bims-celmim 2025-08-31 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–08–31
twenty-six papers selected by
Marc Segarra Mondejar

Mitochondria and lysosomes in T cell immunometabolism.
Neurobiology of mitochondrial dynamics in sleep.
The impact of p53 on the urea cycle and nitrogen metabolism enzymes: Mechanisms and implications for cancer development.
Intracristal space proteome mapping using super-resolution proximity labeling with isotope-coded probes.
Real-time monitoring of mitochondrial temperature and calcium spikes using fluorescent organic probes.
NMR based clinical metabolomics revealed altered lipid and sugar metabolism in systemic sclerosis with implications for diagnosis and therapeutic strategies.
Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
Metabolomics using anion-exchange chromatography mass spectrometry for the analysis of cells, tissues and biofluids.
Cysteine metabolism at the crossroads of ferroptosis and cancer therapy.
Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.
Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.
Glutaminase 1 inhibitors: Therapeutic potential, mechanisms of action, and clinical perspectives.
Impact of O-GlcNAcylation Elevation on Mitophagy and Glia in the Dentate Gyrus.
Dual-key cooperatively activated DNA regulator for controlling mitochondria-lysosome interactions.
Branched-chain amino acids contribute to diabetic kidney disease progression via PKM2-mediated podocyte metabolic reprogramming and apoptosis.
Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.
GPT2 mediates glutamine metabolism-driven metabolic alterations in platinum-resistant ovarian cancer cells.
Detection of Neuronal Glutamate in Brain Extracellular Space In Vivo Using Microdialysis and Metabolic Labeling with Glutamine.
Single cell autofluorescence imaging reveals immediate metabolic shifts of neutrophils with activation across biological systems.
Ca2+-pumping by PMCA-neuroplastin complexes operates in the kiloHertz-range.
Fatty acid addiction in cancer: A high-fat diet directly promotes tumor growth through fatty acid oxidation.
Investigating metabolic changes in single embryos during early development in Drosophila.
Real-time visualization and modulation of endocytic dynamics in osteocytes in vivo.
Malonyl-CoA Promotes Prostate Cancer Progression and Castration Resistance by Enhancing Lipogenesis and Ran Activation.
Integrative analysis of gut microbiota and metabolic pathways reveals key microbial and metabolomic alterations in diabetes.
PKM2 regulates angiogenic activation via ANGPT2 in endothelial cells.

Trends Immunol. 2025 Aug 22. pii: S1471-4906(25)00181-4. [Epub ahead of print]

Mitochondria and lysosomes in T cell immunometabolism.

Erienne G Norton, Nicole M Chapman, Hongbo Chi.

  Metabolic reprogramming and signaling are key orchestrators of T cell immunity. Recent studies have illustrated important roles for intracellular organelles, especially mitochondria and lysosomes, in enforcing T cell metabolism and signaling in response to various extracellular cues. As such, mitochondrial and lysosomal function contributes to adaptive immunity by regulating T cell activation, differentiation, and functional adaptation. In this Review, we discuss how the interplay between organelle biology and metabolism instructs T cell-mediated immunity, with a particular focus on mitochondria and lysosomes. We also summarize how mitochondria and lysosomes, or their crosstalk with other organelles, orchestrate downstream signaling processes and functional reprogramming of T cells. We conclude with a discussion of the pathophysiological outcomes associated with dysregulation of these organelles.

Keywords:  T cells; immunometabolism; lysosomes; metabolic signaling; mitochondria; organelle crosstalk

DOI:  https://doi.org/10.1016/j.it.2025.07.014
J Physiol. 2025 Aug 22.

Neurobiology of mitochondrial dynamics in sleep.

Raffaele Sarnataro.

  The cycling of sleep and wakefulness reshapes neuronal activity, gene expression, and cellular metabolism of the brain. Such reshuffling of brain metabolism implicates key mediation by mitochondria. Mitochondrial dynamics enable organelles to adapt their morphofunction to changing metabolic demands, and experimental evidence increasingly links these processes to sleep-wake regulation. Across species, sleep loss perturbs mitochondrial gene expression, increases oxidative stress, and disrupts organelle structure, particularly in energy-demanding brain regions. In Drosophila, sleep-control neurons projecting to the dorsal fan-shaped body (dFBNs) exhibit a homeostatic feedback mechanism coupling mitochondrial activity to behavioural state. As sleep pressure elevates, dopaminergic inhibition reduces dFBN excitability and ATP consumption, triggering mitochondrial fission and accumulation of reactive oxygen species (ROS) that biochemically prime the neurons for subsequent sleep induction. Upon relief of inhibition during recovery sleep, dFBNs elevate their activity, consume ATP, and undergo mitochondrial fusion to restore energy balance. Artificial modulation of mitochondrial morphology and ATP production in these neurons bidirectionally alters sleep. dFBNs' elevated OxPhos expression and mitochondrial turnover render them sensitive to metabolic shifts and capable of encoding internal states. While dFBNs remain the only known neurons where mitochondrial dynamics are coupled to sleep behaviour, other populations, like mammalian cortical neurons or fly Kenyon cells, also display mitochondrial changes after sleep loss. Sleep, like other state-dependent behaviours including hunger and memory, imposes shifting energetic demands on specific neuronal populations. Mitochondrial dynamics may thus provide a conserved, cell-autonomous mechanism for tuning neural excitability and sleep pressure, enabling brain-wide coordination of metabolic and behavioural homeostasis.

