bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–10–11
thirty-one papers selected by
Brett Chrest, Wake Forest University
  1. Integrated assessment of fatty acid metabolism and cellular energy status using HILIC-MS/MS.
  2. Rod photoreceptors have a dual dependency on both aerobic glycolysis and OXPHOS and diverge metabolically from other retinal neurons.
  3. Ketogenic diet attenuates cardiac aging through inhibiting CD36/MAPK-mediated lipid accumulation: Comparable effects in aged male and female mice.
  4. Reactive oxygen species define leukemia stem cell identity in pediatric acute myeloid leukemia.
  5. Myeloid differentiation-associated autophagy drives venetoclax resistance in AML.
  6. 2-Hydroxyglutarate Redirects Fatty Acid Partitioning to Mitigate Lipotoxic Stress and Preserve Metabolic Fuel.
  7. Respiration-Deficient Cells Require Pyruvate Carboxylase to Suppress Asparagine Auxotrophy.
  8. DHODH is the key target of the KDM4 inhibitor QC6352 in glioblastoma stem cells.
  9. Hepatocyte Serine Palmitoyltransferase 3 is essential for mitochondrial ceramide homeostasis and electron transport chain function.
  10. Glutamine from plasma-like medium fuels nitrogen metabolism and influences proliferation in Leptospira interrogans.
  11. Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer.
  12. Mitochondrial pyruvate carrier inhibition restrains germinal center T follicular helper cells attenuating chronic graft-versus-host disease.
  13. Metabolic Structure: A Paradigm Revisited in Light of the Fundamental Parameters of Living Systems.
  14. A guanosine metabolism-bioenergetics intersection drives Parkinson's disease.
  15. Metabolic advantages of a high-protein, low-carbohydrate diet in in patients with metabolically unhealthy obesity.
  16. Electron competition in yeast mitochondria is governed by dehydrogenases catalytic efficiencies.
  17. Magnitude of serum β-hydroxybutyrate elevations and myocardial glucose suppression in fluorine-18 fluorodeoxyglucose positron emission tomography for cardiac sarcoidosis.
  18. ATP and α-ketoglutarate link nitrogen availability to TORC1-Npr1 signaling in yeast.
  19. Continuous Imaging of the Cardiac Cycle Metabolism With Hyperpolarized [1-13C]Pyruvate.
  20. A membrane-disruptive action of VBIT-4 challenges its role as a widely used VDAC1 oligomerization inhibitor.
  21. Suppressing glutamate dehydrogenase guides hematopoietic stem cell divisions into self-renewal.
  22. Potential for pathogenic protein acylation in succinate dehydrogenase-deficient pheochromocytoma and paraganglioma.
  23. Adaptive rewiring of NADPH electron flow reveals escape routes from redox-balance-based growth coupling in Escherichia coli.
  24. Inhibiting fructose metabolism to treat fatty liver.
  25. The Gibbs free energy landscape based on liver metabolome revealed thermodynamic robustness against fasting and obesity.
  26. Histone acetylation finds its link to transcription.
  27. A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models.
  28. H+ exchange and pH profiling of select non-glycolytic cytosolic phosphate transfer and oxidation-reduction reactions.
  29. Genetically Encoded Glucosensor for Multiplexed 129Xe NMR.
  30. Dihydropyrimidine Dehydrogenase Genotype-Phenotype Correlations in Plasma and Peripheral Blood Mononuclear Cells.
  31. Tafazzin catalyzes transacylation and hydrolysis with inverse acyl specificities.
  1. bioRxiv. 2026 Aug 13. pii: 2026.08.12.744242. [Epub ahead of print]
    Integrated assessment of fatty acid metabolism and cellular energy status using HILIC-MS/MS.
    Mariana Lopes, Kyle D Roberts, Alexis E Heath, Peder J Lund.
      Acetyl-CoA and other acyl-CoA thioesters are critical intermediates in the metabolic reactions that cells rely on to produce energy and carry out biosynthesis. Therefore, the analysis of acyl-CoA provides valuable information about the metabolic activity of cells, especially when combined with stable isotope tracing. Acyl-CoA species are routinely monitored by reversed-phase liquid chromatography coupled to tandem mass spectrometry (RPLC-MS/MS). However, drastic differences in the hydrophobicity of short-chain versus long-chain acyl-CoA species have been challenging to accommodate with a single set of RPLC conditions. Here, we describe a convenient method based on hydrophilic interaction liquid chromatography (HILIC-MS/MS) for the concurrent detection of both short-chain and long-chain acyl-CoA and their corresponding acyl-carnitine species. Using this strategy, we tracked the metabolism of isotope-labeled fatty acids in multiple cell lines, which revealed differences in their propensities for fatty acid oxidation and the extent to which isotope incorporation into acyl-CoA mirrored that of acyl-carnitine. We also applied the HILIC-MS/MS workflow to the analysis of NADH and ATP, making it a useful technique for gauging cellular bioenergetics as reflected by the acetyl-CoA/CoA, NADH/NAD + , and ATP/ADP ratios. Altogether, this HILIC-MS/MS platform enables a streamlined analysis of acyl-CoA species and other key intermediates in cell metabolism.
    DOI:  https://doi.org/10.64898/2026.08.12.744242
  2. Sci Adv. 2026 Oct 09. 12(41): eaeg8687
    Rod photoreceptors have a dual dependency on both aerobic glycolysis and OXPHOS and diverge metabolically from other retinal neurons.
    Gabriele M Wögenstein, Luca Ravotto, Vyara Todorova, Rachel M Meister, Marijana Samardzija, L Felipe Barros, Bruno Weber, Christian Grimm.
