bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–07–06
24 papers selected by
Marc Segarra Mondejar
  1. Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.
  2. Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.
  3. Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.
  4. A constricted mitochondrial morphology formed during respiration.
  5. Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
  6. Uncovering subtype-specific metabolic signatures in breast cancer through multimodal integration, attention-based deep learning, and self-organizing maps.
  7. SLC44A2 negatively regulates mitochondrial fatty acid oxidation to suppress colorectal progression by blocking the MUL1-CPT2 interaction.
  8. The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.
  9. Severe acute hypoxia upregulates anaerobic metabolism in non-reproductive but not queen naked mole-rats.
  10. The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
  11. Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
  12. Molecular machineries and pathways of mitochondrial protein transport.
  13. Theanine modulation of monoamine metabolism visualized by derivatized imaging mass spectrometry.
  14. Dimerization and substrate recognition of human taurine transporter.
  15. Inhibition of the Na+-glucose transporter SGLT2 reduces glucose uptake and IFNγ release from activated human CD4+ T cells.
  16. Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.
  17. The role and therapeutic potential of glucose metabolism in multidrug resistance of cancer.
  18. The intracellular Ca2+ sensitivity of transmitter release in glutamatergic neocortical boutons.
  19. Progress on multifunctional transmembrane protein ATG9A.
  20. Human VDAC3 as a sensor of the intracellular redox state: contribution to cytoprotection mechanisms in oxidative stress.
  21. Dynamic mode decomposition for analysis and prediction of metabolic oscillations from time-lapse imaging of cellular autofluorescence.
  22. Triglycerides are an important fuel reserve for synapse function in the brain.
  23. MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
  24. Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
  1. Int J Biol Sci. 2025 ;21(9): 4252-4269
    Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.
    Zhiwei Xu, Xiangzheng Gao, Dade Rong, Jingyao Wang, Liangliang Gao, Mingzhu Tang, Yiguan Chen, Yichi Zhang, Liming Xie, Liming Wang, Guang Lu, Jia-Hong Lu, Wei Liu, Han-Ming Shen.
      Mitophagy is a selective form of autophagy for the clearance of damaged and dysfunctional mitochondria via the autophagy-lysosome pathway. As mitochondria are the most important metabolic organelles, the process of mitophagy is tightly regulated by glucose metabolism. At present, it is known that glucose is required for the mitophagy process, while the underlying mechanisms remain to be further elucidated. In this study, we establish a novel regulatory role of glucose metabolism in mitophagy via protein O-GlcNAcylation. First, we found that acute mitochondrial damage enhanced glucose uptake and promoted protein O-GlcNAcylation. Second, we provided evidence that protein O-GlcNAcylation promotes PINK1-Parkin-dependent mitophagy. Next, we attempted to illustrate the molecular mechanisms underlying the regulation of O-GlcNAcylation in mitophagy by focusing on PTEN-induced kinase 1 (PINK1). One important observation is that PINK1 is O-GlcNAcylated upon acute mitochondrial damage, and suppression of O-GlcNAcylation impairs PINK1 protein stability and its phosphorylated ubiquitin, leading to impaired mitophagy. More importantly, we found that glucose metabolism promotes mitophagy via regulating O-GlcNAcylation. Taken together, this study demonstrates a novel regulatory mechanism connecting glucose metabolism with mitophagy via O-GlcNAcylation of PINK1. Therefore, targeting the O-GlcNAcylation may provide new strategies for the modulation of mitophagy and mitophagy-related human diseases.
    Keywords:  HBP; O-GlcNAcylation; PINK1; glucose metabolism; mitophagy
    DOI:  https://doi.org/10.7150/ijbs.112672
  2. Nat Commun. 2025 Jul 01. 16(1): 5850
    Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.
    Aliyah Habashy, Christopher Acree, Keun-Young Kim, Ali Zahraei, Martin Dufresne, Sebastien Phan, Melanie Cutler, Emilee Patterson, Alexandra G Mulligan, Kristopher Burkewitz, Charles Robert Flynn, Louise Lantier, Thomas Deerinck, Owen P McGuinness, Jeffrey M Spraggins, Mark H Ellisman, Rafael Arrojo E Drigo.