Keywords:  ATP; energy; homeostasis; metabolism; mitochondria; neurobiology; neuron; sleep

DOI:  https://doi.org/10.1113/JP288054
Biochim Biophys Acta Mol Basis Dis. 2025 Aug 20. pii: S0925-4439(25)00372-2. [Epub ahead of print]1871(8): 168024

The impact of p53 on the urea cycle and nitrogen metabolism enzymes: Mechanisms and implications for cancer development.

Santhanagopalakrishnan Rajesh Iyer, Beata Schlichtholz.

  The tumour suppressor protein p53, encoded by the TP53 gene, is widely celebrated as the "guardian of the genome," yet its role in metabolic reprogramming, particularly nitrogen metabolism, remains underappreciated. This review highlights the emerging nexus between p53 and the urea cycle, a key pathway responsible for ammonia detoxification and the generation of biosynthetic precursors. By regulating the expression and activity of urea cycle enzymes, p53 exerts profound control over interconnected metabolic pathways, including the metabolism of polyamine, methionine, glutathione, and proline. Cancer cells, with their voracious nitrogen demand, co-opt urea cycle dysregulation to fuel tumour growth and survival. Here, we synthesise the latest insights into p53's role in nitrogen homeostasis, delineating its broader implications for cellular metabolism and carcinogenesis. Additionally, we propose the strategic targeting of urea cycle enzymes as novel prognostic biomarkers and therapeutic vulnerabilities in cancer. This work not only redefines the metabolic scope of p53 but also positions nitrogen metabolism at the forefront of cancer research, offering transformative avenues for therapeutic innovation.

Keywords:  Ammonia detoxification; Cellular metabolic adaptation; Enzyme regulation; Glutathione; Methionine metabolism; Nitrogen metabolism; Polyamines; Urea cycle; p53

DOI:  https://doi.org/10.1016/j.bbadis.2025.168024
Nat Commun. 2025 Aug 20. 16(1): 7757

Intracristal space proteome mapping using super-resolution proximity labeling with isotope-coded probes.

Myeong-Gyun Kang, Sanghee Shin, Dong-Gi Jang, Ohyeon Kwon, Song-Yi Lee, Pratyush Kumar Mishra, Minkyo Jung, Ji Young Mun, Jung-Min Kee, Jong-Seo Kim, Hyun-Woo Rhee.

Proximity labeling with engineered ascorbate peroxidase (APEX) has been widely used to identify proteomes within various membrane-enclosed subcellular organelles. However, constructing protein distribution maps between two non-partitioned proximal spaces remains challenging with the current proximity labeling tools. Here, we introduce a proximity labeling approach using isotope-coded phenol probes for APEX labeling (ICAX) that enables the quantitative analysis of the spatial proteome at nanometer resolution between two distinctly localized APEX enzymes. Using this technique, we identify the spatial proteomic architecture of the mitochondrial intracristal space (ICS), which is not physically separated from the peripheral space. ICAX analysis further reveals unexpected dynamics of the mitochondrial spatiome under mitochondrial contact site and cristae organizing system (MICOS) complex inhibition and mitochondrial uncoupling, respectively. Overall, these findings highlight the importance of ICS for mitochondrial quality control under dynamic stress conditions.

DOI: https://doi.org/10.1038/s41467-025-62756-0
Biomater Sci. 2025 Aug 26.

Real-time monitoring of mitochondrial temperature and calcium spikes using fluorescent organic probes.

Mengnan Sun, Bo Chen, Aiguo Wu.

Astrocytes, the abundant glial cells, maintain cerebral homeostasis and cognitive functions through calcium signalling - a regulatory pathway that is frequently altered in brain disease. Mitochondria serve as thermal hubs in living systems, generating metabolic heat during respiratory substrate oxidation and ATP synthesis. Crucially, mitochondrial temperature variations directly reflect metabolic status, as impaired ATP production induces thermodynamic shifts. Here, we utilized a fluorescent thermometer probe MTY for in vitro determination and visualization of intracellular mitochondrial temperatures at the single-cell level. Through precisely controlled thermal modulation of fixed, living, and laser-stimulated astrocytes, we established a platform extendable to MCF-7 and Panc02 cell lines. The methodology enabled real-time tracking of near-infrared-induced thermal perturbations and FCCP-mediated uncoupling effects. Spinning-disk confocal microscopy revealed synchronized mitochondrial thermogenesis and calcium transients, with thermal/laser stimulation inducing 2-4-fold greater calcium spiking versus controls. Mechanistic analysis suggested this response was likely mediated through TRPV4 channel-mediated extracellular Ca2+ influx and/or intracellular calcium release from mitochondrial and endoplasmic reticulum stores.

DOI: https://doi.org/10.1039/d5bm00691k
Sci Rep. 2025 Aug 21. 15(1): 30676

NMR based clinical metabolomics revealed altered lipid and sugar metabolism in systemic sclerosis with implications for diagnosis and therapeutic strategies.

Gurvinder Singh, Sakir Ahmed, Durgesh Dubey, Mohit Kumar Rai, Atul Rawat, Vikas Agarwal, Dinesh Kumar.