      The retina metabolizes glucose into lactate, a hallmark of aerobic glycolysis known as the Warburg effect. Although evidence points to rod photoreceptors as the primary source of aerobic glycolysis, a comparison of the energy metabolism in different retinal neurons has yet to be performed. We combined two-photon fluorescence lifetime imaging of biosensors with pharmacological protocols to analyze metabolic dynamics in healthy and diseased rod photoreceptors and RBPMS-positive ganglion and calretinin-positive amacrine cells. Our data reveal distinct metabolic profiles among retinal neurons, identify rods as the drivers of aerobic glycolysis, demonstrate that inner retinal neurons rely on oxidative phosphorylation, show that rods need both glycolysis and oxidative phosphorylation to maintain ATP levels, and suggest that rods can metabolize lactate. A mutation causing retinitis pigmentosa increases lactate production in rods but changes the energy metabolism only subtly otherwise. Our results improve the understanding of retinal physiology and are relevant for pathologies involving imbalanced energy metabolism.
    DOI:  https://doi.org/10.1126/sciadv.aeg8687
  3. Exp Gerontol. 2026 Oct 07. pii: S0531-5565(26)00328-1. [Epub ahead of print] 113349
    Ketogenic diet attenuates cardiac aging through inhibiting CD36/MAPK-mediated lipid accumulation: Comparable effects in aged male and female mice.
    Chi Sensen, Pengcheng Hu, Gang Xu, Guanglei Chang, Linqiang Zhang, Shujin Wang, Xi Li, Dazhi Ke, Changlong He.
      Aging is accompanied by a decline in circulating ketone bodies and progressive cardiac dysfunction, yet whether dietary ketone repletion counteracts cardiac aging in a sex-specific manner remains unclear. Here, we first investigated the associations between plasma ketone bodies and cardiac function in a human cohort, comprising 120 adults (44.78 ± 10.97 years; 66 male/54 female) and 121 aged individuals (69.59 ± 6.88 years; 75 male/46 female). And, we then evaluated the therapeutic potential of an 8-week ketogenic diet (KD) in physiologically aged mice (22 months, both sexes), which were daily supplemented with either chow diet (3.79 kcal/g, Aged group) or KD (7.24 kcal/g, Aged+KD group). In humans, circulating β-hydroxybutyrate (β-HB) levels were significantly lower in aged human individuals and positively correlated with key parameters of cardiac function, including ejection fraction (EF), fractional shortening (FS) and the ratio of early to late diastolic filling velocity (E/A ratio). In aged mice, 8-week KD supplementation elevated cardiac β-HB concentrations and attenuated cardiac remodeling in both sexes. Notably, KD improved systolic/diastolic function (e.g., EF, FS and E/A ratio), preserved mitochondrial function, reduced myocardial lipid accumulation, and ameliorated systemic dyslipidemia equivalently in both sexes. Mechanistically, KD suppressed CD36 membrane translocation and MAPK activation, whereas CD36 upregulation abolished these protective effects, establishing a causal role of the CD36/MAPK pathway in KD-mediated cardioprotection. Altogether, these findings identify β-HB as a biomarker of cardiac aging and show that KD rescues age-related cardiomyopathies through CD36-MAPK-mediated lipid metabolic regulation, with equivalent benefits in both sexes.
    Keywords:  Cardiac aging; Ketogenic diet; Lipid metabolism; Sexes; β-Hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.exger.2026.113349
  4. Cancer Lett. 2026 Oct 04. pii: S0304-3835(26)00630-0. [Epub ahead of print] 218866
    Reactive oxygen species define leukemia stem cell identity in pediatric acute myeloid leukemia.
    Maddalena Benetton, Ambra Da Ros, Alberto Peloso, Giorgia Longo, Sara Perpinello, Chiara Frasson, Tiago Branco Fonseca, Elena Varotto, Silvia Bresolin, Claudia Tregnago, Luca Scorrano, Benjamin J Huang, Soheil Meshinchi, Franco Locatelli, Martina Pigazzi.
      Standard chemotherapy effectively induces complete remission in most children with acute myeloid leukemia (AML), however relapse remains the main cause of treatment failure. Leukemia stem cells (LSCs) are proposed to constitute a therapy-resistant reservoir driving disease recurrence, but their reliable identification remains unresolved. We explored intracellular reactive oxygen species (ROS) levels in pediatric AML at diagnosis and sorted ROS-low (RL) and ROS-high (RH) cell fractions. We found that RL cells exhibited increased quiescence, sustained serial colony-forming capacity and engraftment in mice when compared to the RH fraction. Moreover, in a 3D niche model, RL cells preferentially localized to hypoxic regions and were resistant to cytarabine, altogether indicating enrichment for functional LSCs. Transcriptomic analyses revealed enrichment of stemness, adhesion and niche-interaction programs in RL cells, alongside downregulation of mitochondrial and oxidative phosphorylation pathways. Consistently, RL cells displayed reduced oxygen consumption and ATP production, together with remodeled cristae structure despite preserved mitochondrial mass. Paradoxically, complex I inhibition selectively impaired RL cell viability, indicating a dependency on oxidative phosphorylation. Using RL transcriptome, we derived a gene signature that, when applied to single-cell RNA-sequencing data of pediatric AML cases, identified LSCs within the bulk regardless of differentiation status, and showed significant prognostic value. Finally, transcriptional program trajectory indicated that RL fraction contributed to generate the whole AML bulk, whereas gene mutations were maintained in RL and RH cells. Overall, this ROS-based strategy represents a new tool to isolate stem cells transcending traditional markers, and identifies novel clinically relevant vulnerabilities to target LSCs.
    Keywords:  cell adhesion; gene signatures; leukemia stem cells; mitochondria; pediatric acute myeloid leukemia; reactive oxygen species; transcriptomics
    DOI:  https://doi.org/10.1016/j.canlet.2026.218866
  5. Res Sq. 2026 Aug 10. pii: rs.3.rs-10617934. [Epub ahead of print]
    Myeloid differentiation-associated autophagy drives venetoclax resistance in AML.
    James DeGregori, Johannes Menzel, Mark Gregory, Daniela Ortiz Chavez, Jacqueline Thorburn, Marco De Dominici, Daniel Pollyea, Craig Jordan, Andrew Thorburn.
