bims-celmim 2026-10-04 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–10–04
33 papers selected by
Marc Segarra Mondejar, AINA

ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesis and fatty acid oxidation in colorectal cancer.
Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in GNAS (Gαs) mutant pancreas cancer.
Hypoxia? NNoT a PROblem!
A mitochondrial carrier turns on the heat.
Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
Metabolic control by liver-kidney crosstalk and glucagon in health and disease.
Cancer stem cell programs S-nitrosylation and deubiquitination of FoxP3 protein to promote regulatory T cell differentiation.
Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
LAT condensation gates PLCγ1 activation via bimodal LAT phosphorylation.
Glutamine Metabolism in Health and Diseases.
A lipid transfer-dependent feedback loop activates ATG9A compartments in autophagy initiation.
BRET-Based Mitochondrial Subcompartment Localization Biosensors Reveal the Impact of Pesticides and Food Additives on Mitochondrial Protein Localization.
Lysine-Targeting Covalent Inhibition of Glutaminase Using Cyanopyrimidines.
Uptake of L-proline by Cultured Primary Rat Astrocytes.
Mitochondria-ER-lipid droplet crosstalk regulates metabolic adaptation to shear stress via VMP1.
Unveiling Functional-Metabolic Synergy in the Healthy Brain: Multivariate Integration of Dynamic [18F]FDG-PET and Resting-State fMRI.
Peroxisomal Import Stress Drives Cellular Senescence through SCAF1-dependent Suppression of Mitoribosome Biogenesis.
α-aminobutyric acid promotes tumor progression by polarizing macrophages through the ASNS-mTORC2 axis.
Folate deficiency disrupts key metabolic transitions within the developing neural ectoderm.
Redox activation of ATG5 licenses autophagy upon nutrient restriction.
Nucleotide metabolic reprogramming: a "double-edged sword" in obesity-related inflammation-from metabolic adaptation to pathological imbalance.
Mitochondrial rewiring supports survival of triple negative breast cancer cells after ionizing radiation.
PTEN-L inhibits mitophagy and GSDME-dependent pyroptosis via Parkin dephosphorylation.
A Cationic 3-hydroxyflavone-Based Fluorescent Probe for Wide Range of pH and Adenosine Triphosphate Determination.
Mechanosignaling Promotes Macrophage Apoptosis Resistance in Pulmonary Fibrosis via Metabolic Reprogramming.
Metabolic-epigenetic coupling between leucine catabolism and glycolysis drives CDK4/6 inhibitor resistance.
Auto-S-fatty acylation of PKM2 regulates its tetramerization and glycolytic metabolism in cancer cells.
Deep learning-enhanced single-shot triorganelle STED-FLIM imaging of lipid dynamics in living cells.
Metabolic Regulation of Angiogenesis in Pancreatic Ductal Adenocarcinoma.
Metabolic licensing and restriction of innate immunity in the tumor microenvironment.
Therapeutic potential of MitoQ, a mitochondria-targeted antioxidant, in age-related physiological dysfunction.
Energetic dysregulations in psychotic disorders: Targets for new therapeutics.
Structural insights into DHODH-mediated catalysis and drug resistance.

bioRxiv. 2026 Sep 25. pii: 2026.09.24.753323. [Epub ahead of print]

ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesis and fatty acid oxidation in colorectal cancer.

Zhiping Feng, Thomas E Bearrood, Sydney L Campbell, Adrianne M Kinsey, Nedas Matulionis, Che-Hong Chen, Takuya Seike, Logan Leak, A Kaan Tarhan, Scott J Dixon, Daria Mochly-Rosen, Heather R Christofk, James K Chen.

Metabolic reprogramming is a hallmark of cancer cells, and stem-like populations often upregulate aldehyde dehydrogenases (ALDHs). Functional studies have established essential roles for individual ALDH isoforms in tumor initiation, progression, and metastasis; however, the mechanisms by which these enzymes promote malignancy remain poorly understood. Here we show that aldehyde dehydrogenase 1B1 (ALDH1B1), a mitochondrial enzyme highly expressed in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), generates γ-butyrobetaine (GBB) and γ-aminobutyric acid (GABA) in CRC cells. The biosynthesis of both aminocarboxylic acids has been attributed to the cytosolic enzyme ALDH9A1, and we demonstrate that mitochondrial GBB and GABA are functionally distinct from the cytosolic pools of these metabolites. We further demonstrate that mitochondrial GBB can function as an antiport substrate of carnitine-acylcarnitine translocase (CACT), the transporter that mediates fatty acid uptake into the mitochondrial inner matrix. This activity complements the role of cytosolic GBB as the biosynthetic precursor to carnitine. Accordingly, ALDH1B1 can markedly enhance mitochondrial fatty acid oxidation (FAO), a catabolic process that has been linked to CRC and PDAC stemness, progression, and metastasis. Our findings reveal an unexpected role for ALDH1B1 in carnitine metabolism, GABA biosynthesis, and FAO and illustrate how the compartmental reprogramming of metabolic pathways can promote tumor growth.

DOI: https://doi.org/10.64898/2026.09.24.753323
Sci Adv. 2026 Oct 02. 12(40): eaeh7186

Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in GNAS (Gαs) mutant pancreas cancer.

Grant A Hagedorn, Jackson C Spieser, Noriko Hirai, Yuki Sato, Jake Valentine, Hanson Jiang, Wang Wang, Maria F Czyzyk-Krzeska, Krushna C Patra.

Maintenance of fissed mitochondria is viewed as a defining feature of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant cancers. However, regulation of this process by accompanying comutations or environmental factors is not clearly defined. Here, by analyzing a subset of pancreatic cancer lesions driven by concurrent KrasG12D and GNAS complex locus gene (GNASR201C/H) mutations, we found that despite the presence of mutant Kras, hyperactive GnasR201C maintains mitochondria predominantly in a fused state, which is necessary for tumor growth. Multiplex proteomics, super-resolution microscopy, loss- and gain-of-function studies, coupled with metabolite rescue experiments, revealed that GnasR201C-regulated branched-chain amino acid (BCAA) pathway is a previously unidentified regulator of mitochondrial morphology. Mechanistically, the BCAA pathway, the associated tricarboxylic acid cycle, and aspartate metabolism converge on nicotinamide adenine dinucleotide (NADH-NAD+) metabolites to promote mitochondrial elongation. NAD+ availability is crucial for mitochondrial fusion, as facilitating NAD+ generation through alternative means promotes fusion. Collectively, we unraveled a new mechanism that drives mitochondrial fusion and showed that the combination of oncogenic signaling and metabolism can maintain distinct mitochondrial morphology within genetic subsets of KRAS-mutant pancreatic cancer.

DOI: https://doi.org/10.1126/sciadv.aeh7186
Mol Cell. 2026 Oct 01. pii: S1097-2765(26)00627-1. [Epub ahead of print]86(19): 3862-3863

Hypoxia? NNoT a PROblem!

Ningning Liang, Costas A Lyssiotis, Daniel R Wahl.

Glioma cells experience profound metabolic stress in hypoxic tumor regions, where mitochondrial respiration is constrained and redox balance becomes difficult to maintain. A recent study by Vettore and colleagues1 in Molecular Cell identifies nicotinamide nucleotide transhydrogenase as a key mitochondrial enzyme that connects NADH oxidation to NADPH production, thereby supporting proline synthesis and growth under hypoxia. This work highlights how distinct redox pools are coordinated in cancer cells and suggests that NNT-dependent metabolism may represent a vulnerability in hypoxic tumors.

DOI: https://doi.org/10.1016/j.molcel.2026.09.007
Science. 2026 Oct;394(6819): 29-30

A mitochondrial carrier turns on the heat.