  Systemic Sclerosis (SSc) is a complex autoimmune disorder characterized by vascular dysfunction, immune dysregulation, and progressive fibrosis of the skin and internal organs. Despite substantial research, its pathophysiology remains enigmatic, necessitating the identification of altered metabolic pathways to improve disease management. This study utilized NMR-based serum metabolomics to identify distinctive metabolic signatures and deranged pathways in SSc. 1D 1H CPMG spectra of sera from 83 SSc patients and 43 age/sex matched HC were measured using 800 MHz NMR. Spectral binning and concentration profiling data were analyzed using multivariate statistical analysis to identify discriminatory metabolic features based variable importance in projection (VIP) scores and mean decrease accuracy (MDA). Univariate statistical analysis and receiver operating characteristic (ROC) curve analysis further evaluated their diagnostic potential. Multivariate analysis revealed clear differentiation between SSc and HC. SSc patients showed decreased levels of alanine, valine, myo-inositol, creatinine, pyruvate, lactate, PUFA, LDL/VLDL, and lipids, alongside elevated levels of acetate, 3-hydroxybutyrate, and mannose. Twelve key metabolites demonstrated high sensitivity and specificity in distinguishing SSc from HC. Pathway analysis revealed disruptions in sugar metabolism, branched-chain amino acids, fatty acid metabolism, and energy metabolism. These findings underscore NMR-based metabolomics as a promising tool for improving SSc diagnosis and understanding its pathogenesis, paving the way for targeted therapeutic strategies.

Keywords:  Circulatory biomarkers; Inositol pathway, mannosylation; NMR based metabolomics; Systemic sclerosis

DOI:  https://doi.org/10.1038/s41598-025-16493-5
Sci Adv. 2025 Aug 29. 11(35): eady0240

Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.

William M Rosencrans, Ryan W Lee, Logan McGraw, Ian Horsburgh, Ting-Yu Wang, Baiyi Quan, Diana Huynh, Jennifer A Johnston, David C Chan, Tsui-Fen Chou.

The PINK1/Parkin pathway targets damaged mitochondria for degradation via mitophagy. Genetic evidence implicates impaired mitophagy in Parkinson's disease, making its pharmacological enhancement a promising therapeutic strategy. Here, we characterize two mitophagy activators: a novel Parkin activator, FB231, and the reported PINK1 activator MTK458. Both compounds lower the threshold for mitochondrial toxins to induce PINK1/Parkin-mediated mitophagy. However, global proteomics revealed that FB231 and MTK458 independently induce mild mitochondrial stress, resulting in impaired mitochondrial function and activation of the integrated stress response, effects that result from PINK1/Parkin-independent off-target activities. We find that these compounds impair mitochondria by distinct mechanisms and synergistically decrease mitochondrial function and cell viability in combination with classical mitochondrial toxins. Our findings support a model whereby weak or "silent" mitochondrial toxins potentiate other mitochondrial stressors, enhancing PINK1/Parkin-mediated mitophagy. These insights highlight important considerations for therapeutic strategies targeting mitophagy activation in Parkinson's disease.

DOI: https://doi.org/10.1126/sciadv.ady0240
Nat Protoc. 2025 Aug 22.

Metabolomics using anion-exchange chromatography mass spectrometry for the analysis of cells, tissues and biofluids.

Rachel Williams, John Walsby-Tickle, Ingvild Comfort Hvinden, Isabelle Legge, Tereza Kacerova, KyoungEun Vicky Lee, Mariya Misheva, David Hauton, Judith B Ngere, John D Sidda, Elisabete Pires, Tom Cadoux-Hudson, James S O McCullagh.

The direct coupling of ion-exchange chromatography with mass spectrometry using electrochemical ion suppression creates a hyphenated technique with selectivity and specificity for the analysis of highly polar and ionic compounds. The technique has enabled new applications in environmental chemistry, food chemistry, forensics, cell biology and, more recently, metabolomics. Robust, reproducible and quantitative methods for the analysis of highly polar and ionic metabolites help meet a longstanding analytical need in metabolomics. Here, we provide step-by-step instructions for both untargeted and semi-targeted metabolite analysis from cell, tissue or biofluid samples by using anion-exchange chromatography-high-resolution tandem mass spectrometry (AEC-MS/MS). The method requires minimal sample preparation and is robust, sensitive and selective. It provides comprehensive coverage of hundreds of metabolites found in primary and secondary metabolic pathways, including glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, purine and pyrimidine metabolism, amino acid degradation and redox metabolism. An inline electrolytic ion suppressor is used to quantitatively neutralize OH- ions in the eluent stream, after chromatographic separation, enabling AEC to be directly coupled with MS. Counter ions are also removed during this process, creating a neutral pH, aqueous eluent with a simplified matrix optimal for negative ion MS analysis. Sample preparation through to data analysis and interpretation is described in the protocol, including a guide to which metabolites and metabolic pathways are suitable for analysis by using AEC-MS/MS.

DOI: https://doi.org/10.1038/s41596-025-01222-z
Crit Rev Oncol Hematol. 2025 Aug 18. pii: S1040-8428(25)00294-X. [Epub ahead of print]215 104906

Cysteine metabolism at the crossroads of ferroptosis and cancer therapy.

Jaewang Lee, Jong-Lyel Roh.

  Cysteine metabolism plays a pivotal role in ferroptosis regulation by modulating antioxidant defense, lipid peroxidation, and iron homeostasis. Cancer cells exploit cysteine availability to evade ferroptotic cell death, contributing to tumor progression and therapy resistance. Despite growing interest in ferroptosis as a therapeutic vulnerability, a comprehensive understanding of cysteine metabolism in this process remains essential. This review explores key sources of intracellular cysteine, its roles in ferroptosis suppression, and therapeutic strategies targeting cysteine metabolism in cancer. We discuss systemic cysteine depletion, xCT inhibition, suppression of H2S biosynthesis, and GPX4-targeted therapies, along with promising drug combinations. While preclinical studies highlight the efficacy of these approaches, in vivo validation and clinical translation remain limited. Advancing cysteine-targeting therapies require further mechanistic insights, biomarker identification, and optimized delivery strategies. A deeper understanding of cysteine metabolism may pave the way for ferroptosis-based cancer treatments with improved precision and efficacy.