      Metabolic homeostasis requires engagement of catabolic and anabolic pathways consuming nutrients that generate and consume energy and biomass. Our current understanding of cell homeostasis and metabolism, including how cells utilize nutrients, comes largely from tissue and cell models analyzed after fractionation, and that fail to reveal the spatial characteristics of cell metabolism, and how these aspects relate to the location of cells and organelles within tissue microenvironments. Here we show the application of multi-scale microscopy, machine learning-based image segmentation, and spatial analysis tools to quantitatively map the fate of nutrient-derived 13C atoms across spatiotemporal scales. This approach reveals the cellular and organellar features underlying the spatial pattern of glucose 13C flux in hepatocytes in situ, including the timeline of mitochondria-ER contact dynamics in response to changes in blood glucose levels, and the discovery of the ultrastructural relationship between glycogenesis and lipid droplets.
    DOI:  https://doi.org/10.1038/s41467-025-60994-w
  3. Nat Commun. 2025 Jul 01. 16(1): 5563
    Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.
    Huiwang Zhan, Dhiman Sankar Pal, Jane Borleis, Yu Deng, Yu Long, Chris Janetopoulos, Chuan-Hsiang Huang, Peter N Devreotes.
      Although glycolysis is traditionally considered a cytosolic reaction, here we show that glycolytic enzymes propagate as self-organized waves on the membrane/cortex of human cells. Altering these waves led to corresponding changes in glycolytic activity, ATP production, and dynamic cell behaviors, impacting energy-intensive processes such as macropinocytosis and protein synthesis. Mitochondria were absent from the waves, and inhibiting oxidative phosphorylation (OXPHOS) had minimal effect on ATP levels or cellular dynamics. Synthetic membrane recruitment of individual glycolytic enzymes increased cell motility and co-recruited additional enzymes, suggesting assembly of glycolytic multi-enzyme complexes in the waves. Remarkably, wave activity and glycolytic ATP levels increased in parallel across human mammary epithelial and other cancer cell lines with higher metastatic potential. Cells with stronger wave activity relied more on glycolysis than on OXPHOS for ATP. These results reveal a distinct subcellular compartment for enriched local glycolysis at the cell periphery and suggest a mechanism that coordinates energy production with cellular state, potentially explaining the Warburg effect.
    DOI:  https://doi.org/10.1038/s41467-025-60596-6
  4. Nat Commun. 2025 Jul 01. 16(1): 5314
    A constricted mitochondrial morphology formed during respiration.
    Manish K Singh, Laetitia Cavellini, Maria Angeles Morcillo-Parra, Christina Kunz, Mickaël Lelek, Perrine Bomme, Aurélia Barascu, Cynthia Alsayyah, Maria Teresa Teixeira, Naïma Belgareh-Touzé, Adeline Mallet, Lea Dietrich, Christophe Zimmer, Mickael M Cohen.
      Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear. Here, we uncover a mitochondrial morphology dedicated to respiratory growth of Saccharomyces cerevisiae, which we refer to as "Ringo". The Ringo morphology is characterized by stable constrictions of mitochondrial tubules. Ringo constrictions are mediated by the yeast dynamin Dnm1 and, unlike mitochondrial fission, occur in the absence of contacts with the endoplasmic reticulum. Our data show that blocking formation of the Ringo morphology correlates with decreased respiration, decreased expression of OXPHOS subunits and perturbed mitochondrial DNA distribution. These results open important perspectives about the link between mitochondrial form and function.
    DOI:  https://doi.org/10.1038/s41467-025-60658-9
  5. Nat Commun. 2025 Jul 01. 16(1): 5465
    Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
    Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.
      The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
    DOI:  https://doi.org/10.1038/s41467-025-60670-z
  6. Sci Rep. 2025 Jul 01. 15(1): 21775
    Uncovering subtype-specific metabolic signatures in breast cancer through multimodal integration, attention-based deep learning, and self-organizing maps.
    Parisa Shahnazari, Kaveh Kavousi, Hamid Reza Khorram Khorshid, Zarrin Minuchehr, Bahram Goliaei, Reza M Salek.