Martin van der Laan.

An orphan protein integrates circadian, dietary, and environmental signals to control brown fat metabolism.

DOI: https://doi.org/10.1126/science.ael7271
Sci Adv. 2026 Oct 02. 12(40): eaei2831

Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.

Nancy T Santiappillai, Andrew Cho, Georg Verch, Ana C Codo, Achuth Nair, Ya-Ting Wang, Allie Lipshutz, Celia Martínez de la Torre, Eric Minwei Liu, Marjan Berishaj, Alissa J Trzeciak, Zhaoquan Wang, Michelle Saoi, Waleska Saitz Rojas, Justin R Cross, Ed Reznik, Justin S A Perry, Kayvan R Keshari.

Triple-negative breast cancer (TNBC) develops in hypoxic, nutrient-limited tumors enriched with macrophages and cell death. We show that metabolically distinct TNBCs differentially exploit macrophage-derived nutrients, influencing tumor growth and therapeutic response. Prolonged hypoxia reprogrammed mouse and human macrophages, enabling them to release metabolites that rescued the growth of select TNBC cell lines during glutamine deprivation or glutamine metabolism inhibition. Hypoxic macrophages reduced glutamine consumption, increased arginine utilization, and secreted higher levels of ornithine, an intermediate of arginine metabolism. Exogenous ornithine, but not arginine, restored the growth of responsive TNBC cells. Mechanistically, TNBC cells diverted ornithine into proline biosynthesis, supporting oxidative pentose phosphate pathway activity. In vivo, depletion of tumor-associated myeloid cells reduced tumor growth and impaired proline synthesis in glutaminase inhibitor-resistant TNBC. These findings identify hypoxia-driven metabolic cross-talk between macrophages and TNBC cells, revealing ornithine-dependent proline metabolism as a mechanism by which macrophages sustain tumor growth under nutrient stress and contribute to resistance to glutamine-targeted therapies.

DOI: https://doi.org/10.1126/sciadv.aei2831
Nat Rev Nephrol. 2026 Sep 29.

Metabolic control by liver-kidney crosstalk and glucagon in health and disease.

Volker Vallon, Nicolai J Wewer Albrechtsen.

Gluconeogenesis, nitrogen metabolism and acid-base regulation are fundamental for the maintenance of metabolic homeostasis. These three processes form an interconnected triangle, with liver-kidney crosstalk and the hormone glucagon at its core. Both kidney and liver perform gluconeogenesis, and they function in co-ordination to regulate the formation and excretion of the organic osmolyte urea and the acid equivalent ammonium, and to determine the usage and de novo generation of bicarbonate. Within the liver, glucagon promotes fasting-induced gluconeogenesis and the bicarbonate-consuming formation of urea from amino acid-derived ammonia in response to protein intake and catabolic states. Within the kidney, glucagon facilitates the excretion of urea. In metabolic acidosis, the liver shifts nitrogen metabolism from ureagenesis to glutamine formation for kidney ammoniagenesis. Liver and kidney disease interfere with whole-body homeostasis of glucose, nitrogen and acid-base by promoting hypo- or hyperglycaemia, ammonia and urea toxicity, and metabolic alkalosis or acidosis. Inhibitors of the sodium glucose cotransporter SGLT2 not only cause glucosuria and compensatory hepatic gluconeogenesis but also interfere with kidney bicarbonate reabsorption, leading to compensatory kidney ammoniagenesis, bicarbonate formation and gluconeogenesis, which mitigates lactate accumulation and is associated with improved kidney health. Glucagon receptor agonists, in combination with GLP1 receptor agonists, also hold therapeutic promise in obesity and fatty liver and potentially kidney disease, but a better understanding of their effects is needed in the pathophysiological setting.

DOI: https://doi.org/10.1038/s41581-026-01111-y
Front Immunol. 2026 ;17 1961819

Cancer stem cell programs S-nitrosylation and deubiquitination of FoxP3 protein to promote regulatory T cell differentiation.

Xiyu Liu, Jiaxin Lei, Xinhang Jiang, Lingyi Li, Longhao Yu, Gengxue Wang, Kaixun Guo, Zhenke Wen, Yan Wang.

   Background: Cancer stem cells (CSCs) are critical drivers of tumor progression and therapeutic resistance in non-small cell lung cancer (NSCLC). However, how CSCs remodel the immunosuppressive tumor microenvironment (TME) of NSCLC remains largely unclear.
Methods: Flow cytometry was performed to evaluate the immunomodulatory effects of NSCLC CSCs on T cell differentiation. RNA-sequencing-based metabolic profiling was conducted to identify pivotal metabolic pathways activated in CSCs. Mitochondrial reactive oxygen species (ROS) encapsulated in CSC-derived exosomes were quantified, and the molecular mechanism by which exosomal ROS modulates intracellular nitric oxide (NO) production and FoxP3 post-translational modifications in T cells was further explored. Patient-derived organoids (PDOs) were utilized as a preclinical model to verify the therapeutic potential of glutamine metabolism targeting.
Results: NSCLC CSCs potently induced tumor immunosuppression by promoting regulatory T (Treg) cell differentiation. Mechanistically, hyperactive glutamine metabolism in CSCs substantially increased mitochondrial ROS generation. Exosomal ROS secreted by CSCs was transferred to T cells, thereby elevating intracellular NO synthesis. Increased NO further triggered S-nitrosylation and deubiquitination of FoxP3, which ultimately stabilized FoxP3 expression and facilitated Treg cell differentiation. In NSCLC PDO models, pharmacological inhibition of glutamine metabolism reversed the immunosuppressive T cell phenotype and efficiently suppressed PDO growth.
Conclusion: NSCLC CSCs mediate TME immunosuppression via a glutamine metabolism-dependent regulatory axis. Exosomal ROS-initiated FoxP3 post-translational modification is a novel mechanism underlying CSC-driven Treg differentiation. This study reveals an unreported immune evasion pathway in NSCLC and identifies glutamine metabolism as a viable therapeutic target for overcoming tumor immunosuppression.

Keywords:  CSCs; Foxp3; S-nitrosylation; deubiquitination; regulatory T cell

DOI:  https://doi.org/10.3389/fimmu.2026.1961819
Nat Commun. 2026 08 31. pii: 10359. [Epub ahead of print]17(1):

Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.

Krystle C Kalafut, Yann Cormerais, Madi Y Cissé, Samuel C Lapp, Karen E Inouye, Gökhan S Hotamışlıgil, Brendan D Manning.

The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, and aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well-defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Here, studies employing a liver-specific genetic mouse model demonstrate that AKT-mediated TSC2 phosphorylation is the predominant mechanism of hepatic mTORC1 induction by insulin but is dispensable for activation by feeding. Furthermore, postprandial activation of hepatic mTORC1 requires dietary protein, which dictates the insulin-responsiveness of the pathway. Contrary to dogma, hepatic mTORC1 signaling was not elevated in response to diet-induced obesity, despite overt impairments in insulin and glucose homeostasis, and blocking hepatic AKT-TSC-mTORC1 signaling did not affect these metabolic phenotypes. Evidence is also provided supporting a role for glucagon in hepatic mTORC1 suppression during fasting. This study reveals a hierarchy of physiological signals regulating hepatic mTORC1.

DOI: https://doi.org/10.1038/s41467-026-77216-6
Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2614738123

LAT condensation gates PLCγ1 activation via bimodal LAT phosphorylation.

He Ren, Hyun-Ro Lee, Yannick A D Omar, Joseph B DeGrandchamp, Chien-Lun Hung, Timothy J Eisen, Dimitrios Stamou, John Kuriyan, Arup K Chakraborty, Jay T Groves.