      Acute myeloid leukemia (AML) is a complex disease that often displays phenotypic and genotypic heterogeneity, where subclones are either refractory or frequently become resistant to treatment. Several studies have shown that the developmental stage of leukemia correlates with the response to therapies combining the BCL2 inhibitor venetoclax (Ven) with hypomethylating agents, such as azacitidine (Aza), where phenotypically primitive AML cells are sensitive and monocytic cells are more resistant. Here we show that resistant monocytic subclones have higher autophagic flux compared to sensitive primitive subclones in AMLs of mixed phenotype. Induction of AML myeloid differentiation with inecalcitol, a potent vitamin D3 analogue and vitamin D receptor (VDR) agonist, increases autophagic flux and Ven/Aza resistance. Pharmacological inhibition or genetic perturbation of autophagy negates differentiation-induced Ven/Aza resistance. We show that this myeloid differentiation-associated autophagy increases mitochondrial reserve capacity and metabolic flexibility. This work shows that autophagy-dependent metabolic rewiring during AML differentiation contributes to Ven/Aza therapy resistance.
    DOI:  https://doi.org/10.21203/rs.3.rs-10617934/v1
  6. bioRxiv. 2026 Aug 13. pii: 2026.08.12.744465. [Epub ahead of print]
    2-Hydroxyglutarate Redirects Fatty Acid Partitioning to Mitigate Lipotoxic Stress and Preserve Metabolic Fuel.
    Niv Vigder, Amit Chandra, Nishith Shrimali, Sergey Tumanov, Vlad Elgart, Huamei He, Ryan Mulhern, Ram P Chakrabarty, Navdeep S Chandel, Stuart Cordwell, Steven P Gygi, João A Paulo, Joseph Loscalzo.
      The role of 2-hydroxyglutarate in lipid metabolism is currently unknown. Here we show that 2HG redistributes the partitioning of fatty acids into triglyceride storage and away from membrane phospholipid synthesis, mitochondrial oxidation, and lipotoxic intermediates. In primary human cardiac and vascular cells, both enantiomers, D2HG and L2HG, expanded triglyceride stores and lipid droplets while selectively depleting phosphatidylethanolamine, with L2HG acting more potently than D2HG despite lower intracellular accumulation. Mechanistically, L2HG increases DGAT-dependent triglyceride synthesis, slows triglyceride turnover, and constrains the ethanolamine branch of the Kennedy pathway. This response limits fatty acid oxidation, long-chain acylcarnitine accumulation, and lipid peroxidation independently of pseudohypoxic transcription or canonical lipid storage regulators, while also remodeling the phosphoproteome and redox proteome. L2HG accumulation induces hypertriglyceridemia in mice, redistributes the acyl chain composition of cardiac triglycerides, and limits ischemia-induced acylcarnitine accumulation in the heart, mirroring a positive association between circulating 2HG and triglycerides in humans. Thus, 2HG expands metabolic flexibility from whether fatty acids are used as fuel to how that fuel is allocated among storage, membrane synthesis, and oxidation.
    DOI:  https://doi.org/10.64898/2026.08.12.744465
  7. bioRxiv. 2026 Aug 13. pii: 2026.08.12.744280. [Epub ahead of print]
    Respiration-Deficient Cells Require Pyruvate Carboxylase to Suppress Asparagine Auxotrophy.
    Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.
      Mutations in mitochondrial DNA (mtDNA) compromise ETC activity and impair oxidative phosphorylation. Since eukaryotic cells contain multiple copies of mtDNA, the resulting phenotype depends on the proportion of mutant mitochondrial genomes (the heteroplasmy level). Using isogenic cell lines carrying similar mtDNA deletions, a linear decline in cellular respiration was observed as mitochondrial DNA heteroplasmy increased. Despite this, cellular redox imbalance did not change until heteroplasmy exceeded 50%. As heteroplasmy increased past 70%, cells also exhibited an integrated stress response (ISR) and impaired translation was observed. These defects were reversed by either addition of asparagine or overexpression of pyruvate carboxylase (PC). The dependence on exogenous asparagine in other respiration-deficient cells was found to correlate inversely with the PC expression level. For example, patient-derived thyroid tumor cells, harboring high heteroplasmy for a Complex I mtDNA mutation and low levels of PC, exhibited asparagine auxotrophy, and L-asparaginase treatment suppressed tumor growth. Together, these findings demonstrate a role for mitochondrial pyruvate carboxylase in cellular asparagine synthesis under conditions of compromised respiratory activity.
    DOI:  https://doi.org/10.64898/2026.08.12.744280
  8. Nat Chem Biol. 2026 Oct 06.
    DHODH is the key target of the KDM4 inhibitor QC6352 in glioblastoma stem cells.
    Jayden R Sterling, Jacinda R Holtsmark, George L Joun, Matthew S Graus, Tian Y Du, Mani Kuchibhotla, Terrance G Johns, Antoine deWeck, Lipin Loo, G Gregory Neely, Karen Tran, Chloe Shard, Guillermo A Gomez, Ashwini Patil, Diana D Shi, Julie-Aurore Losman, Angus J Saxton, Jennifer R Baker, Zhihe Lei, Matthew T O Holland, Paul E Brennan, Mathias Francois, Andreas Kraemer, Susanne Mueller, Yuchen Feng, Paul Workman, Lenka Munoz.
      Histone lysine demethylase 4 (KDM4) enzymes are frequently overexpressed in cancer and are considered to be promising therapeutic targets. QC6352, which is widely used as a best-in-class KDM4 chemical probe, shows potent antitumor activity across cancer models. Using comprehensive chemical biology approaches in glioblastoma models, we demonstrate that the efficacy of QC6352 and that of its clinical analog zavondemstat are independent of KDM4 inhibition. Instead, we identify dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis, as the functional target driving their antiproliferative activity. Uridine supplementation and expression of an inhibitor-resistant DHODH mutant fully abrogate growth inhibition, whereas the orthogonal KDM4 inhibitor ML324, which lacks DHODH inhibition, fails to phenocopy QC6352. These findings establish QC6352 and zavondemstat as dual KDM4-DHODH inhibitors and identify DHODH inhibition as the dominant driver of their antiglioblastoma efficacy, as well as demonstrating the need for orthogonal chemical probes to accurately define drug mechanisms in cells.