      This study integrates multimodal metabolomic data from three platforms-LC-MS, GC-MS, and NMR-to systematically identify biomarkers distinguishing breast cancer subtypes. A feedforward attention-based deep learning model effectively selected 99 significant metabolites, outperforming traditional static methods in classification performance and biomarker consistency. By combining data from diverse platforms, the approach captured a comprehensive metabolic profile while maintaining biological relevance. Self-organizing map analysis revealed distinct metabolic signatures for each subtype, highlighting critical pathways. Group 1 (ER/PR-positive, HER2-negative) exhibited elevated serine, tyrosine, and 2-aminoadipic acid levels, indicating enhanced amino acid metabolism supporting nucleotide synthesis and redox balance. Group 3 (triple-negative breast cancer) displayed increased TCA cycle intermediates, such as α-ketoglutarate and malate, reflecting a metabolic shift toward energy production and biosynthesis to sustain aggressive proliferation. In Group 4 (HER2-enriched), elevated phosphatidylcholines and phosphatidylethanolamines suggested upregulated mono-unsaturated phospholipid biosynthesis. The study provides a framework for leveraging multimodal data integration, attention-based feature selection, and self-organizing map analysis to identify biologically meaningful biomarkers.
    Keywords:  Attention-Based Deep Learning; Breast Cancer Subtypes; Feature Selection; Metabolic Signatures; Multimodal Metabolomics; Random Forest; SVM-RFE; Self-Organizing Map; XGB-RFE
    DOI:  https://doi.org/10.1038/s41598-025-06459-y
  7. Cell Death Dis. 2025 Jul 01. 16(1): 468
    SLC44A2 negatively regulates mitochondrial fatty acid oxidation to suppress colorectal progression by blocking the MUL1-CPT2 interaction.
    Ying Yang, Longlong Zheng, Jiaxing He, Tao Wu, Haicheng Yang, Bo Zhang, Shuai Zhou, Yueyue Lu, Xianli He, Jibin Li, Nan Wang.
      The dependence of cancer cells on mitochondrial metabolism has been revealed in various cancer types. However, the mechanisms underlying this metabolic remodeling remain largely unclear. Solute carrier family 44 member 4 (SLC44A2) is a mitochondrial membrane-localized transmembrane protein belonging to the choline transporter-like protein family. Recently, it was reported that deletion of SLC44A2 impairs adhesion and increases proliferation in cultured lung mesenchymal cells. This finding implies that SLC44A2 may play a role in the malignant phenotypes of human cancers. However, the effects of SLC44A2 on malignant phenotypes and mitochondrial metabolism in human cancers remain unexplored. In the present investigation, we observed a significant reduction in SLC44A2 expression in colorectal cancer (CRC), and low SLC44A2 expression was closely associated with poorer survival of CRC patients. Functional assays demonstrated that SLC44A2 suppressed CRC growth and metastasis both in vitro and in vivo. Mechanistically, SLC44A2 inhibits mitochondrial fatty acid oxidation, thereby reducing energy supply and increase ROS stress. This effect is achieved by promoting mitochondrial E3 ubiquitin ligase 1 (MUL1)-regulated degradation of carnitine palmitoyltransferase 2 (CPT2) via enhancing the interaction between MUL1 and CPT2, without increasing MUL1 expression, which ultimately contributes to the proliferation and metastasis of CRC. Together, SLC44A2 functions as a critical tumor suppressor in CRC and potential therapeutic target in the treatment of this malignancy.
    DOI:  https://doi.org/10.1038/s41419-025-07781-z
  8. J Cell Biochem. 2025 Jun;126(6): e70050
    The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.
    Sajad Ehtiati, Behzad Hatami, Seyyed Hossein Khatami, Kiarash Tajernarenj, Saeed Abdi, Majid Sirati-Sabet, Seyyed Amir Hossein Ghazizadeh Hashemi, Reyhane Ahmadzade, Nastran Hamed, Marziyeh Goudarzi, Fatemeh Namvarjah, Melika Hajimohammadebrahim-Ketabforoush, Abbas Tafakhori, Vajiheh Aghamollaii, Saeed Karima.
