-phosphate pathway. C-D stretches of deuterated PA provide complementary molecular details, supporting a model whereby PA acyl chain packing in the ER reduces enzyme diffusion slowing PA metabolism. Our results provide a deeper understanding of how phase changes induced by high melting temperature fatty acids and their metabolites change ER chemistry as well as provides a tool for detecting chemical and environmental changes associated with lipotoxicity in live cells.
    Teaser: Sub-micron IR imaging of palmitic acid metabolism in live cells reveals diacylglycerol buildup and gel phase changes in the ER.
    DOI:  https://doi.org/10.64898/2025.12.09.693044
  16. Sci Rep. 2026 Jan 21.
    Deploying the high-throughput virtual screening (HTVS) approach for the identification of new lactate dehydrogenase (LDH) inhibitors with anticancer assets.
    Yaxun Huang, Sangeeta Benni, Umesh Prasad Yadav, M Arockia Babu, Akash Verma, Thakur Gurjeet Singh, Nisha Bansal, Yulong Zhang.
      The tumor cells frequently rely on glycolysis to produce adenosine 5'-triphosphate (ATP), even when sufficient oxygen is available to allow oxidative phosphorylation (the Warburg effect). In these malignancies, the breakdown of glucose to pyruvate, instead of reaching the mitochondria, is transformed to lactate by an enzyme called lactate dehydrogenase (LDH) and then expelled by the cells, further fuelling the tumour microenvironment (TME). LDH facilitates the translation of pyruvate to lactate, hence replenishing the required NAD + equivalents for the ongoing glycolysis process. Having a pivotal role in cancer cells' prognosis and survival, and affecting the TME. To date, no inhibitors have yet been approved against the LDH. However, numerous clinical trials are ongoing, and results are yet to be awaited. Considering the existing gap, we present herein a high-throughput virtual screening (HTVS) approach to identify new compounds that effectively inhibit LDH activity. We generated the pharmacophore model based on 28 LDH enzyme inhibitors from previous literature. The model was used to screen 500,000 ligands in addition to their molecular docking and drug-likeness filtering. The analysis led to the identification of 5 hits, which were further subjected to the MD simulations. Further considering the outcome of molecular dynamics results, we selected ligands 15 and 422 to corroborate their anticancer potential via inhibiting the LDH enzyme. The biological validation revealed that both ligands, 15 and 422, possess IC50 values of 147.34 and 206.35 nM, respectively, against LDH. The anticancer potential analysis of DU-145 and PC-3 also established their anticancer properties, and both compounds were found to marginally elevate oxidative stress, change mitochondrial membrane potential, and induce apoptosis in DU-145 cells.
    DOI:  https://doi.org/10.1038/s41598-026-36385-6
  17. Biochem Biophys Rep. 2026 Mar;45 102427
    Mammalian fatty acid synthase and O-GlcNAc transferase preferentially interact via their respective N-terminal regions.
    Dimitri Vanauberg, Céline Schulz, Guillaume Brysbaert, Nessim Raouraoua, Peggy Mistarz-Gruau, Marc F Lensink, Anne-Sophie Vercoutter-Edouart, Tony Lefebvre.
      Fatty Acid Synthase (FASN) is a central enzyme in the de novo lipogenesis pathway. By producing fatty acids, FASN is implicated in numerous crucial cellular processes, but it is also frequently overexpressed in cancer. O-GlcNAc Transferase (OGT) governs the addition of N-acetylglucosamine residues onto cytosolic, nuclear and mitochondrial proteins. Like FASN, OGT actively participates in carcinogenesis. We previously showed that OGT regulates FASN in different ex vivo and in vivo models. Reciprocally, FASN promotes OGT expression and activity. The two enzymes physically interact together and contribute to cancer cell survival. It is therefore fundamental to define the respective interaction region of each enzyme to explore new therapeutic solutions for patients suffering from cancer. By using the hepatocarcinoma cell line Hep3B, we show thanks to two series of deletion mutants that both enzymes preferentially interact via their respective N-terminal regions. Analysis of the O-GlcNAc status of the various FASN deletion mutants shows that stronger interaction with OGT correlates with higher glycosylation, suggesting that OGT catalyzes the transfer of GlcNAc with limited substrate specificity.
    Keywords:  Fatty acid synthase; Liver cancer cells; N-terminal region; O-GlcNAc transferase; O-GlcNAcylation
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102427
  18. PLoS Biol. 2026 Jan 20. 24(1): e3003617
    Targeting immunometabolism in cancer through pharmacological and lifestyle interventions.
    Rachael Julia Yuenyinn Tan, Yalei Liu, Weixin Chen, Yuteng Liang, Guang Sheng Ling.
      Immunometabolism, a fundamental biogenic process that supports the function of immune cells, is often disrupted in diseases such as cancer. Tackling metabolic dysregulation at a cellular level has therefore emerged as a focus in drug development. However, as cellular metabolic rewiring takes place in response to both intrinsic factors, which can be targeted pharmacologically, and environmental changes, which cannot, fostering a homeostatic systemic metabolism through diet, exercise, and stress management is essential to support and sustain cellular fitness. This Essay conceptualizes immunometabolism as a process that can be regulated intrinsically and extrinsically and explores the potential for incorporating lifestyle changes and drug therapies that target immunometabolism into treatments for cancer.