  T cells can respond to even a single molecular binding event of antigen to a TCR. A key step in the TCR signaling pathway that definitively exhibits this single-molecule response is the initiation of calcium influx by activation of PLCγ1 in the LAT protein condensate. Here, we describe detailed kinetic measurements examining how protein condensation of LAT regulates activation of PLCγ1 using a reconstituted membrane system. The results reveal that membrane recruitment of PLCγ1 is tightly controlled by the LAT phosphorylation state, with no measurable independent recruitment to PIP2 or PIP3 lipids via the PLCγ1 PH domains. We further observe PLCγ1 is rapidly activated by membrane-associated kinase upon recruitment, irrespective of the LAT condensation state. These studies also reveal a crosstalk mechanism in which the TEC family kinases responsible for PLCγ1 activation also phosphorylate LAT. This interaction establishes a positive feedback loop in LAT phosphorylation, mediated through LAT condensation, which drives a bimodal LAT phosphorylation response to TCR activation. Kinetic modeling reveals how this LAT phosphorylation response can cooperatively gate PLCγ1 activation from a single TCR. These results suggest the LAT condensate facilitates both signal amplification and noise suppression in PLCγ1 activation through a bimodal switch affecting LAT phosphorylation.

Keywords:  T cell receptor signaling; kinetics; phospholipase C gamma; protein condensation

DOI:  https://doi.org/10.1073/pnas.2614738123
MedComm (2020). 2026 Oct;7(10): e71035

Glutamine Metabolism in Health and Diseases.

Yi Ding, Fan Tong, Jing Zeng, Chun-Ping Cui.

  Glutamine, the most abundant nonessential amino acid in the blood and tissues, plays essential roles in cellular proliferation, immune regulation, acid-base homeostasis, and metabolic balance. Although traditionally classified as a nonessential amino acid, glutamine becomes conditionally essential under pathological conditions and physiological stress due to its critical role in supporting cellular adaptation. Under diverse pathological states, glutamine metabolism undergoes extensive reprogramming, and cancer cells exhibit a particularly high dependence on glutamine to sustain proliferation, redox balance, and biosynthetic demands. In this review, we summarize the multifaceted functions of glutamine metabolism in physiological and pathological processes. We first discuss the fundamental pathways of glutamine synthesis, transport, and utilization, followed by an overview of its regulatory roles in cellular responses to oxidative, nutritional, thermal, mechanical, DNA damage, and osmotic stresses. We further highlight the involvement of glutamine metabolism in cancer progression, immune regulation, metabolic plasticity, and therapeutic resistance. Finally, we summarize emerging glutamine-targeted therapeutic strategies, including metabolic inhibitors, combination therapies, and advanced technologies for metabolic imaging and single-cell analysis. This review provides a comprehensive perspective on glutamine metabolism and highlights its potential as a therapeutic target for cancer and other metabolic disorders.

Keywords:  cell metabolism; cellular homeostasis; glutamine; pathological conditions; therapeutic target

DOI:  https://doi.org/10.1002/mco2.71035
Nat Commun. 2026 08 31. pii: 10374. [Epub ahead of print]17(1):

A lipid transfer-dependent feedback loop activates ATG9A compartments in autophagy initiation.

Elisabeth Holzer, Justyna Sawa-Makarska, Daniel Bernklau, Julia Romanov, Martina Schuschnig, Sascha Martens.

Autophagy degrades cellular material by sequestering it within autophagosomes, which form de novo from precursors called phagophores. Phagophore assembly and expansion require ATG9A-positive seed compartments, the lipid transfer protein ATG2A, and the class III phosphatidylinositol 3-phosphate kinase complex I (PI3KC3-C1). PI3KC3-C1 synthesizes phosphatidylinositol 3-phosphate (PI3P), a key lipid that drives downstream processes for phagophore expansion, including ATG8 lipidation. We find that ATG9A compartments contain only traces of phosphatidylinositol (PI), likely insufficient for efficient PI3P production or recruitment of PI3P-binding effectors. Nevertheless, ATG2A is recruited to these compartments and mediates lipid transfer, including PI, into them. Remarkably, even without detectable PI3P, ATG9A compartments are direct substrates for ATG8 lipidation, and ATG8 proteins themselves enhance ATG2A-mediated lipid transfer. In cells, ATG2A is essential for the appearance of PI3P on ATG9A compartments. Our findings support a model in which a lipid transfer-driven feedback loop activates ATG9A compartments for phagophore expansion.

DOI: https://doi.org/10.1038/s41467-026-77368-5
ACS Sens. 2026 Sep 27.

BRET-Based Mitochondrial Subcompartment Localization Biosensors Reveal the Impact of Pesticides and Food Additives on Mitochondrial Protein Localization.

Abdulrasheed O Abdulrahman, Mathias Lescuyer, Rami El Zein, Rim Debbiche, Erika Cecon, Julie Dam, Bernard Masri, Ralf Jockers.

  The last decade has witnessed a marked increase in interest in mitochondria, whose dysfunction leads to the development of multiple diseases. Mitochondria are unique as they are highly compartmentalized organelles that are composed of two closely apposed membranes. Here, we developed a series of bioluminescence resonance energy transfer (BRET)-based localization sensors that accurately report the localization and orientation of mitochondrial proteins (TOM20, TOM22, VDAC1, MICU1, ATP5F1C, OTC, and SIRT3) within their respective mitochondrial compartments. These biosensors also dynamically detect stressor-induced translocation of cytosolic proteins, such as Drp1 and BAX, to mitochondria. Screening of a series of endocrine disruptors with our BRET sensors uncovered deleterious effects of paraquat, di-tert-butyl-4-methylphenol, and 4-hydroxynonenal on mitochondrial protein localization. Altogether, the localization sensors provide noninvasive tools to monitor mitochondrial protein localization in a time-resolved manner, with nanometer-scale resolution, in intact cells exposed to diverse cellular stressors.

Keywords:  BAX; BRET; Drp1; VDAC; biosensors; mitochondria

DOI:  https://doi.org/10.1021/acssensors.6c01115
JACS Au. 2026 Sep 28. 6(9): 5243-5253

Lysine-Targeting Covalent Inhibition of Glutaminase Using Cyanopyrimidines.

Xiwen Xiao, Hibiki Okuno, Saki Inoue, Naoki Zenmyo, Yuya Matsumoto, Emi Mishiro-Sato, Keiko Kano, Kazuaki Yoshimune, Shohei Uchinomiya, Akio Ojida.

  Aberrant metabolic activity is a hallmark of cancer and is recognized as a promising target for cancer therapy. However, covalent inhibitors that irreversibly modulate cancer-associated metabolic states remain largely unexplored. Here, we report the development of covalent inhibitors targeting glutaminase 1 (GLS1), a rate-determining enzyme in the glutamine metabolism. To develop covalent inhibitors of GLS1, we systematically evaluated the reactivity of N-heteroaryl nitriles and identified 2-cyanopyrimidine as a lysine-reactive electrophile suitable for selective covalent protein targeting. A covalent inhibitor bearing a 2-cyanopyrimidine irreversibly binds GLS1 in cancer cells with excellent proteome-wide selectivity. This mode of action effectively suppresses glutamine metabolism and induces death of glutamine-dependent cancer cells, highlighting the therapeutic potential of covalent targeting of GLS1.

Keywords:  covalent inhibitor; cyanopyrimidine; glutaminase 1; glutamine metabolism; lysine-reactive warhead

DOI:  https://doi.org/10.1021/jacsau.6c00924
Neurochem Res. 2026 Sep 30. pii: 279. [Epub ahead of print]51(5):

Uptake of L-proline by Cultured Primary Rat Astrocytes.