      Beta-hydroxybutyrate (BHB), a key ketone body produced during fatty acid metabolism, plays critical roles in various physiological and pathological conditions. Synthesized in the liver through ketogenesis, BHB serves as an essential energy substrate during glucose deprivation, supporting survival by efficiently utilizing fat reserves. It crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels. BHB's impact extends to cellular pathways, including autophagy, mitochondrial biogenesis, and epigenetic regulation. By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others. This regulation plays vital roles in neurodegenerative diseases, metabolic disorders, cancer, and cardiovascular diseases, reducing oxidative stress and preventing cellular dysfunction. Epigenetically, BHB acts as an endogenous histone deacetylase inhibitor, inducing beneficial histone modifications that enhance cellular resilience and stress responses. This epigenetic influence is crucial in conditions like diabetes and cancer, aiding insulin secretion, protecting pancreatic beta cells, and impacting cancer cell gene expression and survival. Furthermore, BHB's therapeutic potential is evident in its ability to improve mitochondrial function across various tissues, including neurons, muscle, and liver. By enhancing mitochondrial respiration, reducing oxidative stress, and altering metabolic pathways, BHB mitigates conditions such as ICU-acquired weakness, nonalcoholic fatty liver disease, and cardiovascular diseases. BHB's modulation of autophagy and epigenetic regulation underscores its comprehensive role in cellular homeostasis and health across multiple physiological contexts, providing a foundation for future therapeutic strategies.
    Keywords:  autophagy; beta‐hydroxybutyrate; epigenetic; mitochondrial biogenesis; therapeutic strategies
    DOI:  https://doi.org/10.1002/jcb.70050
  9. J Exp Biol. 2025 Jun 30. pii: jeb.250397. [Epub ahead of print]
    Severe acute hypoxia upregulates anaerobic metabolism in non-reproductive but not queen naked mole-rats.
    Mohammad Ojaghi, Matthew E Pamenter.
      Most vertebrates upregulate anaerobic metabolism in severe hypoxia, which results in metabolic acidosis that must be resolved during reoxygenation. Naked mole-rats (NMRs) are hypoxia-tolerant mammals and drastically reduce their metabolic rate while maintaining systemic pH homeostasis during acute hypoxia. Whether or not NMRs employ anaerobic metabolism in hypoxia is currently debated. Given the robust systemic hypoxic hypometabolism of this species we hypothesized that anaerobic metabolism is recruited on a tissue-specific basis that varies between developmental stages and colony caste position. To test this, we treated subordinate juvenile and adult, and breeding (queen) NMRs in normoxia (21% O2) or hypoxia (3% O2) for 1 h, and then measured blood lactate, glycolytic enzyme activity, and the expression of genes that encode for enzymes involved in glycogen and glucose metabolism, and lactate transport. We found that (1) blood lactate levels increase similarly during hypoxia across developmental stages and castes; but that (2) glycolytic activity increased or remained stable in subordinates and juveniles but was unchanged or reduced in queens; (3) MCT4 gene expression decreased markedly in subordinate and juvenile brain and increased in muscle and kidney, but was unchanged in queens; and (4) the expression of genes associated with glycogenolysis and gluconeogenesis varied across tissues in subordinates/juveniles with some markers being down or upregulated or unchanged, but were always unchanged or downregulated queens. Taken together, our results suggest that hypoxia upregulates glycolysis and glycogen mobilization in subordinates and juveniles, but not in queens.
    Keywords:  Breeder; Development; Glycolysis; Hypoxic metabolic response; Juvenile
    DOI:  https://doi.org/10.1242/jeb.250397
  10. Nat Commun. 2025 Jul 01. 16(1): 5996
    The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
    Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K Boneski, Hiromi Sesaki, Ruteja A Barve, John A Collins, Makarand V Risbud.
      Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and 13C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1AcanCreERT2 mice showed age-dependent disc degeneration, osteoarthritis, and vertebral osteopenia. RNA-Sequencing of Opa1cKO NP tissue revealed dysregulation of metabolism, autophagy, cytoskeletal reorganization, and extracellular matrix and shared strong thematic similarities with a subset of human degenerative NP samples. Our findings underscore that maintenance of mitochondrial dynamics and multi-organelle cross-talk is critical in preserving metabolic homeostasis of disc and cartilage.
    DOI:  https://doi.org/10.1038/s41467-025-60933-9
  11. Trends Endocrinol Metab. 2025 Jul 02. pii: S1043-2760(25)00120-1. [Epub ahead of print]
    Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
    Daniel Jimenez-Blasco, Rebeca Lapresa, Jesus Agulla, Angeles Almeida, Juan P Bolaños.
      Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD+), a vital cofactor consumed by glycolysis. NAD+ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD+, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis.