    DOI:  https://doi.org/10.1038/s41589-026-02306-x
  9. J Biol Chem. 2026 Oct 09. pii: S0021-9258(26)02502-0. [Epub ahead of print] 113630
    Hepatocyte Serine Palmitoyltransferase 3 is essential for mitochondrial ceramide homeostasis and electron transport chain function.
    Maryam Jamil, Anna Kovilakath, Yolander Valentine, Saaid Farooq, David Montefusco, Yang Yue, Gisela Beutner, Qun Chen, Jeremy Thompson, Komuraiah Myakala, Xiaoxin Wang, Christiane Carter, Jinze Liu, Arjun Rijal, Charles E Lyons, Devanand Sarkar, Moshe Levi, George A Porter, Sushil Mahata, Tytus Bernas, Edward J Lesnefsky, L Ashley Cowart.
      Sphingolipids constitute essential membrane lipids that also function as signaling molecules mediating fundamental cellular processes. Disruption of constitutive sphingolipid metabolism contributes to a range of metabolic diseases. Sphingolipid biosynthesis is initiated by serine palmitoyltransferase (SPT), a heteromeric enzyme composed of Sptlc1 and either Sptlc2 or the less-characterized subunit Sptlc3. While the canonical Sptlc1/Sptlc2 complex generates most sphingolipids, Sptlc1/Sptlc3 produces non-canonical sphingolipids that remain poorly understood. Sptlc3 expression increases in liver disease in both mouse models and humans, yet its biological role remains unclear. To address this, we generated a liver-specific SPTLC3 knockout (SPT3-hKO) mouse model. Loss of SPTLC3 resulted in severe mitochondrial dysfunction in hepatocytes, characterized by reduced oxygen consumption, decreased ATP production, and elevated NADH/NAD+ ratios with a concomitant increase in glycolytic activity. Mechanistically, we found a defect in the electron transport chain (ETC) which stemmed not from intrinsic impairment of the ETC complexes but rather from hindered electron flow between complex I and complex III likely due to reduced availability of Coenzyme Q. While atypical ceramides constituted (∼4% of total ceramides) when measured in liver homogenates, there measurements in mitochondria-enriched fractions revealed enrichment in this cell compartment. Together, our findings identify SPTLC3 as a critical modulator of mitochondrial ceramide composition and ETC function, revealing a specialized role for non-canonical sphingolipids in hepatocyte energy metabolism.
    Keywords:  Ceramides; Complex I; ETC; Hepatocytes; SPTLC3
    DOI:  https://doi.org/10.1016/j.jbc.2026.113630
  10. PLoS Pathog. 2026 Oct;22(10): e1014534
    Glutamine from plasma-like medium fuels nitrogen metabolism and influences proliferation in Leptospira interrogans.
    Matthew H Ward, Nathan Scherer, Leah P Shriver, Gary J Patti.
      Leptospirosis, caused by pathogenic Leptospira spp. such as L. interrogans, is a bacterial zoonosis of increasing prevalence with no consistently effective treatments in severe cases. We sought to characterize metabolic mechanisms that support L. interrogans infection, with the ultimate goal of revealing unexplored therapeutic opportunities. We first established and validated a culture medium, which we refer to as supplemented Human Plasma-Like Medium (sHPLM). sHPLM more closely resembles the physiological environment of the human host than standard culture media, such as the EMJH (Ellinghausen-McCullough-Johnson-Harris) medium typically used for Leptospira culture. We also pioneered metabolomics approaches to study sHPLM-cultured Leptospira. Specifically, we developed a liquid chromatography/mass spectrometry (LC/MS) workflow for both medium metabolomics and stable isotope tracing with L. interrogans cultures. The application of these technologies in L. interrogans revealed that the amino acid glutamine is a major nitrogen source among the many available in sHPLM. Subsequent growth studies in three pathogenic Leptospira strains and the nonpathogenic strain L. biflexa Patoc-1 showed robust proliferation when only glutamine-derived nitrogen was available. Further, a small-molecule inhibitor designed to target glutamine utilization, JHU-083, effectively impaired the proliferation of L. interrogans cultures. Adding glutamine to non-physiological EMJH medium also rapidly induced a short-term proliferative boost in L. interrogans and increased biofilm formation. RNA-sequencing after glutamine exposure revealed transcriptional trends for increases in biosynthesis to support these phenotypes. Although ammonium has long been thought to be the sole nitrogen source for Leptospira spp., our results demonstrate that glutamine provides a second source of nitrogen for biosynthesis in multiple strains and may act as a metabolite signal to alter L. interrogans physiology in ways that could influence infection. This work highlights that studying L. interrogans under physiological conditions is key to understanding mechanisms supporting infection and points to nitrogen assimilation as a potential target for therapies.
    DOI:  https://doi.org/10.1371/journal.ppat.1014534
  11. bioRxiv. 2026 Aug 14. pii: 2026.08.13.744642. [Epub ahead of print]
    Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer.
    Johnvesly Basappa, Cosimo Lobello, Anneliese M Faustino, Cristina Uribe-Alvarez, David Rushmore, Niel Sen, Li Wang, Andrey Efimov, Kathy Q Cai, Jaime L Schneider, Lori Rink, Aaron N Hata, Luca Mologni, Wujuan Zhang, Aaron R Goldman, Hsin-Yao Tang, Reza Nejati, Roland Dunbrack, Jonathan Chernoff, Joseph A Baur, Mariusz A Wasik.
      Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage pathway, is frequently upregulated in cancer, yet mechanisms regulating its catalytic activity remain undefined. We identify NAMPT as a direct substrate of multiple proto-oncogenic tyrosine kinases, including ALK, insulin receptor, IGF1R, and PDGFRA. Phosphoproteomics identified NAMPT Y188 as the major phosphorylation site, including the oncogenic fusion kinase NPM1::ALK. NAMPT interacted with NPM1::ALK in the cytoplasm, nucleus, and mitochondria, while Y188 phosphorylation enhanced catalytic activity, NMN/NAD⁺ biosynthesis, and downstream metabolism. Conversely, the Y188F mutant reduced enzymatic activity, proliferation, and clonogenicity, whereas disrupting dimerization similarly impaired phosphorylation and function. Interactome analyses showed phosphorylation and dimerization cooperatively remodel NAMPT-associated networks, enriching phosphorylated dimers for metabolic/redox regulators and monomeric NAMPT for ribosome biogenesis. NAMPT inhibition suppressed the growth of both ALK inhibitor-sensitive and -resistant lymphoma cells and enhanced the efficacy of ALK inhibition, revealing kinase-dependent NAMPT activation as a metabolic vulnerability in oncogene-driven cancers.
    DOI:  https://doi.org/10.64898/2026.08.13.744642
  12. Am J Transplant. 2026 Oct 06. pii: S1600-6135(26)02803-0. [Epub ahead of print]
    Mitochondrial pyruvate carrier inhibition restrains germinal center T follicular helper cells attenuating chronic graft-versus-host disease.
    Eun Ko, Fathima A Mohamed, Stephanie Y Rhee, Yujie Zhao, Rocio Amaro Marquez, Joanna Ly, Ethan G Aguilar, Haley Melin, Peter T Sage, Tanner Schumacher, Conor Ronayne, Angela Panoskaltsis-Mortari, Megan Riddle, Mark Osborn, Govindarajan Thangavelu, Peter A Crawford, Roddy S O'Connor, Michael C Zaiken, Keli L Hippen, Leslie S Kean, Jeffrey C Rathmell, Juan Liu, Jason W Locasale, Venkatram Mereddy, Bruce R Blazar.
      Chronic graft-versus-host disease (cGVHD) is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. During cGVHD, T follicular helper cells (TFH) and germinal center B-cells (GCB) interactions produce pathogenic class-switched allo- and auto-antibodies. We utilized a multi-organ cGVHD mouse model with bronchiolitis obliterans (BO) to investigate TFH metabolism and metabolic vulnerabilities at early and late times post-transplant. We found that TFH were highly glycolytic early in cGVHD/BO progression but later transitioned to a more oxidative metabolic profile. The mitochondrial pyruvate carrier (MPC) transports pyruvate into the mitochondria, directly linking glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). To disrupt the TFH glycolysis to OXPHOS transition that accompanies cGVHD/BO progression, we tested 7ACC2, a potent MPC inhibitor, in ex vivo and in vivo cGVHD-related assays. In a co-culture assay, 7ACC2 significantly reduced TFH:B dependent class-switched immunoglobulin production. In vivo, mice with established cGVHD/BO given 7ACC2 from days 28-49 significantly improved pulmonary function associated with lower TFH and GCB frequencies. Because MPC inhibitors are tested in clinical trials to treat metabolic diseases, cancer and neurodegenerative disease, clinical trials to test this novel MPC-based approach to stifle TFH metabolic demands in patients with treatment refractory cGVHD/BO progression warrants future consideration.
    Keywords:  Bronchiolitis Obliterans; Chronic graft-versus-host disease; T follicular helper cells; metabolic regulation
    DOI:  https://doi.org/10.1016/j.ajt.2026.09.041
  13. Bioessays. 2026 Oct;48(10): e70193
    Metabolic Structure: A Paradigm Revisited in Light of the Fundamental Parameters of Living Systems.
    Jacques Fantini.
      The concept of 'metabolic structure', which considers metabolism as a stable, genetically encoded architecture with enzymes occupying fixed control positions, is indispensable but incomplete, and it obscures metabolism's true nature. I propose redefining metabolism as a dynamic field of emergent biochemical fluxes, governed by six fundamental parameters: time, water, entropy, quantum effects, space, and electrostatic potential, shaping the thermodynamic trajectories of living matter. Metabolic control analysis already supports this view: flux control coefficients are state- and time-dependent coordinates within a thermodynamic field, not intrinsic enzyme properties. This perspective manifests across scales: electrostatics govern fructose 1,6-bisphosphate cleavage in aldolase; hepatic zonation shows spatial reorganization through a single parameter; glucose deprivation quantitatively redirects intestinal cancer cell metabolism from glycolytic to oxidative flux, driving differentiation into an enterocyte-like state; post-meal walking redirects glucose flux from storage to oxidation without pharmacological intervention; inherited metabolic diseases can sometimes be managed without correcting the causal mutation. These examples converge into a new framework: metabolism possesses not only a sophisticated architecture but also states that shape its fluxes. And states, unlike static structures, can be reconfigured.
    Keywords:  Warburg effect; electrostatic potential; emergent properties; flux control coefficients; fundamental biological parameters; hepatic zonation; inherited metabolic diseases; lipid rafts; metabolic control analysis
    DOI:  https://doi.org/10.1002/bies.70193
  14. bioRxiv. 2026 Aug 10. pii: 2026.07.29.741503. [Epub ahead of print]
    A guanosine metabolism-bioenergetics intersection drives Parkinson's disease.
    Alexandros C Kokotos, Santiago R Unda, Paula Reyes-Pérez, Mariam Isayan, Maria Teresa Periñan, Michael G Kaplitt, Timothy A Ryan.