Paul Spellerberg, Ralf Dringen.

  The proteinogenic amino acid L-proline can be efficiently metabolized by cultured astrocytes as exogenous substrate to fuel mitochondrial ATP regeneration. To investigate the properties of the transport processes involved in astrocytic L-proline uptake, we used primary rat astrocyte cultures as model system. After application of L-proline, cultured astrocytes efficiently accumulated the amino acid in a time- and concentration-dependent saturable manner. Omission of sodium ions drastically lowered cellular L-proline accumulation to low values that increased proportional to the concentration of L-proline applied. The saturable sodium-dependent L-proline accumulation followed apparent Michaelis-Menten kinetics with a calculated KM value of around 1.0 mM and a Vmax value of around 20 nmol/(5 min x mg). In contrast to L-proline, D-proline was hardly taken up by the cells. L-Proline uptake was strongly affected by lowering the incubation temperature, while alterations of the extracellular pH value did not affect the accumulation of L-proline. An excess of the amino acids L-alanine, L-asparagine, L-methionine, L-serine, L-threonine or L-valine severely lowered the uptake of L-proline. Inhibition of uptake was also found in the presence of L-4-hydroxyproline and L-homocysteine as well as in the presence of the ASCT1 inhibitor L-4-chlorophenylgycine, but not after exposure to inhibitors of other potential astrocytic L-proline transporters. These data suggest that L-proline uptake by cultured rat astrocytes is mainly mediated by the sodium-dependent neutral amino acid transporter ASCT1.

Keywords:  ASCT; Active transport; Astrocytes; Proline; Uptake

DOI:  https://doi.org/10.1007/s11064-026-04886-5
Curr Biol. 2026 Oct 02. pii: S0960-9822(26)01198-X. [Epub ahead of print]

Mitochondria-ER-lipid droplet crosstalk regulates metabolic adaptation to shear stress via VMP1.

Maria Laura Rojas, Maribel Lara Corona, Carla Alemany, Juliane Da Graça, Nicolas Goudin, Ivan Nemazanyy, Ida Chiara Guerrera, Aurore Claude-Taupin, Etienne Morel.

  Kidney tubular epithelial cells adapt to physiological urinary flow through rapid metabolic remodeling,1,2 but the mechanisms coordinating this response remain poorly understood. Shear stress promotes lipid catabolism and mitochondrial activity in these cells,3,4 but how changes in mitochondrial dynamics contribute to this metabolic adaptation remains poorly understood.5,6,7,8,9 Here, we show that physiological shear stress rapidly remodels mitochondrial morphology in kidney epithelial cells in vitro and in the zebrafish pronephros, characterized by the emergence of a distinct pool of donut-shaped mitochondria. This remodeling is accompanied by a transient stabilization of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs), occurring independently of any increase in overall ER volume. Using split-TurboID proximity labeling and mass spectrometry, we detected subtle changes in the molecular environment of MERCs during shear stress, including increased proximity of proteins implicated in lipid transfer and membrane contact-site biology. We further show that shear stress promotes the formation of ER-lipid droplet (LD)-mitochondria contact sites and facilitates the local transfer of fatty acids from LDs to mitochondria. This lipid transfer requires vacuolar membrane protein 1 (VMP1), a component of membrane contact sites, whose depletion perturbs LDs and compromises metabolic adaptation to shear stress. Together, our findings identify ER-LD-mitochondria contact sites as dynamic platforms that coordinate lipid transfer and mitochondrial remodeling during the early adaptation of kidney epithelial cells to physiological shear stress, highlighting membrane contact sites as important components of the cellular response to mechanical forces.

Keywords:  contact sites; endoplasmic reticulum; kidney epithelial cells; lipid droplets; metabolic adaptation; mitochondria; shear stress; zebrafish

DOI:  https://doi.org/10.1016/j.cub.2026.09.021
Hum Brain Mapp. 2026 Oct 01. 47(14): e70651

Unveiling Functional-Metabolic Synergy in the Healthy Brain: Multivariate Integration of Dynamic [18F]FDG-PET and Resting-State fMRI.

Claudia Tarricone, Giulia Vallini, Giorgia Baron, Massimiliano Facca, Erica Silvestri, Tommaso Volpi, Andrei G Vlassenko, Manu S Goyal, Alessandra Bertoldo.

  Despite accounting for only 2% of body weight, the human brain requires significant amounts of glucose, even at rest, underscoring the importance of functional-metabolic relationships. Previous studies revealed moderate associations between resting-state fMRI functional connectivity (FC) and local metabolism via [18F]FDG-PET, yet much remains to be understood, particularly regarding their coupling between functional and metabolic networks. To this end, we employed multivariate Partial Least Squares Correlation (PLSC) to investigate the functional-metabolic relationship at both nodal and network levels. From dynamic [18F]FDG-PET data we estimated parameters describing glucose metabolism-delivery rate (K1), phosphorylation rate (k3), and fractional uptake (Ki)-and generated within-individual metabolic connectivity (MC) networks. FC was derived from fMRI data filtered into two frequency bands and summarized as region-wise strength to capture nodal characteristics. Our findings revealed that glucose delivery is linked with FC strength, particularly when fMRI signal frequencies include greater hemodynamic contributions. Even stronger functional-metabolic coupling occurs at the network level in the low-frequency fMRI band, with higher MC between sensory/attention and transmodal networks supporting stronger FC within sensory/attention areas. By leveraging PLSC, this work deepens our understanding of the functional-metabolic synergy in the healthy brain, providing new insights into its organization.

Keywords:  BOLD frequency bands; dynamic [18F]FDG‐PET; functional‐metabolic integration; hemodynamics; partial least squares correlation

DOI:  https://doi.org/10.1002/hbm.70651
bioRxiv. 2026 Sep 23. pii: 2026.09.19.752713. [Epub ahead of print]

Peroxisomal Import Stress Drives Cellular Senescence through SCAF1-dependent Suppression of Mitoribosome Biogenesis.

Jacinta Correia, Jinoh Kim, Pham Thuy Tien Vo, Hua Bai.

Communication between peroxisomes and mitochondria is essential for cellular metabolic homeostasis, yet how peroxisomal import stress impacts mitochondria function during aging and cellular senescence remains poorly defined. Using a genome-wide CRISPR screening in HEK293 cells under peroxisome import stress, we identified SCAF1 (SR-related CTD-associated factor 1) a known canonical nuclear pre-mRNA splicing factor, as an essential regulator of mitochondrial homeostasis. Under peroxisome stress SCAF1 undergoes proteolytic processing and translocates to the mitochondria, where its N-terminal region acts as an autonomous repressor module that blocks mitoribosomal subunit joining. Consequently, SCAF1 depletion accelerates subunit joining and elevates oxidative phosphorylation protein levels, whereas its overexpression in IMR90 fibroblast cells triggers robust cellular senescence characterized by increased senescence associated β gal staining. Together, our findings uncover a stress-responsive peroxisome-to-mitochondria signaling axis mediated by SCAF1 translocation. This pathway directly modulates mitoribosome assembly to maintain translational homeostasis, providing a precise molecular mechanism for how upstream peroxisomal decline drives downstream mitochondrial dysfunction and cellular senescence.

DOI: https://doi.org/10.64898/2026.09.19.752713
Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2606579123

α-aminobutyric acid promotes tumor progression by polarizing macrophages through the ASNS-mTORC2 axis.

Fei Li, Xiaorong Xie, Tongran Xu, Yu Tang, Yuting Xia, Yali Tang, Shijie Yuan, Mengdi Zhu, Xuwei Wu, Lan He, Shu-Hai Lin, Ran He.