    Keywords:  NAD; glycolysis; mitophay; neuron; organismal wellbeing
    DOI:  https://doi.org/10.1016/j.tem.2025.05.005
  12. Nat Rev Mol Cell Biol. 2025 Jul 03.
    Molecular machineries and pathways of mitochondrial protein transport.
    Toshiya Endo, Nils Wiedemann.
      Mitochondria contain about 1,000-1,500 different proteins, most of which are encoded by the nuclear genome and synthesized in the cytosol, although a handful are specified by the mitochondrial DNA and translated within mitochondria. The coordinated transport of nucleus-encoded proteins into mitochondria, followed by their proper folding, assembly and/or integration into mitochondrial membranes, is central to mitochondrial biogenesis. In this Review, we describe the pathways and machineries for protein transport across and insertion into the inner and outer mitochondrial membranes, as well as the targeting and sorting signals, and energy requirements for these processes. These machineries include the TOM and SAM complexes in the outer membrane and the TIM complexes in the inner membrane, and some components in the intermembrane space. We emphasize recent developments in our understanding of the protein structures of the transport machineries and discuss mechanisms for the shift of protein localization and correction of mislocalization.
    DOI:  https://doi.org/10.1038/s41580-025-00865-w
  13. Sci Rep. 2025 Jul 02. 15(1): 23075
    Theanine modulation of monoamine metabolism visualized by derivatized imaging mass spectrometry.
    Shu Taira, Aya Abe, Makoto Ozeki, Hitomi Shikano, Mahendra P Kapoor, Makoto Muto, Shoko Kobayashi.
      L-Theanine (LT), a derivative of glutamic acid, is abundant in tea leaves and contributes to tea's umami and sweetness. In recent years, its neurological effects, notably its role in promoting relaxation, have attracted intense research interest. The purpose of this study was to elucidate the detailed mechanisms underlying the relaxation effects of LT by thoroughly investigating the dynamics of neurotransmitters in the brain using mice after LT administration. Imaging mass spectrometry (IMS) was employed to visualize changes in the catecholamine system within the brain after LT administration. Simultaneous imaging of catecholamines, such as L-dihydroxyphenylalanine, dopamine, and norepinephrine, as well as representative amino acids such as γ-aminobutyric acid, revealed dynamic variations across time. Our findings revealed links between LT administration and the modulation of both inhibitory and excitatory neurotransmission, through its influence on the GABAergic and catecholaminergic systems, following the entry of exogenous LT into the brain. This approach enhanced our understanding of the mechanisms underlying LT's effects on the brain by visualizing neurotransmitter and amino acid distribution, as well as accompanying metabolic processes, at specific time points using IMS.
    DOI:  https://doi.org/10.1038/s41598-025-08190-0
  14. Nat Commun. 2025 Jul 04. 16(1): 6163
    Dimerization and substrate recognition of human taurine transporter.
    Yimin Zhang, Jiahui Chen, Nanhao Chen, Haolin Xiong, Zhengjiang Zhu, Dongxue Yang, Jingpeng Ge, Jie Yu.
      Taurine is a conditionally essential nutrient and one of the most abundant amino acids in humans, with diverse physiological functions. The cellular uptake of taurine is primarily mediated by the taurine transporter (TauT), and its dysfunction leads to retinal regeneration, cardiomyopathy, neurological and aging-associated disorders. Here we determine structures of TauT in two states: the apo inward-facing open state and the occluded state bound with substrate taurine or γ-aminobutyric acid (GABA). In addition to monomer, the structures also reveal a TauT dimer, where two cholesterol molecules act as "molecular glue", and close contacts of two TM5 from each protomer mediate the dimer interface. In combination with functional characterizations, our results elucidate the detailed mechanisms of substrate recognition, specificity and transport by TauT, providing a structural framework for understanding TauT function and exploring potential therapeutic strategies for taurine-deficiency-related disorders.
    DOI:  https://doi.org/10.1038/s41467-025-60967-z
  15. Front Immunol. 2025 ;16 1576216
    Inhibition of the Na+-glucose transporter SGLT2 reduces glucose uptake and IFNγ release from activated human CD4+ T cells.
    Zhe Jin, Hayma Hammoud, Amol K Bhandage, Stasini Koreli, Azazul Islam Chowdhury, Peter Bergsten, Bryndis Birnir.