Keywords:  Cancer therapy; Cyst(e)inases; Cysteine metabolism; Ferroptosis; XCT targeting

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104906
Nat Commun. 2025 Aug 25. 16(1): 7671

Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.

Kayleigh M Voos, Joyce Tzeng, Priya Patel, Sophie Rubinsky, Ha E Choi, Trevor Pharr, Sebastian Sookram, Joseph A Baur, Erik J Soderblom, Damaris N Lorenzo.

Mitochondrial dynamics enable cellular adaptation to fluctuations in energy demand, such as those imposed on skeletal muscle by exercise, metabolic disorders, or aging. Here, we report a novel pathway that modulates mitochondria dynamics in skeletal muscle involving the scaffolding protein ankyrin-B. Rare variants in ankyrin-B, encoded by ANK2, increase risk for cardio-metabolic syndrome in humans and mice. We show that mice selectively lacking skeletal muscle ankyrin-B have reduced endurance exercise capacity without alterations in muscle strength or systemic glucose regulation. Muscle fibers in these mice have increased oxidative stress, reduced fatty acid oxidation, and enlarged and hyperconnected mitochondria. We found that ankyrin-B interacts with and is required for efficient mitochondria recruitment of fission modulators and sarcoplasmic reticulum-mitochondria coupling. Thus, we conclude that ankyrin-B enables substrate adaptability and bioenergetic homeostasis under energetic stress, and exercise capacity by promoting efficient mitochondrial fission in skeletal muscle.

DOI: https://doi.org/10.1038/s41467-025-62977-3
Biochim Biophys Acta Mol Basis Dis. 2025 Aug 19. pii: S0925-4439(25)00369-2. [Epub ahead of print]1871(8): 168021

Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.

Anna Fernàndez-Bernal, Natàlia Mota, Reinald Pamplona, Estela Area-Gómez, Manuel Portero-Otin.

  Cholesterol is a central determinant of membrane architecture, signaling, and cellular homeostasis in the central nervous system (CNS). While historically viewed as a structural component, emerging evidence highlights its dynamic regulatory role in neuronal function, particularly through its compartmentalized synthesis, trafficking, and turnover. This review examines the complex landscape of cholesterol metabolism in the CNS, emphasizing the cooperative roles of astrocytes and neurons, the partitioning of biosynthetic pathways, and the barriers that distinguish brain cholesterol pools from peripheral sources. We focus on mitochondria-associated endoplasmic reticulum membranes (MAMs) as key regulatory platforms for cholesterol sensing, esterification, and signaling, underscoring their emerging role in neurodegenerative diseases. Disruptions in MAM integrity, lipid raft composition, and transcriptional regulation of cholesterol-handling genes have been linked to pathologies such as amyotrophic lateral sclerosis (ALS), particularly through the actions of TDP-43. By consolidating recent findings from lipidomics, cell biology, and disease models, we propose that cholesterol dyshomeostasis constitutes a shared mechanistic axis across diverse neurodegenerative conditions. Understanding this axis offers novel insights into the metabolic vulnerability of neurons and highlights cholesterol metabolism as a promising target for therapeutic intervention.

Keywords:  Amyotrophic Lateral Sclerosis; Astrocyte; Blood-brain-barrier; Endoplasmic reticulum; Neuron

DOI:  https://doi.org/10.1016/j.bbadis.2025.168021
Biochem Pharmacol. 2025 Aug 22. pii: S0006-2952(25)00540-4. [Epub ahead of print]242(Pt 1): 117275

Glutaminase 1 inhibitors: Therapeutic potential, mechanisms of action, and clinical perspectives.

Hui Wang, Xiandeng Li, Haitao Hu, Zhan Gao.

  Glutaminase 1 (GLS1) is a critical enzyme in glutamine metabolism, supporting both energy production and biosynthesis in tumor cells. Inhibitors targeting GLS1 have emerged as promising metabolic therapies. Notably, it exhibits antiproliferative and pro-apoptotic effects in various cancers. This review systematically discusses GLS1's structure and function, the major classes of inhibitors, and the principles behind their design. It also explores the molecular mechanisms underlying GLS1 inhibition, including disruption of glutamine metabolism, induction of oxidative stress, and modulation of key signaling pathways. Furthermore, we evaluated the current clinical applications and therapeutic potential of GLS1 inhibitors in cancer and metabolic disorders. Themes such as drug safety, resistance development, and patient stratification are also addressed. Future research should highlight the potential of combination therapies and precision medicine approaches. Collectively, targeting GLS1 represents a promising strategy with significant translational potential in metabolism-related diseases.

Keywords:  Cancer; GLS1; GLS1 inhibitors; Glutamine metabolism; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.bcp.2025.117275
J Neurochem. 2025 Aug;169(8): e70205

Impact of O-GlcNAcylation Elevation on Mitophagy and Glia in the Dentate Gyrus.

Joshua Kramer, Sarah Fu, Xiaosen Ouyang, Eric Rohwer, John C Chatham, Martin E Young, Victor Darley-Usmar, Jianhua Zhang.