    DOI:  https://doi.org/10.1371/journal.pbio.3003617
  19. Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2514994123
    Nuclear MBL-1 modulates mitochondrial morphology through carnitine palmitoyltransferase in Caenorhabditis elegans with toxic trinucleotide repeats.
    Joana Teixeira, Mikko J Frilander, Ove Eriksson, Susana M D A Garcia.
      Expansion of nucleotide repeat sequences is linked to a growing number of neuromuscular degenerative disorders. Metabolic changes, including disruptions in mitochondrial function and dynamics, characterize these disorders and are believed to contribute to organismal toxicity. To investigate how toxic RNA repeats affect mitochondria, we used a Caenorhabditis elegans model that expresses expanded CUG repeat RNAs in muscle cells and recapitulates muscle dysfunction. We found that the RNA-binding protein Muscleblind-like 1 (MBL-1) is essential for normal mitochondrial function and regulates organelle morphology. In animals expressing expanded CUG repeats, where MBL-1 function is impaired, we identified two distinct mechanisms of mitochondrial disruption: altered mitochondrial morphology regulated by MBL-1, and oxidative phosphorylation (OxPhos) dysfunction occurring independently of MBL-1. Our data further show that changes in mitochondrial morphology are specifically linked to nuclear MBL-1 dysfunction, which affects cpt-3 expression, a gene encoding carnitine palmitoyltransferase-an enzyme required for fatty acid transport into mitochondria. This mechanism is conserved, with similar disruptions observed in patients with Myotonic Dystrophy type 1. Importantly, our findings indicate that increased organelle fragmentation is not central to cellular pathogenesis. Instead, OxPhos dysfunction appears to be a primary contributor to organismal toxicity.
    Keywords:  Caenorhabditis elegans; RNA repeat toxicity; carnitine palmitoyl transferase; mitochondrial dysfunction; muscleblind-like
    DOI:  https://doi.org/10.1073/pnas.2514994123
  20. FASEB J. 2026 Jan 31. 40(2): e71467
    TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
    Yuxuan Zhang, Ximeng Wang, Dachuan Li, Xiao Lu, Zhaoyang Gong, Zhidi Lin, Hanqiu Sun, Hongli Wang, Zian Lu, Xiaosheng Ma, Guangyu Xu, Jianyuan Jiang.
      The polarization state of microglia exerts an influence on neuroinflammation and neural tissue repair after injury. Modulating microglial polarization is emerging as a potential therapeutic strategy for various types of neural injuries and neurodegenerative diseases. However, the causal relationship between microglial polarization and mitochondrial dynamics, which include mitochondrial fusion and fission, remains to be fully clarified. Our study demonstrates that mitochondrial fusion promoter M1 promotes mitochondrial fusion in mouse microglial cells, leading to reduced glycolysis and increased fatty acid oxidation, and this metabolic reprogramming impacts microglial polarization. Additionally, in both cellular and animal experiments, it was observed that knocking down mitochondrial transcription factor A (TFAM) results in increased mitochondrial fission, decreased fatty acid β-oxidation, enhanced glycolysis, and promotes the polarization of microglia toward the pro-inflammatory M1 phenotype. In conclusion, our study has, for the first time, provided evidence that TFAM may play a role in the regulation of mitochondrial dynamics. Furthermore, we provide a detailed elucidation of the chronological sequence and underlying causal relationships among mitochondrial dynamics, mitochondrial metabolic reprogramming, and microglial polarization. These findings offer novel targets and strategies for the treatment of various neural injuries and neurodegenerative diseases.
    Keywords:  TFAM; cell polarization; fatty acid oxidation; glycolysis; metabolism; microglia; mitochondria
    DOI:  https://doi.org/10.1096/fj.202503182RR
  21. Sci Rep. 2026 Jan 22.
    Unraveling COPD pathogenesis: a multi-omics approach to identify metabolites and genetic links.
    MingQiang Zeng, JinWang Liu, XiaoYing Cao, XiaoRong Deng, Wei Li, Jing Qiu, Kai Yang, YiKe Huang.
      
    Keywords:  ACACA; COPD; Fatty acid metabolism; Mendelian randomization; Multi-omics validation; Salbutamol
    DOI:  https://doi.org/10.1038/s41598-026-36368-7
  22. PLoS Biol. 2026 Jan 21. 24(1): e3003620
    Immunometabolism in obesity: Understanding the beneficial and detrimental roles of inflammation.
    Yun Sok Lee.