      Glucose uptake in activated CD4+ T cells is essential for increased metabolic needs, synthesis of biomolecules and proliferation. Although, facilitated glucose transport is the predominant route for glucose entry at the time of activation, here we demonstrate role for the sodium-dependent glucose transporter SGLT2. By 72 h after activation, SGLT2 is expressed and functional in the human CD4+ T cells. SGLT2 inhibitors, phlorizin and empagliflozin decreased glucose uptake into the human CD4+ T cells compared to untreated cells. Phlorizin (25 μmol/L) reduced glycolysis at 5.6 mmol/L glucose and IFNγ levels at both 5.6 mmol/L and 16.7 mmol/L glucose. In contrast, empagliflozin (0.5 μmol/L) only decreased IFNγ levels in 16.7 mmol/L glucose. GABA enhanced phlorizin inhibition at both 5.6 mmol/L and 16.7 mmol/L glucose in the presence of insulin. Insulin strengthens GABAA receptors signaling in CD4+ T cells. The results are consistent with expression of SGLT2 after activation of human CD4+ T cells, that facilitates concentrating glucose uptake into the cells, enabling enhanced release of inflammatory molecules like IFNγ. Importantly, inhibition of SGLT2 decreases IFNγ release.
    Keywords:  GLUT1; IFNγ; SGLT2; T cells; empagliflozin; glucose uptake; immunomodulation; phlorizin
    DOI:  https://doi.org/10.3389/fimmu.2025.1576216
  16. Cell Commun Signal. 2025 Jul 01. 23(1): 307
    Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.
    Yiyi Shou, Ruiqi Liu, Hao Xiong, Keke Xu, Xiaoyan Chen, Luanluan Huang, Yitian Zhang, Hailong Sheng, Haibo Zhang, Yanwei Lu.
      Cancer cells experience metabolic reprogramming to enhance the synthesis of nitrogen and carbon, facilitating the production of macromolecules essential for tumor proliferation and growth. A central strategy in this process involves reducing catabolic activities and managing nitrogen, thereby improving the efficiency of nitrogen utilization. The urea cycle (UC), conventionally recognized for its role in detoxifying excess nitrogen in the liver, is pivotal in this metabolic transition. Beyond the hepatic environment, the differential expression of UC enzymes facilitates the utilization of nitrogen for the synthesis of metabolic intermediates, thereby addressing the cellular metabolic requirements, especially under conditions of nutrient scarcity. In oncogenic contexts, the expression and regulation of UC enzymes undergo substantial modification, promoting metabolic reprogramming to optimize nitrogen assimilation into cellular biomass. This reconfigured UC not only enhances tumor cell survival but also plays a pivotal role in the reorganization of the tumor microenvironment (TME), thereby aiding in immune evasion. This review examines the mechanistic underpinnings of urea cycle dysregulation (UCD) in cancer, highlighting its dynamic roles across various tumor types and stages, as well as the therapeutic implications of these alterations. Understanding how UC relaxation promotes metabolic flexibility and immune evasion may help develop novel therapeutic strategies that target tumor metabolism and enhance anti-cancer immunity.
    Keywords:  Cancer metabolism; Cancer treatment; Metabolic reprogramming; Tumor immunogenicity; Urea cycle
    DOI:  https://doi.org/10.1186/s12964-025-02328-3
  17. Front Cell Dev Biol. 2025 ;13 1584630
    The role and therapeutic potential of glucose metabolism in multidrug resistance of cancer.
    Qijing Wang, Kai Li, Liang Li, Qin Li, Yanyu Qi, Kai Liu, Hang Yuan, Ping Lin.
      Cancer represents a serious threat to human health and life. Despite recent advances in the cancer therapy that significantly extend patient survival, many individuals still undergo drug resistance, even to multiple chemotherapeutic drugs, known as multidrug resistance (MDR). MDR causes the treatment failure and promotes the risk of tumor recurrence and metastasis, which has been a critical clinical challenge. The molecular mechanisms for cancer cells developing MDR are complex and largely unclarified. ATP-binding cassette (ABC) transporters-mediated enhanced drug efflux and glucose metabolic reprogramming have been recently identified as key factors that limit drug efficacy. In addition to regulating glucose metabolism, several glycolytic enzymes exhibit aberrant cellular localization, including translocation to the nucleus, cell membrane or mitochondria, which imparts their non-classical pro-oncogenic functions to facilitate tumor progression and MDR. In this review, we summarize the roles and molecular insights of glycometabolic enzymes in MDR progression and discuss existing therapeutic strategies of targeting glucose metabolic enzymes for overcoming MDR.