      Several Parkinson's Disease (PD) linked mutations are known to drive deficits in a pathway that relies on an adequate supply of guanosine nucleotide triphosphate (GTP) to drive cellular neuronal processes. Similarly, there is strong evidence that a deficit in bioenergetic support for neuron function is also a major genetic driver of PD. We show here that the reliance on these two purine-based metabolites intersect at another PD susceptibility gene that encodes nucleoside diphosphate kinase (NDK) which converts ATP into GTP. We show that overexpression of NDK is strongly protective both in-vivo and in-vitro to metabolic lesions and identify mutations in NDK in humans associated both with increased risk and protection from PD. We discovered that NDK lies at the intersection of proper ATP production, de novo synthesis of guanosine diphosphate and the activity of GTP cyclohydrolase I, a consumptive pathway needed to produce the bioactive metabolite tetrahydrobiopterin (BH 4 ) required for mitochondrial function. Loss of NDK and impairment in guanosine nucleotide synthesis exacerbate synaptic dysfunction, while boosting the GTP consuming pathway promotes bioenergetics. Additionally, analysis of genetic data taken from over 64,000 PD affected individuals and 38,000 controls from diverse ancestries reveal that several genes lying at the intersection of guanosine nucleotide metabolism and bioenergetics pose a significant risk burden for PD.
    DOI:  https://doi.org/10.64898/2026.07.29.741503
  15. Cell Metab. 2026 Oct 06. pii: S1550-4131(26)00368-2. [Epub ahead of print]38(10): 1941-1942
    Metabolic advantages of a high-protein, low-carbohydrate diet in in patients with metabolically unhealthy obesity.
    Nicola Guess.
      Whether dietary macronutrient content has metabolic benefits beyond weight loss is unknown. In this issue, a carefully controlled trial demonstrates that a higher-protein, lower-carbohydrate dietary pattern improves hepatic glucose and lipid metabolism in people with prediabetes and steatosis compared to a lower-protein, high-carbohydrate diet, even though all groups lost 10% of body weight.
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.016
  16. Biochim Biophys Acta Bioenerg. 2026 Oct 05. pii: S0005-2728(26)00035-6. [Epub ahead of print]1868(1): 149615
    Electron competition in yeast mitochondria is governed by dehydrogenases catalytic efficiencies.
    Mélanie Martins Pinto, Corinne Pellon, Nicole Averet, Emmanuel Suraniti, Camille Colin, Stéphane Ransac, Jean-Pierre Mazat, Stéphane Arbault, Anne Devin, Michel Rigoulet.
      In Saccharomyces cerevisiae, cytosolic NADH generated during biomass production must be efficiently reoxidized to sustain metabolic flux. Under aerobic conditions, this process is primarily mediated by the oxidative phosphorylation and specifically via external NADH dehydrogenases (Nde1p/Nde2p) and the glycerol-3-phosphate (G3P) shuttle. Although these pathways perform equivalent redox functions, their relative contributions vary with physiological conditions, indicating the existence of regulatory mechanisms governing electron partitioning. Here, we combined experimental measurements and kinetic modeling to investigate the mechanisms underlying electron competition between NADH and G3P oxidation in isolated yeast mitochondria. Using wild-type and Δnde1 strains, we determined the kinetic parameters of the relevant dehydrogenases and analyzed their dependence on the quinone redox state. A mathematical model incorporating these parameters reproduced the experimentally observed preferential utilization of NADH in wild-type mitochondria as well as the simultaneous oxidation of NADH and G3P in the Δnde1 mutant. Our results demonstrate that, under conditions where the downstream respiratory chain is rate-limiting, electron partitioning is governed by the ratio of catalytic efficiencies (Vmax/K0.5) of NADH and G3P dehydrogenases with respect to the quinone redox ratio (Q/QH₂). These findings identify a simple kinetic principle underlying substrate competition in mitochondrial electron transport and provide a quantitative framework for understanding metabolic flux distribution in eukaryotic cells.
    Keywords:  Catalytic efficiency; Enzyme kinetics; Glycerol-3-phosphate dehydrogenase; Metabolic flux; Mitochondria; NADH dehydrogenase; Quinone; Redox state; Yeast
    DOI:  https://doi.org/10.1016/j.bbabio.2026.149615
  17. Eur Heart J Imaging Methods Pract. 2026 Aug;4(3): qyag161
    Magnitude of serum β-hydroxybutyrate elevations and myocardial glucose suppression in fluorine-18 fluorodeoxyglucose positron emission tomography for cardiac sarcoidosis.
    Lamis El Harake, Richard Weinberg, Ike Okwuosa, Ryan Avery, Susan Lehrer, Paul C Cremer.
      This retrospective cohort study evaluated the relationship between serum β-hydroxybutyrate (BHB) levels and myocardial glucose suppression in 74 patients undergoing fluorine-18 fluorodeoxyglucose positron emission tomography for suspected cardiac sarcoidosis. The average BHB concentration prior to FDG administration was 0.94 ± 0.78 mmol/L. The septal-to-blood pool uptake ratio (SUVmax_septal/SUVmean_blood pool) ranged from 0.50 to 0.88, with a median of 0.66 (Quartile 1 = 0.58; Quartile 3 = 0.73). No significant association was found between BHB levels and the septal-to-blood pool uptake ratio (r = 0.09; P = 0.48), suggesting a metabolic plateau regarding myocardial glucose utilization once adequate ketosis is achieved. These preliminary findings support a threshold effect rather than a dose-dependent relationship between serum BHB levels and myocardial glucose suppression following appropriate dietary preparation.
    DOI:  https://doi.org/10.1093/ehjimp/qyag161
  18. Mol Biol Cell. 2026 Oct 08. mbcE26050241
    ATP and α-ketoglutarate link nitrogen availability to TORC1-Npr1 signaling in yeast.
    Christopher Dereppe, Minoas Evangelinos, Elie Saliba, Viktória Ďurčová, Valentin Dubois, Ann Van Schepdael, Cédric Delporte, Bruno André.