  O-GlcNAcylation is a dynamic and reversible protein posttranslational modification of serine or threonine residues which modulates the activity of transcriptional and signaling pathways and controls cellular responses to metabolic and inflammatory stressors. We and others have shown that O-GlcNAcylation has the potential to regulate autophagy and mitophagy to play a critical role in mitochondrial quality control, but this has not been assessed in vivo in the brain. This is important since mitochondrial dysfunction contributes to the development of neurodegenerative diseases. We used mito-QC reporter mice to assess mitophagy in diverse cells in the dentate gyrus in response to pharmacological inhibition of O-GlcNAcase (OGA) with thiamet G which leads to elevation of protein O-GlcNAcylation. We demonstrate that mitophagy occurs predominantly in the GFAP-positive astrocytes and is significantly decreased in response to elevated O-GlcNAcylation. Furthermore, with increased O-GlcNAcylation, the levels of astrocyte markers GFAP and S100B, and the microglial cell marker IBA1, decreased in the dentate gyrus, while the levels of microglial cell marker TMEM119 were increased, indicating significant changes in glia homeostasis. These results provide strong evidence of the regulation of mitophagy and glia signatures by the O-GlcNAc pathway.

Keywords:  O‐GlcNAc; astrocyte; hippocampus; microglia; mitophagy

DOI:  https://doi.org/10.1111/jnc.70205
Nat Commun. 2025 Aug 22. 16(1): 7811

Dual-key cooperatively activated DNA regulator for controlling mitochondria-lysosome interactions.

Yang Xiao, Longyi Zhu, Songyuan Du, Xinyi Ge, Lequn Ma, Shengyuan Deng, Kewei Ren.

Mitochondria-lysosome interactions are critical for maintaining cellular homeostasis. Although genetically encoded protein based optogenetic technique is developed to regulate such interactions, it still suffers from shortcomings including complicated operation and potential interference to organelle functions. Here, we present a fast, simple, biocompatible and programmable platform via activable DNA regulators to achieve spatiotemporal regulation of mitochondria-lysosome interactions in living cells. In our system, two locked DNA regulators, OK-MLIR and DK-MLIR, that can be respectively activated with UV light (One Key) as well as UV light and endogenous glutathione (Dual Keys), are modularly designed for modulating mitochondria-lysosome contacts. We show that these DNA regulators can be used for facilitating mitochondrial fission and autophagy. Moreover, the DK-MLIR enables selective and efficient manipulation of target cell migration and proliferation with highly temporal and spatial controllability. This programmable and modular design principle provides a platform for organelle interaction study, cellular regulation and precision therapy.

DOI: https://doi.org/10.1038/s41467-025-63040-x
Nat Commun. 2025 Aug 25. 16(1): 7846

Branched-chain amino acids contribute to diabetic kidney disease progression via PKM2-mediated podocyte metabolic reprogramming and apoptosis.

Huishou Zhao, Dan Sun, Shan Wang, Yi Liu, Xiaojuan Zhao, Wenqi Tian, Xiuhong Dou, Jilong Liu, Jinyang Xu, Lu Peng, Shiren Sun, Yunlong Xia, Xiaoming Xu, Cheng Wang, Di Wang, Guohong Zhao, Xin Wang, Huanze Weng, Fengyue Ding, Pingping Xing, Fuyang Zhang, Shiyu Liu, Wenjun Yan, Ling Tao.

Approximately 30-40% of patients with diabetes develop diabetic kidney disease (DKD). Identifying decisive factors for DKD initiation is crucial. Here, we observed that glomerular podocytes in male and female patients with DKD and db/db mice specifically displayed BCAA catabolic defects. Podocyte-specific PP2Cm (a key BCAA catabolism enzyme) knockout or exogenous BCAA supplementation induced DKD phenotypes including podocyte dysfunction/apoptosis, glomerular pathology, and proteinuria in high-fat (HF)-diet-fed male mice. Mechanistically, BCAAs promoted PKM2 depolymerization and inactivation in podocytes. Depolymerized PKM2 suppressed glucose oxidative phosphorylation (OXPHOS), diverting glucose metabolism towards serine biosynthesis and folate metabolism. Depolymerized PKM2 is also co-transported with DDIT3 into the nucleus, acting as a co-transcriptional factor to enhance DDIT3 transcriptional activity, which promotes Chac1 and Trib3 expression and directly inducing podocyte apoptosis. Thus, BCAA catabolic defects may be one of the missing factors that determine DKD initiation. Targeting BCAA catabolism or PKM2 activation is a promising DKD prevention strategy.

DOI: https://doi.org/10.1038/s41467-025-62890-9
Nat Commun. 2025 Aug 26. 16(1): 7934

Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.

Xinzhu Li, Ying Zhu, Ting Li, Xinyi Tu, Shiyu Zhu, Lingzhi Wang, Fei Li, Chenglong Sun, Xin Li, Haiyi Zhao, Tang Tang, Qingce Zang, Ruiping Zhang, Zeper Abliz.

Organs collaborate to maintain metabolic homeostasis in mammals. Spatial metabolomics makes strides in profiling the metabolic landscape, yet can not directly inspect the metabolic crosstalk between tissues. Here, we introduce an approach to comprehensively trace the metabolic fate of 13C-nutrients within the body and present a robust computational tool, MSITracer, to deep-probe metabolic activity in a spatial manner. By discerning spatial distribution differences between isotopically labeled metabolites from ambient mass spectrometry imaging-based isotope tracing data, this approach empowers us to characterize fatty acid metabolic crosstalk between the liver and heart, as well as glutamine metabolic exchange across the kidney, liver, and brain. Moreover, we disclose that tumor burden significantly influences the host's hexosamine biosynthesis pathway, and that the glucose-derived glutamine released from the lung as a potential source for tumor glutamate synthesis. The developed approach facilitates the systematic characterization of metabolic activity in situ and the interpretation of tissue metabolic communications in living organisms.

DOI: https://doi.org/10.1038/s41467-025-63243-2
Sci Rep. 2025 Aug 20. 15(1): 30528

GPT2 mediates glutamine metabolism-driven metabolic alterations in platinum-resistant ovarian cancer cells.