    Keywords:  cancer metabolism; cancer therapy; glucose metabolism; glycolysis; multidrug resistance
    DOI:  https://doi.org/10.3389/fcell.2025.1584630
  18. Science. 2025 Jul 03. 389(6755): 48-52
    The intracellular Ca2+ sensitivity of transmitter release in glutamatergic neocortical boutons.
    Grit Bornschein, Simone Brachtendorf, Anja Reinert, Abdelmoneim Eshra, Robert Kraft, Johannes Hirrlinger, Jens Eilers, Stefan Hallermann, Hartmut Schmidt.
      Synaptotagmin-1 (Syt1) and Syt2 are the main calcium (Ca2+) sensors triggering synchronous release in the brain. In this work, we studied the mechanisms mediating Syt1-triggered release from neocortical synapses. We measured the Ca2+ dependency of release in layer 5 pyramidal neuron synapses by laser photolysis of caged Ca2+. Release had high Ca2+ affinity and positive cooperativity. Measurements at cerebellar Purkinje cell synapses and kinetic models indicate substantial differences compared with Syt2-triggered release. Our results suggest that Syt1-controlled release machineries are optimized for high reliability at moderate Ca2+ elevations and high plastic controllability.
    DOI:  https://doi.org/10.1126/science.adp0870
  19. Cell Commun Signal. 2025 Jul 01. 23(1): 314
    Progress on multifunctional transmembrane protein ATG9A.
    Xi Lin, Lin Liang, Shan Liao, Yanling Li, Yanhong Zhou.
      ATG9A is the only transmembrane protein among the components required for autophagosome formation and participates in multiple cellular biological processes. ATG9A undergoes intracellular transport via microtubules and actin. As a lipid scramblase, ATG9A facilitates the random movement of lipid molecules between the inner and outer leaflets of lipid bilayers. Additionally, it can influence the homeostasis of the plasma membrane and membranous organelles. In autophagy, ATG9A is recruited to autophagic initiation sites to initiate cellular autophagy and subsequently participates in the process by promoting lipid transfer. Moreover, ATG9A also plays roles in maintaining neuronal homeostasis and is involved in embryonic development, infection, and immune responses. In this review, we comprehensively and systematically summarize the roles and mechanisms of ATG9A, aiming to provide a new perspective for understanding its functions.
    Keywords:  ATG9A; Autophagosome formation; Autophagy; Disease progression; Regulatory factors
    DOI:  https://doi.org/10.1186/s12964-025-02317-6
  20. Biochim Biophys Acta Bioenerg. 2025 Jun 28. pii: S0005-2728(25)00031-3. [Epub ahead of print]1866(4): 149565
    Human VDAC3 as a sensor of the intracellular redox state: contribution to cytoprotection mechanisms in oxidative stress.
    Martyna Baranek-Grabińska, Tomasz Skrzypczak, Hanna Kmita, Andonis Karachitos.
      Voltage-dependent anion channels (VDACs) are essential for mitochondrial function, facilitating the exchange of metabolites between the cytosol and mitochondria. This study investigated the role of human VDAC paralogs, hVDAC1, hVDAC2, and hVDAC3, in maintaining mitochondrial function under oxidative stress in Saccharomyces cerevisiae strains lacking endogenous VDACs (encoded by POR1 and POR2) and antioxidant enzymes, i.e., superoxide dismutases (encoded by SOD1 and SOD2). The yeast cells expressing hVDAC3 showed stable growth under oxidative stress, maintained mitochondrial membrane potential and morphology, exhibited reduced superoxide anion levels, and achieved efficient ATP synthesis with minimal proton leak. In contrast, the cells expressing hVDAC1 or hVDAC2 presented impaired mitochondrial function which was supported by differences in bioenergetic profiles including ATP synthesis and proton leak but also FCCP uncoupling capacity and spare respiratory capacity. The cysteine-depleted variant of hVDAC3 (hVDAC3ΔCys) showed impaired cell growth under stress conditions, indicating that the cysteine residues in hVDAC3 are essential for its protective role. These findings highlight the unique protective function of hVDAC3 under oxidative stress, which is attributed to efficient metabolite transport and regulation via cysteine oxidation.