  Tumor-associated macrophages (TAMs), the most abundant immune cell subset in the tumor microenvironment (TME), exhibit phenotypic plasticity and exert critical roles in tumor progression and antitumor immunity. Targeting TAM polarization has emerged as a promising strategy for cancer immunotherapy, yet the key regulators governing this process remain incompletely defined. Here, we identified α-aminobutyric acid (AABA) as a pro-tumor metabolite that drives M2-like polarization of TAMs to promote tumor progression. Mechanistically, AABA binds to asparagine synthetase (ASNS), reinforcing the mTORC2-IRF4 signaling axis to reprogram TAMs, switching macrophage metabolism from glycolysis to oxidative phosphorylation, a hallmark of pro-tumor M2-like phenotypes. Moreover, tumor-derived AABA was transported into macrophages by monocarboxylate transporters 1 and compromised the therapeutic efficacy of PD-1 checkpoint inhibition. Collectively, our findings uncover AABA as a previously unrecognized signaling metabolite to control TAM polarization, providing insights into the metabolic crosstalk within the TME and offering a potential therapeutic target to improve cancer immunotherapy outcomes.

Keywords:  asparagine synthetase; mTORC2; macrophage; tumor microenvironment; α-aminobutyric acid

DOI:  https://doi.org/10.1073/pnas.2606579123
bioRxiv. 2026 Sep 22. pii: 2026.09.18.752622. [Epub ahead of print]

Folate deficiency disrupts key metabolic transitions within the developing neural ectoderm.

Nicolas Dias, Daniel P Lewinsohn, William N Colgan, Minming Wang, Yusuke Kijima, JoAnne Villagrana, Tien-Chi Jason Hou, Gokul Gowri, Adelina Chau, Tuğçe Aktaş, Kaelyn Sumigray, Jonathan S Weissman, Luke W Koblan, Allon Wagner, Zachary D Smith.

Despite long-standing epidemiological associations, the mechanism linking folate availability to gestational neural tube defects remains unclear, partly because measuring and interpreting metabolic activity in dynamic biological systems remains challenging. Here, we apply a deep-learning-based graph-guided variational autoencoder (MeRN; Metabolic Representation Network) to infer single-cell metabolic activity and states from scRNA-seq data of mouse embryogenesis. By analyzing folate-deficient embryogenesis from E7.0-E9.0, we identify a transient state within the nascent neural lineage that is acutely sensitive to folate availability, leading to an interconnected disruption between key bioenergetic pathways and de novo purine biosynthesis. Moreover, metabolically induced growth defects lead to permanent morphological disruptions along the dorsal-ventral axis, which we confirm by generating whole-embryo fate maps using a prime-editing-based lineage recorder (PEtracer). Collectively, our results establish a highly scalable framework for interpreting dynamic changes in embryonic metabolism and elucidating the mechanistic bases underlying environmentally linked congenital disorders.
Research highlights: Developing embryos adopt metabolic states that are distinct from cell lineageMetabolic states are organized temporally and spatially along key body axesNeural tube development depends on a rapid transition between metabolic statesActivation of transient neural metabolic states is highly sensitive to disrupted folate absorptionThe floor plate is preferentially resistant to folate deprivation and distorts subsequent neural patterning.

DOI: https://doi.org/10.64898/2026.09.18.752622
bioRxiv. 2026 Sep 24. pii: 2026.09.23.753803. [Epub ahead of print]

Redox activation of ATG5 licenses autophagy upon nutrient restriction.

Sanghee Shin, Ekaterina D Korobkina, Claudia Lennicke, Nils Burger, Bingsen Zhang, Haopeng Xiao, Yaoyu Wang, Jonathan J Petrocelli, Shelley M Wei, David Wood, Yu Lei, Xiaomei Zhang, Maria C Perez-Matos, Muneeb A Sharif, Jiuchun Zhang, Helena M Cochemé, William B Mair, Edward T Chouchani.

Dietary restriction (DR) protects against metabolic disease, extends lifespan, and is associated with remodeling of tissue reactive oxygen species (ROS). ROS control biological adaptation through reversible oxidation of protein cysteines, yet the targets of DR-initiated redox signaling are unknown. Here we generate OxiDR, a tissue-resolved atlas of the cysteine redox proteome that quantifies oxidation state under DR. Rather than oxidizing the proteome broadly, DR selectively targets a high-amplitude set of cysteines in a tissue-specific manner, allowing systematic classification of biological processes subject to DR-mediated redox regulation. Among the cysteines most highly oxidized upon DR is Cys19 of the core autophagy protein ATG5. We show oxidation of Cys19 is required for ATG5-mediated autophagosome formation and for autophagy triggered by nutrient restriction in human cells and mice. Reversible oxidation of this cysteine promotes ATG5 binding to ATG10, thus forming the ATG5-ATG12 conjugate that lipidates LC3B/ATG8 and matures the autophagosome. In mice, loss of this redox switch prevents effective initiation of autophagy upon nutrient restriction, resulting in gross tissue pathology and rapid onset of mortality. The autophagic response to nutrient restriction is thus gated by oxidation of a single cysteine.

DOI: https://doi.org/10.64898/2026.09.23.753803
J Physiol Biochem. 2026 Sep 26. pii: 97. [Epub ahead of print]82(1):

Nucleotide metabolic reprogramming: a "double-edged sword" in obesity-related inflammation-from metabolic adaptation to pathological imbalance.

Zijing Li, Yushang Liu, Xinye Ouyang, Wenjuan Wu, Maoyuan Wang.

  Obesity has become a serious global public health challenge, characterized by chronic, sterile, low-grade inflammation with excessive NLRP3 inflammasome activation; however, the mechanism underlying the reduced activation threshold remains unclear. A recent study by Liu et al. demonstrated that obesity induces the phosphorylation and inactivation of SAMHD1, leading to a massive accumulation of cytosolic dNTPs. This causes excess dNTPs to enter mitochondria via the PNC1/2 transporters, bypassing the classical CMPK2 salvage synthesis pathway and triggering uncontrolled mtDNA synthesis and oxidative damage, ultimately resulting in the excessive activation of NLRP3 and an inflammatory response. Based on this finding, this paper presents a "double-edged sword" model of nucleotide metabolic reprogramming in obesity-related inflammation. Early reversible inactivation of SAMHD1 may represent a metabolic adaptive response that confers functional benefits to macrophages; however, once metabolic stress persists and causes nucleotide metabolic reprogramming to exceed a yet-to-be-defined threshold, an inflammatory positive feedback loop may be established. In terms of clinical translation, targeting PNC1/2 could specifically inhibit NLRP3 activation, which may provide new upstream intervention strategies for various aseptic inflammatory conditions such as gout; however, this approach also carries potential risks of mitochondrial toxicity and impaired anti-infective immunity. Future efforts should focus on macrophage-specific delivery, precision interventions tailored to disease stages, and precise anti-inflammatory strategies based on biomarkers such as circulating dNTPs, p-SAMHD1, and ox-mtDNA, thereby advancing the clinical translation of metabolism-related inflammation within safe parameters.

Keywords:  Metabolic inflammation; NLRP3 inflammasome; Nucleotide metabolic reprogramming; Obesity; SAMHD1; mtDNA

DOI:  https://doi.org/10.1007/s13105-026-01238-3
bioRxiv. 2026 Sep 07. pii: 2026.09.03.748963. [Epub ahead of print]

Mitochondrial rewiring supports survival of triple negative breast cancer cells after ionizing radiation.

Steven W Wall, Karen Wang, Allison Greer, Mokryun L Baek, Audra Lane, Mariah J Berner, Jonathan T Lei, Ángel A Garcés, Sofia Khoury, Emily G Caggiano, Matthew D Meyer, Sarah Latka, Hugo Villanueva, Emil Schüler, Cullen M Taniguchi, Rutulkumar Patel, Gloria V Echeverria.