Adriana Ponton-Almodovar, Mary P Udumula, Vrinda Khullar, Faraz Rashid, Ramandeep Rattan, Jamie J Bernard, Sachi Horibata.

  Metabolic reprogramming is recognized as a hallmark of cancer frequently associated with drug resistance in ovarian cancer. This is problematic as ovarian cancer is one of the deadliest gynecologic cancers with platinum resistance contributing to poor survival. However, the mechanism by which ovarian cancer cell metabolism contributes to platinum resistance is not well understood. Herein, metabolic signatures were determined in platinum-resistant ovarian cancer cell lines compared to the more platinum-sensitive parental lines. Chemoresistant ovarian cancer cells showed increased oxidative phosphorylation (OXPHOS) compared to chemosensitive cells. This was associated with elevated levels of glutaminolysis and tricarboxylic acid (TCA)-related metabolites supporting their dependence on OXPHOS. Key enzymes involved in glutaminolysis, specifically, glutamic-pyruvic transaminase 2 (GPT2), were upregulated in chemoresistant compared to chemosensitive cells. Interestingly, high GPT2 gene expression is associated with worse prognosis in ovarian cancer patients, adding translational relevance to the pre-clinical findings. GPT2 knockout in chemoresistant cells restored the metabolic phenotype to that of the sensitive cells and reversed drug resistance. These data suggest that GPT2 is a critical link between glutaminolysis, the TCA cycle, and OXPHOS and is a potential target to attenuate the increased metabolic activity associated with a chemoresistant phenotype.

Keywords:  GPT2; Glutamine; Metabolism; Ovarian cancer

DOI:  https://doi.org/10.1038/s41598-025-15707-0
ACS Chem Neurosci. 2025 Sep 03. 16(17): 3398-3409

Detection of Neuronal Glutamate in Brain Extracellular Space In Vivo Using Microdialysis and Metabolic Labeling with Glutamine.

Neil D Hershey, Pavlo Popov, Nick Oliver, Colleen E Dugan, Robert T Kennedy.

  Extracellular glutamate (Glu) concentration measured in the brain using microdialysis sampling is regulated differently from that expected for classical neurotransmitters; e.g., the basal Glu concentration is not affected by blocking action potentials. Additionally, other sources, such as glial cells, contribute to Glu extracellular concentration making it difficult to interpret detected changes. We have found that infusing 2.5 μM 13C5-glutamine (Gln) through a microdialysis probe inserted in the rat cortex results in collection of 144 ± 35 nM (n = 11) 13C5-Glu in dialysate. The recovered 13C5-Glu was reduced by 33% by infusion of 20 mM α-(methylamino)isobutyric acid and 58% by 500 mM riluzole, inhibitors of glutamine transport into neurons. The 13C5-Glu measured was reduced by 62% with tetrodotoxin (TTX), a sodium channel blocker, and 59% with (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a metabotropic glutamate agonist, while endogenous Glu remained unchanged. These results support the hypothesis that the measured 13C5-Glu is derived from neurons via the Gln-Glu shuttle. To further investigate regulation of 13C5-Glu, we applied a stressor (tail pinch), observing a 155% increase in dialysate 13C5-Glu concentration. This effect was blocked by infusion of TTX indicating neuronal release. Local infusion of l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC), a Glu uptake inhibitor, increased both endogenous Glu and 13C5-Glu concentrations, consistent with reverse transport and spread of neuronal release. Taken together, these experiments show that metabolic labeling of Glu via Gln delivered through a microdialysis probe allows differentiation of neuronal and other sources of Glu in the brain. The results support the concept of compartmentalized Glu in the brain.

Keywords:  astrocyte; glutamate-glutamine shuttle; mass spectrometry; microdialysis; neuronal glutamate

DOI:  https://doi.org/10.1021/acschemneuro.5c00518
Front Immunol. 2025 ;16 1617993

Single cell autofluorescence imaging reveals immediate metabolic shifts of neutrophils with activation across biological systems.

Rupsa Datta, Veronika Miskolci, Gina M Gallego-López, Emily Britt, Amani Gillette, Aleksandr Kralovec, Morgan A Giese, Tongcheng Qian, James Votava, Wenxuan Zhao, Jing Fan, Anna Huttenlocher, Melissa C Skala.

   Introduction: Neutrophils are critical innate immune cells that heterogeneously respond to infection and inflammation by performing functions such as oxidative burst and NETosis, which require significant metabolic adaptation. Deeper insights into the single cell diversity of such metabolic changes will help identify regulation of neutrophil functions in health and diseases. Due to their short lifespan and associated technical challenges, the early metabolic processes of neutrophil activation are not completely understood. New tools are needed to measure rapid changes in neutrophil metabolism on a single cell level.
Methods: To address this, we use optical metabolic imaging (OMI), which entails optical redox ratio and fluorescence lifetime imaging microscopy of intrinsic metabolic coenzymes NAD(P)H and FAD to assess the metabolic state of single neutrophils. Primary human neutrophils were imaged in vitro under a variety of activation conditions and metabolic pathway inhibitors, while metabolic and functional changes were confirmed with mass spectrometry, oxidative burst, and NETosis measurements.
Results: Our findings show rapid metabolic remodeling to a reduced redox state during activation. Additionally, heterogeneous metabolic response to pathogens (Pseudomonas aeruginosa and Toxoplasma gondii) was observed across neutrophils and human donors. Finally, consistent OMI changes with activation were confirmed between in vitro human and in vivo zebrafish larvae neutrophils. This study demonstrates the potential of OMI as a versatile tool for studying neutrophil metabolism and underscores its use across different biological systems, offering insights into neutrophil metabolic activity and function at a single cell level.
Conclusion: This work addresses the critical need for advanced single-cell tools to monitor rapid and diverse metabolic changes in neutrophils, an underexplored area with significant implications for understanding immune responses and developing therapies for inflammatory diseases. Neutrophils, the body's first responders to infection and inflammation, undergo rapid metabolic changes upon activation. Using label-free optical metabolic imaging of intrinsic metabolic coenzymes NAD(P)H and FAD, we reveal distinct metabolic signatures in activated primary human neutrophils as well as neutrophils in live zebrafish larvae. Our findings highlight how pathogens and pharmacological stimuli heterogeneously rewire neutrophil metabolism within minutes, influencing immune responses. This noninvasive method offers insights into single-cell neutrophil metabolism immediately following activation, with implications for infection, inflammation, and immune disorders.