    Keywords:  ATP synthesis; Cysteine residues; Human VDAC3; Oxidative stress; Reactive oxygen species; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149565
  21. Sci Rep. 2025 Jul 02. 15(1): 23489
    Dynamic mode decomposition for analysis and prediction of metabolic oscillations from time-lapse imaging of cellular autofluorescence.
    Daniel Wüstner, Henrik Helge Gundestrup, Katja Thaysen.
      Oscillations are a common phenomenon in cell biology. They are based on non-linear coupling of biochemical reactions and can show rich dynamic behavior as found in, for example, glycolysis of yeast cells. Here, we show that dynamic mode decomposition (DMD), a numerical algorithm for linear approximation of non-linear dynamics, can be combined with time-delay embedding (TDE) to dissect damped and sustained glycolytic oscillations in simulations and experiments in a fully data-driven manner. Together with an assessment of spurious eigenvalues via residual DMD, this provides a unique spectrum for each scenario, allowing for high-fidelity time-series and image reconstruction. By machine-learning-based clustering of identified DMD modes, we are able to classify NADH oscillations, thereby discovering subtle phenotypes and accounting for cell-to-cell heterogeneity in metabolic activity. This is demonstrated for varying glucose influx and for yeast cells lacking the sterol transporters Ncr1 and Npc2, a model for Niemann Pick type C disease in humans. DMD with TDE can also discern other types of oscillations, as demonstrated for simulated calcium traces, and its forecasting ability is on par with that of Long Short-Term Memory (LSTM) neural networks. Our results demonstrate the potential of DMD for analysis of oscillatory dynamics at the single-cell level.
    DOI:  https://doi.org/10.1038/s41598-025-07255-4
  22. Nat Metab. 2025 Jul 01.
    Triglycerides are an important fuel reserve for synapse function in the brain.
    Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L Pontius, Daehun Park, Rose E Witte, Rachel McAllister, Kallol Gupta, Kartik N Rajagopalan, Pietro De Camilli, Timothy A Ryan.
      Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01321-x
  23. Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00505-2. [Epub ahead of print]85(13): 2610-2625.e5
    MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
    Zhangcheng Ding, Rui Wang, Yuhua Li, Xiaodong Wang.
      Necroptosis is a pro-inflammatory, lytic cell death executed by a pseudokinase mixed lineage kinase-like protein MLKL. Upon necroptosis induction by various inflammatory signals, MLKL is phosphorylated by receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and translocates from the cytosol to the plasma membrane, causing membrane disruption and the release of damage-associated molecular patterns (DAMPs). We report here that phosphor-MLKL also translocates to mitochondria and induces a microtubule-dependent release of mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway, resulting in the upregulation of interferon-beta (Ifnb) expression. In a necroptosis-mediated inflammatory bowel disease (IBD) mouse model, interfering with the cGAS-STING pathway reduced inflammation and promoted intestinal recovery. Thus, MLKL induces inflammation not only in a cell non-autonomous fashion by releasing DAMP signals, but also in a cell-autonomous manner by causing mtDNA leakage into the cytosol, thereby activating the cGAS-STING pathway.
    Keywords:  IBD; MLKL; cGAS; mitochondrail DNA; mitochondria; mtDNA; necroptosis
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.005
  24. Nat Commun. 2025 Jul 02. 16(1): 6083
    Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
    Iman Man Hu, Marte Molenaars, Yorrick R J Jaspers, Bauke V Schomakers, Michel van Weeghel, Amber Bakker, Melanie Modder, Joseph P Dewulf, Guido T Bommer, Arwen W Gao, Georges E Janssens, Riekelt H Houtkooper.
      Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Here, we explore whether other mechanisms may contribute to lifespan extension upon mitochondrial translation inhibition. Using multi-omics and functional in vivo screening, we identify the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as an essential factor for longevity induced by mitochondrial translation inhibition. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition, while mitochondrial unfolded protein response activation remains unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Mechanistically, sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the "immuno-metabolic stress responses" in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses.
    DOI:  https://doi.org/10.1038/s41467-025-61433-6
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