Triple negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Conventional treatments include neoadjuvant chemo-immunotherapy followed by surgical resection and may include further adjuvant immunotherapy and/or radiotherapy of the tumor bed and lymph nodes. Nonetheless, TNBC patients with residual disease have rapid metastatic recurrence. While the roles of metabolic and mitochondrial adaptations in chemotherapeutic resistance have been the subject of many studies, their importance in the context of ionizing radiation (IR) therapy remains poorly understood. We established longitudinal in vitro models of post-IR human TNBC, characterized by cellular regression to a residual phenotypic state, then eventual cell repopulation. This was accompanied by plastic adoption of unique metabolic, proteomic, and morphologic features that largely reverted when cells regrew. Following IR, residual cells exhibited extensive mitochondrial rewiring, including elevated mitochondrial content, oxidative phosphorylation (oxphos) rates, cristae structures, and metabolite levels. Concomitantly, levels of the short protein isoform of the mitochondrial inner membrane protein optic atrophy 1 (OPA1) were significantly elevated in residual cells, and OPA1 knockout ablated mitochondrial adaptations induced by IR. OPA1 genetic or pharmacologic perturbations led to improved cellular responses to IR. Metabolomic and proteomic analyses of radio-residual cells uncovered a coordinated program of antioxidant and redox capacity elevation with mitochondrial metabolism, which was corroborated by analyses of external datasets. Together, these findings provide evidence that TNBC cells surviving radiotherapy adopt an OPA1-dependent program of mitochondrial reorganization that supports their survival and regrowth, thereby positioning OPA1 as a therapeutic dependency that could improve radiotherapy efficacy in TNBC.

DOI: https://doi.org/10.64898/2026.09.03.748963
EMBO Rep. 2026 Sep 28.

PTEN-L inhibits mitophagy and GSDME-dependent pyroptosis via Parkin dephosphorylation.

Chenghao Yan, Cainian Huang, Xu Liu, Yifan Liu, Yancheng Tang, Zhixuan Zhu, Jiaqi Qi, Hao Guo, Ying Li, Yuyuan Zhu, Lijie Wang, Yufei Luo, Linlin Xing, Haiji Wang, Faxiang Li, Bo Sun, Sulai Liu, Guang Lu, Haodong Xu, Bo Zhou, Han-Ming Shen, Liming Wang.

Mitochondrial dysfunction is a potent trigger of inflammatory cell death; however, the precise signaling pathways linking mitochondrial damage to pyroptosis remain incompletely understood. Here, we identify a previously unrecognized pathway in which mitochondrial depolarization activates the PINK1-Parkin axis to drive GSDME-mediated pyroptosis, a process negatively regulated by the phosphatase PTEN-L. Upon activation, Parkin promotes the ubiquitination and proteasomal degradation of MCL-1, facilitating mitochondrial translocation and activation of BAX. This triggers cytochrome c release, caspase-3 activation, and subsequent cleavage and plasma membrane targeting of GSDME, ultimately leading to pyroptotic cell death. Conversely, PTEN-L functions as a master negative regulator that counteracts Parkin through dephosphorylation and inactivation of Parkin. This action not only suppresses mitophagy but also stabilizes MCL-1, thereby inhibiting the downstream BAX/BAK-caspase-3-GSDME cascade and subsequent pyroptosis. Thus, our findings reveal a phosphorylation-dependent regulatory switch centered on Parkin that functionally couples mitophagy regulation to GSDME-dependent pyroptosis, delineating a novel mitochondrial signaling pathway that integrates organelle quality control with cellular fate decisions under stress conditions.

DOI: https://doi.org/10.1038/s44319-026-00957-4
Chemistry. 2026 Sep 29. e71735

A Cationic 3-hydroxyflavone-Based Fluorescent Probe for Wide Range of pH and Adenosine Triphosphate Determination.

Vladyslav Kozenko, Vasyl Pivovarenko, Oksana Tananaiko, Rostyslav Linnik.

  Cellular ATP concentration is a key marker of viability and metabolic activity, as well as pathological conditions such as cancer, hypoxia, and neurodegenerative diseases. Therefore, its determination is of great importance. Fluorescent probes used for this purpose often lack sufficient selectivity over other nucleotides. In this work, the ATP-sensing properties of the synthetic wide-range pH indicator FAM345 (bis-(dimethylaminomethyl)flavone) were investigated. At physiological pH, FAM345 exists in a protonated form, and its association with ATP yields a fourfold fluorescence enhancement and a 35 nm redshift in the excitation spectrum. Maximum fluorescence is achieved at pH 6.7-7.2, where the FAM345+ and ATP4- species dominate. The formation of a 1:1 associate with an apparent association constant of 5.8×103 M-1 has been confirmed. The limit of quantification is 5.87 µM within a linear range of 1.76-50 µM. ADP, AMP, GTP, CTP, UTP, and NAD+ exhibit negligible interference, with spectral responses 2- to 5-fold lower than that of ATP. FAM345 was successfully applied for precise and accurate ATP determination in the pharmaceutical formulation "Cocarnit," demonstrating its suitability for analyzing sample with complex matrices. Thus, we have developed a highly selective ATP probe capable of simultaneously monitoring the pH of the medium.

Keywords:  3‐hydroxyflavone derivative; ATP; fluorescence spectroscopy; fluorescent probes; pharmaceutical preparation

DOI:  https://doi.org/10.1002/chem.71735
bioRxiv. 2026 Sep 28. pii: 2026.08.23.746574. [Epub ahead of print]

Mechanosignaling Promotes Macrophage Apoptosis Resistance in Pulmonary Fibrosis via Metabolic Reprogramming.

Chao He, Cristian Coarfa, Neftali Garcia, Cynthia O Lebimoyo, Haiwei Gu, Elisa Ruiz-Echartea, Xiaoli Ji, Alan W Cohen, Juan A Zuluaga, Lindsay J Celada, Scott A Ochsner, Neil J McKenna, Jennifer L Larson-Casey, Sandeep K Agarwal, Farrah Kheradmand, Yong Zhou, A Brent Carter, Ivan Rosas.

The mechanisms underlying the progression of pulmonary fibrosis in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases remain unclear. Increased extracellular matrix stiffness is a hallmark of fibrotic lung diseases. Monocyte-derived macrophages can promote fibrosis progression. However, there is limited understanding of how the mechanical properties of the fibrotic microenvironment influence macrophage phenotypes. Profibrotic macrophages are apoptosis-resistant, and this phenotype is modulated by enhanced mitochondrial bioenergetics. The objective of the study was to determine how lung tissue stiffness impacts macrophage phenotypes and fibrotic progression. We demonstrate that mechanoactivated macrophages exhibit apoptosis-resistance, increased expression of the antiapoptotic protein Bcl-xL and increased mitochondrial oxidative phosphorylation. Critically, the metabolic reprogramming observed in mechanoactivated macrophages is dependent on increased glutaminolysis. Inhibition of glutaminolysis attenuated apoptosis resistance in mechanoactivated macrophages. Moreover, inhibition of Bcl-xL in vivo protected mice against experimental pulmonary fibrosis. Lastly, mechanoactivated primary IPF macrophages produce more profibrotic cytokines and promote extracellular matrix production in precision-cut lung slices. We describe a mechanism for acquired macrophage apoptosis resistance dependent on metabolic reprogramming regulated by extracellular matrix stiffness. Our results identify mechanoactivated apoptosis-resistant macrophages as pro-fibrotic mediators, suggesting a novel therapeutic target in IPF and related fibrotic disorders.