      In obesity, nutrient excess and altered adipocyte secretory profiles reprogram cell-intrinsic metabolism, leading to the activation of immune cells within metabolically active tissues such as adipose tissue. This obesity-associated chronic low-grade metabolic inflammation (often referred to as metaflammation) is a well-established driver of insulin resistance and metabolic dysfunction. However, several lines of emerging evidence suggest that metaflammation is not merely a pathologic process, but may also serve as an adaptive response that supports metabolic homeostasis, particularly at the early stages of obesity. This Essay discusses immunometabolic mechanisms underlying the dual nature of metaflammation in obesity, highlighting how its initially beneficial effects can transition into detrimental outcomes.
    DOI:  https://doi.org/10.1371/journal.pbio.3003620
  23. Trends Biochem Sci. 2026 Jan 16. pii: S0968-0004(25)00306-8. [Epub ahead of print]
    A metabolic link between DNA synthesis and chromatin assembly.
    Laura Quintero-Pantoja, Gonzalo Millán-Zambrano.
      Metabolic enzymes are emerging as key regulators of nuclear processes. A recent study by Srivastava et al. shows that the nucleotide biosynthetic enzyme phosphoribosyl pyrophosphate synthetase 1 participates in early histone maturation, highlighting a direct molecular link between metabolic state and chromatin assembly.
    Keywords:  H3–H4 chromatin assembly; histone maturation; nucleotide metabolism; phosphoribosyl pyrophosphate synthetase 1
    DOI:  https://doi.org/10.1016/j.tibs.2025.12.014
  24. J Cell Biol. 2026 Mar 02. pii: e202504025. [Epub ahead of print]225(3):
    Mechanometabolism of cell adhesion: Vinculin regulates bioenergetics via RhoA-ROCK.
    Emily D Fabiano, Elle P Techasiriwan, Lindsey N Sabo, Nathaniel Seluga, Brenton D Hoffman, Cynthia A Reinhart-King.
      Cell migration and cytoskeletal remodeling are energetically demanding processes. Reorganizing the cytoskeleton requires ATP to fuel the actomyosin complex, enabling cells to adhere to and migrate through a matrix. While it is known that energy is required for cell migration, the mechanism by which cell-extracellular matrix adhesion influences cell energetics is unclear. Here, we investigated the relationship between cell-extracellular matrix adhesion and cellular metabolic state with a focus on vinculin given its role in connecting the cytoskeleton to focal adhesions and extracellular space. Knocking out vinculin increases the metabolic activity in cells and results in fast, frequent Rho kinase activity-dependent changes in cell shape and protrusions. The cellular protrusion dynamics and bioenergetics are interrelated processes, as stimulating RhoA/Rho kinase activity increases dynamic blebbing protrusions and energy production, and inhibiting metabolism decreases the frequency of blebbing cell protrusions. This link between cell-extracellular matrix adhesion and bioenergetics provides a novel basis by which cellular metabolism and cell migration could be controlled.
    DOI:  https://doi.org/10.1083/jcb.202504025
  25. Nat Immunol. 2026 Jan 19.
    Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.
    Floortje J van Haften, Tetje C van der Sluis, Hanna S Hepp, Nils Mülling, Reza Nadafi, Bharath Sampadi, Suzanne van Duikeren, J Shirin Mostert, Rosemarijn van der Sterre, Peter A van Veelen, Graham A Heieis, Dominique M B Veerkamp, Thomas H Wesselink, Ward Vleeshouwers, Macha Beijnes, Iris N Pardieck, Eralin L F van Horssen, Anne F de Groot, Manon van der Ploeg, Judith R Kroep, Noel F C C de Miranda, Sabina Y van der Zanden, Jacques Neefjes, Hailiang Mei, Alfred C O Vertegaal, Bart Everts, Sjoerd H van der Burg, Ramon Arens.
      Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8+ T cells that undergo synchronized proliferation and differentiation. How CD8+ T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8+ T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8+ T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8+ T cells following arrest. Transient arrest in vivo enables superior CD8+ T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8+ T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.
    DOI:  https://doi.org/10.1038/s41590-025-02407-0
  26. iScience. 2026 Jan 16. 29(1): 114277
    Basal level of ATF4 promotes T cell readiness for activation-induced proliferation.
    Yushan Yi, Ce Luo, Jingyi Wang, Yujia Wang, Lixue Jin, Xiuyuan Sun, Jie Hao, Guoping Deng, Rong Jin, Qing Ge.
      Stress-response elements are required during late-phase T cell activation and differentiation. To investigate whether they are indispensable during the first 12-24 h post-stimulation when mitochondrial activation and metabolic reprogramming are critical, we activated Atf4-sufficient and Atf4-deficient T cells and tracked their earliest activation dynamics. We demonstrate that T cell activation-induced mTOR and GCN2 phosphorylation leads to the upregulation of ATF4 protein as early as 12 h after stimulation. This early induction of ATF4 has transcriptional activities that regulate stress response, signaling, and metabolism. Loss of Atf4 in T cells alters transcriptome dynamics, impairs amino acid transport and biosynthesis, and disrupts adaptive responses to ER stress and oxidative stress, resulting in defective effector cell differentiation in vitro or in vivo. Our findings suggest that a basal level of ATF4 during the early phase of T cell activation enhances the preparedness of cells to cope with integrated stresses during the activation course.
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2025.114277
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