Keywords:  fluorescence lifetime imaging microscopy (FLIM); label-free; metabolism; neutrophil; optical metabolic imaging; single-cell

DOI:  https://doi.org/10.3389/fimmu.2025.1617993
Nat Commun. 2025 Aug 20. 16(1): 7550

Ca2+-pumping by PMCA-neuroplastin complexes operates in the kiloHertz-range.

Cristina E Constantin, Barbara Schmidt, Yvonne Schwarz, Harumi Harada, Astrid Kollewe, Catrin S Müller, Sebastian Henrich, Botond Gaal, Akos Kulik, Dieter Bruns, Uwe Schulte, Heiko Rieger, Bernd Fakler.

Ca2+-ATPases in the plasma membrane extrude Ca2+ ions from the cytosol to the extracellular space thereby terminating Ca2+-signals and controlling Ca2+-homeostasis in any type of cell. Recently, these Ca2+-pumps have been identified as protein complexes of the transporting subunits PMCAs1-4 and the single-span membrane proteins Neuroplastin (NPTN) or Basigin that are obligatory for efficient trafficking of the pump complexes to the surface membrane. Quantitative investigation of the pumping velocity controlling the time course of Ca2+-signals, however, has remained unresolved. Here we show, using Ca2+-activated K+ channels as fast native reporters of intracellular Ca2+ concentration(s) together with membrane-tethered fluorescent Ca2+-indicators, that under cellular conditions PMCA2-NPTN complexes can clear Ca2+ in the low millisecond-range. Computational modeling exploiting EM-derived densities of Ca2+-source(s) and Ca2+-transporters in freeze-fracture replicas translated these fast kinetics into transport rates for individual PMCA2-NPTN pumps of more than 5000 cycles/s. Direct comparison with the Na+/Ca2+-exchanger NCX2, an alternate-access transporter with established cycling rates in the kHz range, indicated similar efficiencies in Ca2+-transport. Our results establish PMCA2-NPTN complexes, the most abundant Ca2+-clearing tool in the mammalian brain, as transporters with unanticipated high cycling rates and demonstrate that under cellular conditions ATPases may operate in the kHz-range.

DOI: https://doi.org/10.1038/s41467-025-62735-5
Biochim Biophys Acta Rev Cancer. 2025 Aug 20. pii: S0304-419X(25)00170-2. [Epub ahead of print]1880(5): 189428

Fatty acid addiction in cancer: A high-fat diet directly promotes tumor growth through fatty acid oxidation.

Soo-Youl Kim.

  Tumor growth promoted by a high-fat diet (HFD) was completely reversed by inhibiting fatty acid oxidation (FAO). The promotion of tumors by an HFD is known to result from the indirect effects of sex hormones, leptin, and adipokines such as insulin-like growth factor-1 (IGF-1) on cancer cells. However, even though HFD notably increased blood levels of IGF-1, knocking down the carnitine-acylcarnitine carrier (CAC) to inhibit FAO completely reversed the tumor-promoting effects in pancreatic cancer cells, accompanied by a significant decrease in ATP production. When ATP levels dropped due to FAO inhibition in cancer cells, mTOR - a key regulator of survival - became inactive, leading to reduced cell viability and increased cell death. This shows that HFD promotes cancer cell growth by supplying more calories through FAO, indicating that cancer is addicted to fatty acids. This review emphasizes the crucial role of cancer-specific FAO in tumor growth and proposes potential new therapeutic strategies targeting various FAO enzymes as innovative anti-cancer treatments.

Keywords:  ATP production; Fatty acid oxidation; High-fat diet (HFD); Obesity; cancer

DOI:  https://doi.org/10.1016/j.bbcan.2025.189428
Nat Metab. 2025 Aug 22.

Investigating metabolic changes in single embryos during early development in Drosophila.

DOI: https://doi.org/10.1038/s42255-025-01375-x
Sci Rep. 2025 Aug 26. 15(1): 31454

Real-time visualization and modulation of endocytic dynamics in osteocytes in vivo.

Melia D Matthews, Alexander Saffari, Nuzhat Mukul, Lanlan Hai, Nada Naguib, Ulrich B Wiesner, Karl J Lewis.

Endocytosis is a critical cellular process involved in many physiological functions, including mechanotransduction. Recent advancements in intravital imaging have led to in vivo analysis of endocytosis, and these tools can now be translated to study the highly mechanosensitive bone tissue. Here, we present a live-cell study of endocytosis in osteocytes, mechanosensory cells embedded in mouse bone. Using intravital multiphoton microscopy and fluorescently labeled nanoparticles, we visualized real-time uptake and trafficking within osteocytes in vivo. We applied pharmacologic inhibitors to assess both general and receptor-specific modes of endocytosis. Our results demonstrate rapid and dynamic nanoparticle internalization by osteocytes, with distinct differences in uptake kinetics and subcellular distribution depending on nanoparticle surface functionalization. Notably, we observed sex-specific differences in dynamin-dependent endocytic activity. These results offer the first in vivo derived insights into how osteocytes take up materials and provide new evidence for chemically altering receptor-mediated endocytosis in live bone tissue.