DOI: https://doi.org/10.64898/2026.08.23.746574
bioRxiv. 2026 Sep 24. pii: 2026.09.23.752387. [Epub ahead of print]

Metabolic-epigenetic coupling between leucine catabolism and glycolysis drives CDK4/6 inhibitor resistance.

Michael Uj Oliphant, Klarisa Norton, Kiran Kurmi, Howard Yang, Shakchhi Joshi, Jonah Lee, Nina Kozlova, Taru Muranen, John G Clohessy, Marcia Haigis, Senthil K Muthuswamy.

Resistance to CDK4/6 inhibitors limits the durability of therapy for ER+ breast cancer. Despite the identification of mechanisms that regulate resistance, the metabolic adaptations that enable therapeutic escape remain poorly understood. Here, we identify a metabolic-epigenetic circuit that drives resistance by coordinately rewiring amino acid and glucose metabolism. CDK4/6 inhibitor-resistant ER+ tumor cells upregulate the leucine transporter SLC7A5, enhancing leucine uptake. SLC7A5 overexpression is sufficient to confer palbociclib resistance across ER+ cell lines, patient-derived organoids and xenografts. Stable isotope tracing in cell lines and in xenograft tumors revealed that leucine is catabolized through BCAT2 and HMGCL to increase acetyl-CoA levels, and elevated acetyl-CoA promotes H3K27 acetylation at the GLUT1 promoter, upregulating GLUT1 expression and glycolytic activity. Disrupting leucine transport, catabolism, or availability suppresses GLUT1 expression and restores therapeutic sensitivity in resistant models. In patients receiving palbociclib-based therapy, high SLC7A5 expression and coordinated SLC7A5-GLUT1 co-expression are associated with shorter progression-free survival. Together, these findings define a metabolic- epigenetic mechanism linking branched-chain amino acid catabolism to glycolysis and identify a biomarker-associated metabolic vulnerability in advanced ER+ breast cancer.
Statement of Significance: Resistance to CDK4/6 inhibitors is nearly universal in ER+ breast cancer. We identify a metabolic- epigenetic circuit in which acetyl-coA derived from leucine catabolism promotes epigenetic changes at the GLUT1 promoter, thereby increasing glucose uptake and driving glycolysis. Disrupting leucine transport, catabolism, or availability suppresses this program and restores drug sensitivity, identifying crosstalk between amino acid metabolism and glycolysis in regulating drug resistance. High expression of the leucine transporter, SLC7A5, is associated with shorter progression-free survival, revealing a biomarker-associated metabolic vulnerability.

DOI: https://doi.org/10.64898/2026.09.23.752387
J Mol Biol. 2026 Sep 26. pii: S0022-2836(26)00414-6. [Epub ahead of print] 170041

Auto-S-fatty acylation of PKM2 regulates its tetramerization and glycolytic metabolism in cancer cells.

Chen Miao, Zhen Wang, Kelin Li, Jian Lin, Xiaoyan Wu, Ziye Zhu, Xuanpu Zhang, Xinmei Zhou, Jie Zou, Yibing Zhu, Fei Ye, Baoen Chen.

  Cancer cells rely on aerobic glycolysis to fuel proliferation, yet how lipid metabolism dynamically regulates glycolysis remains incompletely understood. Here, we identify pyruvate kinase M2 (PKM2) is regulated by auto-S-fatty acylation. Using bioorthogonal chemical reporters, we demonstrate that PKM2 is S-fatty acylated at a conserved cysteine residue (Cys474), preferentially incorporating C18 stearate and C16 palmitate. This modification destabilizes PKM2's active tetramer, thereby suppressing pyruvate kinase activity and altering the abundance of glycolytic intermediates. Genetic ablation of PKM2 S-fatty acylation (C474S mutant) enhances mitochondrial respiration, alters glycolytic metabolite abundance, and impairs lung cancer cell growth in vitro and in vivo. Our findings establish PKM2 auto-S‑fatty acylation as a mechanism that links fatty acid availability to glycolysis and tumor cell growth, highlighting a potential vulnerability in cancers dependent on aerobic glycolysis.

Keywords:  PKM2; S-fatty acylation; auto-acylation; cancer metabolism; glycolysis

DOI:  https://doi.org/10.1016/j.jmb.2026.170041
Sci Adv. 2026 Oct 02. 12(40): eaeh3416

Deep learning-enhanced single-shot triorganelle STED-FLIM imaging of lipid dynamics in living cells.

Lu Gao, Beibei Gao, Wei Ge, Tianze Sun, Wenshuang Liang, Li Jiang, Linyong Zhu, Fu Wang.

Lipid homeostasis is orchestrated by rapid exchange and remodeling across the endoplasmic reticulum (ER), lipid droplets (LDs), and mitochondria. However, live-cell visualization of this triorganelle network remains limited by subdiffraction structures, multiplexed labeling burden, and the ambiguity of intensity-only readouts. Here, we introduce a single-shot stimulated emission depletion-fluorescence lifetime imaging (STED-FLIM) workflow that combines Nile Red analogs with deep learning-based demultiplexing to generate compartment-resolved maps of lipid-organelle organization and dynamics. By combining the STED-resolved nanoscale ultrastructure with lifetime-encoded microenvironmental contrast, our approach separates ER, LDs, and mitochondria from a single acquisition and enables automated tricompartment quantification using a lightweight VGG16-UNet segmentation model. This platform captures coordinated remodeling across the ER-LD-mitochondria axis during lipid stress, including ferroptosis- and apoptosis-associated transitions, while simultaneously reporting nanoscale organization and microenvironmental shifts. Together, this strategy provides a practical route to high-spatiotemporal-resolution, lifetime-encoded multiorganelle lipid imaging in living cells.

DOI: https://doi.org/10.1126/sciadv.aeh3416
J Vis Exp. 2026 Oct 01.

Metabolic Regulation of Angiogenesis in Pancreatic Ductal Adenocarcinoma.

Xin Ye, Zihan Wang, Ping Wang.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, with a 5‑year survival of only 13%. Its aggressive biology and late diagnosis often lead to metastatic spread at presentations. This review examines how metabolic reprogramming regulates angiogenesis in PDAC and explores the therapeutic implications of this coupling. We systematically analyzed published studies on glucose, amino acid, and lipid metabolic alterations and their interconnection with neovascularization through hypoxia-inducible factor-1α (HIF-1α), oncogenic signaling, and metabolite-mediated pathways. Based on a synthesis of the current literature, metabolic-angiogenic coupling appears to operate through at least three interconnected mechanisms: the HIF‑1α/pyruvate kinase M2 (PKM2)-driven glycolytic-vascular endothelial growth factor (VEGF) axis; lactate acting as a signaling molecule that promotes M2‑polarized tumor‑associated macrophages and stabilizes HIF‑1α; and lipid metabolites--including eicosanoids and fatty acid‑binding protein 4 (FABP4)-that modulate endothelial function and survival. In addition, glutamine-derived intermediates support endothelial sprouting and extracellular matrix remodeling, while tryptophan and serine pathways influence the immune-angiogenic balance. Importantly, compensatory pathways (e.g., HIF-1α-independent angiogenesis via glycogen accumulation and protease-activated receptor‑2 activation) limit the efficacy of single‑agent interventions, highlighting the need for combination strategies. Understanding these metabolic-angiogenic networks provides a rationale for biomarker‑guided therapies that simultaneously target tumor metabolism and vascularization. Integrating metabolic and angiogenic biomarkers (e.g., VEGF, lactate dehydrogenase A) with imaging-based metabolic profiling may improve patient stratification and treatment monitoring in PDAC.