      The TORC1 (Target of Rapamycin Complex 1) kinase complex coordinates eukaryotic cell growth and metabolism in response to nutrient availability. In yeast, one of the proteins under TORC1 control is the Npr1 kinase mediating nitrogen control of several plasma membrane transporters, yet the metabolic signals governing this pathway remain poorly understood. Here, we first investigated the previously described and unexpected activation of TORC1-Npr1 signaling upon acute glucose starvation. We show that this response occurs only under specific nitrogen conditions, notably in cells grown on proline or glutamine, and depends on increased ATP production driven by stimulated respiration. In proline-grown cells, this respiration is fueled by catabolism of α-ketoglutarate, while high α-ketoglutarate levels negatively affect TORC1-Npr1 activation. We next analyzed TORC1-Npr1 activation following NH4+ addition to proline-grown cells. Our results confirm that glutamine accumulation is not required for this activation and instead show that NH4+ assimilation is associated with a decrease in α-ketoglutarate levels and a sustained increase in ATP production, concomitant with TORC1-Npr1 activation. In cells lacking the NH4+-assimilating glutamate dehydrogenases, both increased ATP production and TORC1-Npr1 activation are impaired. Together, these findings identify ATP and α-ketoglutarate as important metabolic determinants of TORC1-Npr1 signaling in response to nitrogen availability.
    DOI:  https://doi.org/10.1091/mbc.E26-05-0241
  19. NMR Biomed. 2026 Nov;39(11): e70422
    Continuous Imaging of the Cardiac Cycle Metabolism With Hyperpolarized [1-13C]Pyruvate.
    Mohsen Redda, Nikolaj Bøgh, Esben Søvsø Szocska Hansen, Uffe Kjærgaard, Rolf F Schulte, Christoffer Laustsen.
      Hyperpolarized (HP) 13C MRI enables noninvasive assessment of myocardial metabolism. Current approaches typically acquire data only during diastole, ignoring phase-dependent metabolic changes. This study aimed to develop an imaging technique to capture HP [13C]bicarbonate production across both systole and diastole in healthy porcine hearts under rest and stress conditions. Six Danish domestic pigs underwent conventional cardiac MRI and HP [1-13C]pyruvate MRI on an MR750 3 T system (GE HealthCare) before and during pharmacological stress by injecting adenosine (250 μg/min/kg) and dobutamine (5 μg/min/kg). Metabolic imaging was obtained by single-frequency imaging on [13C]bicarbonate. Concurrent off-resonance excitation on [1-13C]pyruvate was utilized to generate a simultaneous pyruvate input function. Bicarbonate-to-pyruvate ratios (Bic/Pyr ratio) were compared from rest to stress throughout the cardiac cycle. Dynamic metabolic changes were successfully captured with sufficient temporal resolution to resolve both systolic and diastolic phases. From rest to stress, during systole the Bic/Pyr ratio increased by 150% (95% CI 50%-330%, p = 0.0076) and during diastole it increased by 170% (95% CI 50%-380%, p = 0.0083). During rest, the Bic/Pyr ratio decreased by 21% from systole to diastole (95% CI 4%-35%, p = 0.027), and during stress, it decreased by 16% (95% CI 4%-26%, p = 0.019). Simultaneous phase-resolved imaging of [1-13C]pyruvate and [13C]bicarbonate enables high-temporal-resolution assessment of myocardial metabolism during both systole and diastole compared to conventional single-frequency acquisitions. This simultaneous acquisition strategy removes the need for separate pyruvate and bicarbonate acquisitions, doubling the temporal resolution of the resulting image series, while revealing dynamic increases in Bic/Pyr ratio from rest to stress and between systole and diastole. This approach overcomes the limitations of single-phase imaging and provides a foundation for investigating phase-dependent metabolic alterations in disease.
    DOI:  https://doi.org/10.1002/nbm.70422
  20. Elife. 2026 Oct 09. pii: RP111980. [Epub ahead of print]15
    A membrane-disruptive action of VBIT-4 challenges its role as a widely used VDAC1 oligomerization inhibitor.
    Varun Ravishankar, Luís Borges-Araújo, Megha Rajendran, Elodie Lafargue, Deborah Byrne, Nicolas Buzhinsky, Mya S Wolfe, Wendy Fitzgerald, Nina A Bautista, Bethel G Beyene, Motahareh G Larimi, Jean-Pierre Duneau, James Sturgis, Sergey M Bezrukov, Ignacio Casuso, Tatiana K Rostovtseva, Lucie Bergdoll.
      Voltage-dependent anion channel (VDAC) is the most abundant protein of the mitochondrial outer membrane and a key regulator of metabolite exchange and mitochondrial physiology. Its oligomerization has been proposed to control processes such as mitochondrial DNA release and membrane remodeling, yet the underlying mechanisms remain poorly defined. VBIT-4 has been widely used as a putative inhibitor of VDAC1 oligomerization, despite limited mechanistic validation. Here, using high-speed atomic force microscopy (AFM), we visualized VDAC1 assemblies in lipid membranes and examined the effect of VBIT-4. Unexpectedly, VBIT-4 induced membrane defects and permeabilization at micromolar concentrations, independently of VDAC1. Quantitative AFM analysis further shows that VBIT-4 does not alter VDAC1 cluster organization. Complementary electrophysiology, microscale thermophoresis, and coarse-grained molecular dynamics demonstrate that VBIT-4 partitions into lipid bilayers, increases membrane permeability, and destabilizes membrane structure, without detectable effects on VDAC1 channel properties or assemblies. Consistent with this mechanism, VBIT-4 induces VDAC1-independent cytotoxicity in HeLa cells at concentrations above 10 µM. Together, these results demonstrate that VBIT-4 does not act as a specific inhibitor of VDAC1 oligomerization but instead functions as a membrane-active compound. This work provides a revised framework for interpreting studies using VBIT-4 and highlights the importance of systematically assessing drug-membrane interactions when targeting membrane proteins.