DOI: https://doi.org/10.1038/s41598-025-05735-1
Cancer Res. 2025 Aug 27.

Malonyl-CoA Promotes Prostate Cancer Progression and Castration Resistance by Enhancing Lipogenesis and Ran Activation.

Yiheng Dai, Lilong Liu, Yongbo Luo, Cai Zhang, Sayu Xiao, Kaixuan Du, Yuanhao Liu, Youmiao Zeng, Zhengfeng Wang, Zhaohui Chen, Ke Chen, Lijie Zhou.

Malonyl-CoA, a key metabolite, is not only the building block for lipogenesis, but also a critical regulator of mitochondrial fatty acid (FA) β-oxidation. Given the altered metabolic state of many cancers, malonyl-CoA may play a role in tumor development and drug resistance, especially in malignancies characterized by abnormal lipid metabolism, such as prostate cancer (PCa). Here, we showed that the levels of malonyl-CoA were increased in PCa, especially in castration-resistant prostate cancer (CRPC). Abnormal accumulation of malonyl-CoA promoted lipogenesis and regulated metabolic processes, maintaining endoplasmic reticulum (ER) homeostasis and mitochondrial function and ultimately contributing to PCa progression. Restoration of malonyl-CoA decarboxylase (MLYCD) expression activated the unfolded protein response via the consumption of malonyl-CoA. Importantly, malonyl-CoA accumulation promoted lysine malonylation in PCa. Ran K141 malonylation increased Ran activity and enhanced androgen receptor nuclear translocation and transcriptional activity, ultimately contributing to PCa development and resistance to antiandrogens. These findings highlight the function of malonyl-CoA in PCa progression by regulating metabolic processes and malonylating Ran K141, revealing that the malonyl-CoA axis might be a reliable biomarker and a potential therapeutic target in PCa.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4247
Sci Rep. 2025 Aug 21. 15(1): 30686

Integrative analysis of gut microbiota and metabolic pathways reveals key microbial and metabolomic alterations in diabetes.

GP2324 consortium

  Type 2 diabetes mellitus (T2DM) is increasingly recognized as a condition influenced by gut microbiota composition and associated metabolic pathways. This study investigated the differences in gut microbial diversity, composition, and metabolomic profiles between diabetic and control individuals. Using 16 S rRNA gene sequencing and metabolomic analyses, we observed significantly higher microbial diversity and evenness in the diabetic group, with distinct clustering patterns as revealed by Principal Coordinate Analysis (PCoA). Taxonomic profiling demonstrated an increased relative abundance of Bacteroidaceae and Lachnospiraceae in the diabetic group, while Streptococcaceae was more prevalent in the control group. LEfSe analysis identified key microbial taxa such as Bacteroides, Blautia, and Lachnospiraceae_FCS020_group enriched in diabetic individuals, suggesting a role in metabolic dysregulation. Metabolomic pathway enrichment analysis revealed significant differences in pathways related to fatty acid metabolism, glucose homeostasis, bile acid metabolism, and amino acid biosynthesis in diabetic individuals. Enriching fatty acid elongation and β-oxidation pathways, alongside disrupted glucose metabolism, indicate profound metabolic changes associated with diabetes. Bile acid metabolism and branched-chain amino acid (BCAA) pathways were also elevated, linking these metabolites to the observed gut microbiota shifts. These findings suggest that diabetes is associated with significant alterations in the gut microbiome's composition and function, leading to disruptions in critical metabolic pathways. This study provides insights into potential microbial biomarkers and therapeutic targets for improving metabolic health in diabetic patients.

Keywords:  Diabetes; Gut microbiota; LEfSe analysis; Metabolic pathways; Metabolomics; Microbial diversity

DOI:  https://doi.org/10.1038/s41598-025-09328-w
Sci Rep. 2025 Aug 26. 15(1): 31448

PKM2 regulates angiogenic activation via ANGPT2 in endothelial cells.

Qiangqiang Ge, Jianan Guo, Liyuan Ye, Yifei Le, Ji Zhu.

  Endothelial cells constitute the primary barrier within the vessel wall, exhibiting the capacity for angiogenesis, a process implicated in revascularisation.Endothelial cell-mediated angiogenesis is further recognised as a pivotal pathological factor in tumours, pulmonary hypertension, and ocular diseases. Pyruvate kinase type M2 (PKM2) represents a pivotal enzyme in glycolysis, exerting a role in the pathogenic process of diverse diseases through metabolic processes and the transcriptional regulation of key genes. This study established a correlation between PKM2 and angiogenesis in tumours, with the knockdown of PKM2 inhibiting proliferation, migration and angiogenesis in endothelial cells and the over-expression of PKM2 promoting it. Further studies identified ANGPT2 as a downstream target of PKM2, and the supplementation of endothelial cells with ANGPT2 restored proliferation, migration and angiogenesis inhibited by knockdown of PKM2. Collectively, these findings imply that ANGPT2 contributes significantly to the regulation of PKM2-mediated proliferation, migration and angiogenesis.

Keywords:  ANGPT2; Angiogenesis; Endothelial cells; Glycolysis; PKM2

DOI:  https://doi.org/10.1038/s41598-025-17147-2