DOI: https://doi.org/10.3791/71765
Front Immunol. 2026 ;17 1935435

Metabolic licensing and restriction of innate immunity in the tumor microenvironment.

Ji Min Shin, Hye Yeon Choi, Jihyoun Kim, Seon Ah Lim.

  Tumor progression is driven by metabolic remodeling that generates a microenvironment characterized by nutrient deprivation, hypoxia, lactate accumulation, lipid dysregulation, and oxidative stress. These conditions affect innate immune populations, including natural killer (NK) cells, dendritic cells (DCs), macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs), shaping their activation, persistence, and functional states. Although many studies have defined metabolic pathways that regulate innate immune function in cancer, these findings are often discussed at the level of individual pathways or individual cell types, obscuring shared principles by which the tumor microenvironment controls innate immunity. Here, we use the concepts of metabolic licensing and metabolic restriction to describe how metabolic capacity and environmental constraints interact to shape innate immune function. Metabolic licensing refers to context-dependent metabolic states that provide sufficient bioenergetic and biosynthetic capacity to support sustained antitumor effector function, whereas metabolic restriction describes conditions in which nutrient limitation, mitochondrial dysfunction, redox imbalance, or suppressive metabolites constrain or progressively erode these functions. Rather than representing fixed binary states, licensing and restriction can occur along a continuum shaped by cell identity, signal duration, and local tumor conditions. We discuss how metabolic licensing and restriction shape antitumor and immunosuppressive innate immune populations, examine the stress-sensing pathways that connect environmental cues to innate immune fate, and summarize therapeutic strategies aimed at restoring metabolic fitness or alleviating metabolic restriction. Considering innate immune responses in terms of metabolic licensing and restriction helps explain how shared metabolic pressures within tumors can impair effector cells while supporting suppressive innate populations and may inform the development of immunometabolic approaches to cancer therapy.

Keywords:  immunometabolism; innate immunity; metabolic licensing; metabolic restriction; metabolic stress; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1935435
Geroscience. 2026 Sep 28.

Therapeutic potential of MitoQ, a mitochondria-targeted antioxidant, in age-related physiological dysfunction.

Siyun Kim, Sung Gi Noh, Minje Ji, Kai Chen, George A Kuchel, Iman M Al-Naggar, Oh Sung Kwon.

  Aging is an inevitable and progressive physiological process marked by a decline in cellular function, accumulation of somatic mutations, decreased ability to maintain homeostasis, and increased tissue and organ dysfunction. These changes contribute to the onset and progression of various age-related diseases. Accumulation of reactive oxygen species (ROS) has been identified as a key mediator of the aging process. Mitochondria, the primary producers of ROS, accumulate defects with aging, leading to increased mitochondrial oxidative stress. These defective mitochondria are both a source and a target of oxidative stress, creating a vicious cycle that accelerates aging and the progression of age-related diseases. Consequently, targeting mitochondria represents a promising therapeutic approach to prevent aging-related physiological dysfunction. MitoQ, a mitochondria-targeted antioxidant, has been extensively studied due to its ability to effectively scavenge mitochondria-derived ROS, owing to its lipophilic cation properties. This review explores the effects of MitoQ on aging-associated physiological dysfunction, specifically exploring its impact on cardiovascular, neuronal, and skeletal muscle functions. By addressing the central role of mitochondrial oxidative stress, we propose that MitoQ represents a promising strategy to counteract aging-associated physiological dysfunction.

Keywords:  Age-related disease; Aging; MitoQ; Mitochondria-derived ROS; Mitochondria-targeted antioxidants; Oxidative stress

DOI:  https://doi.org/10.1007/s11357-026-02515-1
FEBS J. 2026 Sep 29.

Energetic dysregulations in psychotic disorders: Targets for new therapeutics.

Jacey Anderson, Kai-Christian Sonntag, Thao Do Vy Le, Kaitlin Shannon, Chao Wang, Fei Du, Xi Chen, Donna McPhie, Dost Ongur, Bruce Cohen, Virginie-Anne Chouinard.

  Converging findings point to brain- and body-wide energetic dysregulation in psychotic disorders, implicating metabolic abnormalities across different levels of investigation, including genetic, cellular, postmortem, and in vivo neuroimaging studies. The present review synthesizes this literature documenting aberrant energy production and use, specifically related to mitochondrial and redox dysregulation, in psychotic disorders. Mitochondrial DNA, copy number variants, polygenic risk, and candidate genes involved in metabolic pathways converge on glycolytic, mitochondrial, redox, and oxidative stress mechanisms. Consistent with these findings, cell studies, primarily from ex vivo brain tissue samples and induced pluripotent stem cells (iPSC), show misdistribution and structural fragmentation of mitochondrial networks and dysregulation in the expression of proteins involved in several metabolic processes. Inherent dysregulations, at the genetic and cellular level, may affect both neuronal and glial health, as observed at the tissue level. Neuroimaging studies demonstrate metabolic dysregulations in vivo, including central insulin resistance and redox and bioenergetic aberrations that are associated with cognitive impairment and altered brain networks. We also consider the effects of antipsychotic medications on energy metabolism. Finally, we propose a framework for future work and treatment approaches to target energetic dysregulations, including existing metabolic treatments. The metabolic mechanisms that interact to produce and perpetuate aberrant neuronal health and functioning in psychotic disorders are complex. Nevertheless, the findings highlight pathways that might be targeted for the development of novel treatments, providing an opportunity to develop more efficacious and better-tolerated interventions.

Keywords:  bipolar disorder; energy metabolism; induced pleuripotent stem cells; magnetic resonance spectroscopy; mitochondrial DNA; mitochondrial function; proteomics; psychosis; redox; schizophrenia

DOI:  https://doi.org/10.1111/febs.70719
bioRxiv. 2026 Sep 24. pii: 2026.09.23.753858. [Epub ahead of print]

Structural insights into DHODH-mediated catalysis and drug resistance.

Ruchika Pokhriyal, Hyuk-Soo Seo, Mio Murakoso, Sonia E Trojan, Laura Evans, Jillian K O'Neil, Komal Chauhan, Shakchhi Joshi, Hanna Meyer, Anders Friberg, Judith Günther, Sven Giese, Sven Christian, Xiaoping Yang, Robert E Lintner, David E Root, Marcia C Haigis, Matthew Vander Heiden, Marco Mravic, Sirano Dhe-Paganon, Julie-Aurore Losman.

Dihydroorotate dehydrogenase (DHODH), which catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, is a validated therapeutic target in cancer, autoimmune disorders and infectious diseases. DHODH is hypothesized to utilize a 'ping-pong' catalytic mechanism. However, available crystal structures of DHODH in complex with small molecule inhibitors are irreconcilable with this model, showing simultaneous occupancy of both substrate binding sites. To elucidate the structural basis for DHODH-mediated catalysis, we resolved the structures of two DHODH holoenzymes. These structures capture novel conformational states that show mutually exclusive substrate binding. The holoenzyme structures also suggest that conformational changes in the catalytic loop of DHODH play a critical role in regulating enzyme activity. To map the functional landscape underlying DHODH inhibitor resistance, we performed deep mutational scanning drug-resistance screens with two clinically-relevant structurally distinct DHODH inhibitors, BAY2402234 and brequinar. Resistance variants cluster in the inhibitor binding site and at a previously unappreciated surface pocket on DHODH that allosterically regulates ubiquinone binding. Together, our findings provide structural evidence for the 'ping pong' model of catalysis, define the mutational landscape governing inhibitor resistance, and reveal novel structural vulnerabilities in DHODH that can be utilized for future drug development.

DOI: https://doi.org/10.64898/2026.09.23.753858