    Keywords:  VBIT-4; biochemistry; chemical biology; cytotoxicity; membrane destabilization; mitochondrial outer membrane; oligomerization; voltage-dependent anion channel
    DOI:  https://doi.org/10.7554/eLife.111980
  21. Nat Commun. 2026 09 05. pii: 10558. [Epub ahead of print]17(1):
    Suppressing glutamate dehydrogenase guides hematopoietic stem cell divisions into self-renewal.
    Michihiro Hashimoto, Michie Uchikawa, Yuichiro Arima, Akiyasu Iwase, Ayano Yahagi, Mizuki Ishimaru, Tomomasa Yokomizo, Ayako Nakamura-Ishizu, Yosuke Tanaka, Kenichi Miharada, Hiroki Kurihara, Goro Sashida, Toshio Suda, Terumasa Umemoto.
      Hematopoietic stem cells (HSCs) self-renew to expand their pool but often differentiate upon division. Thus, it remains unclear how HSCs maintain their stemness during or after division. Here, we show that the suppression of glutamate dehydrogenase (Glud1), a key enzyme responsible for glutamate (Glu) catabolism, supports the maintenance of HSCs during division. We find that self-renewing mouse HSCs during hematopoietic regeneration exhibited lower intracellular Glu levels compared to HSCs differentiating during ex vivo culture. We therefore focus on the negative regulation of Glu catabolic reactions as a candidate factor to maintain HSCs during division, and find that treatment with the Glud1 inhibitor, R162, maintains a subset of HSCs that would otherwise differentiate during division under normal culture conditions. This treatment successfully results in an approximately 500-fold expansion of functional mouse HSCs that maintain expression pattern of conventional stem cell markers over a 30-day culture period. Importantly, this positive effect of Glud1 inhibition is independent of suppressing cell divisions and dependent on robust JAK2-STAT signaling. Overall, our findings propose that Glud1 inhibition, coupled with robust JAK2-STAT signaling, characterizes a functional HSC state during division, enabling ex vivo expansion of mouse HSCs under conventional culture conditions.
    DOI:  https://doi.org/10.1038/s41467-026-77151-6
  22. Endocr Relat Cancer. 2026 Oct 07. pii: ERC-26-0243. [Epub ahead of print]
    Potential for pathogenic protein acylation in succinate dehydrogenase-deficient pheochromocytoma and paraganglioma.
    Sherry X Zhou, L James Maher.
      Historically, the study of cellular metabolism and the cellular proteome have largely focused on specific proteins and metabolites in certain cellular pathways. With the advent of new "omics" technologies, researchers have been able to probe disruptions and alterations in cellular homeostasis on a near proteome-wide and metabolome-wide basis. Yet the truly interconnected and interdependent nature of the cellular metabolome and proteome has only become more evident with the discovery of proteome-wide protein post-translational modifications (PTMs) such as lysine acylation by acetyl-CoA or succinyl-CoA. Such PTMs link proteome function to fluctuating concentrations of tricarboxylic acid (TCA) cycle metabolites. Tumorigenesis in TCA cycle-defective tumors that upregulate acylating agents such as succinyl-CoA and acetyl-CoA provides a relevant context for understanding the breadth of protein acylation in disease. In particular, succinate dehydrogenase (SDH)-loss chromaffin cells can be transformed to the neuroendocrine tumors pheochromocytoma and paraganglioma (PPGL), but sensitive diagnostic and effective therapeutic options for metastatic disease remain limited. Interrogating cell models of SDH-loss PPGL provides a unique opportunity to capture the effects of SDH loss on cellular metabolism and protein acylation while exploring new avenues for improved diagnostics and novel therapeutic targets in these rare diseases.
    DOI:  https://doi.org/10.1530/ERC-26-0243
  23. Metab Eng. 2026 Oct 06. pii: S1096-7176(26)00156-4. [Epub ahead of print] 102561
    Adaptive rewiring of NADPH electron flow reveals escape routes from redox-balance-based growth coupling in Escherichia coli.
    Aidan E Cowan, Mason Hillers, Dennis Wu, Bridgie Cawthon, Samer Saleh, Sean Perea, Jennifer Gin, Yan Chen, Christopher J Petzold, Jay D Keasling.
      Redox-balance-based growth coupling links oxidoreductase activity to cellular fitness and can enable high-throughput enzyme selection and strain evolution. However, because growth reflects the fitness of the whole cell, metabolic adaptation can circumvent the intended selective pressure. Here, we investigated the evolutionary stability of an aerobic NADPH redox-balance selection strain of Escherichia coli engineered to accumulate NADPH during growth on glucose. Adaptive evolution first selected mutations predicted to relax cofactor specificity in NADH-dependent quinone oxidoreductases, allowing NADPH-derived reducing equivalents to enter respiratory electron flow. Removing major NADH-to-quinone oxidoreductases did not eliminate the capacity for evolutionary escape; in one successfully evolving lineage, adaptive evolution uncovered a latent lactate-mediated route for electron transfer into the quinone pool. These results reveal strong selective pressure to reconnect soluble nicotinamide redox metabolism with energy-conserving respiration and demonstrate that E. coli can access multiple pathways for restoring electron flux between these systems. Overall this work outlines design principles for aerobic, growth-coupled strains which rely upon redox balance, illustrating that successful designs must limit respiratory rewiring while preserving sufficient carbon and energy flux to support growth and pathway selection.
    Keywords:  NADPH; adaptive laboratory evolution; cofactor specificity; directed evolution; growth-coupled selection; redox balance
    DOI:  https://doi.org/10.1016/j.ymben.2026.102561
  24. Nat Metab. 2026 Oct 07.
    Inhibiting fructose metabolism to treat fatty liver.
    Richard J Johnson, Miguel A Lanaspa, Dean R Tolan.
      
    DOI:  https://doi.org/10.1038/s42255-026-01627-4
  25. iScience. 2026 Oct 16. 29(10): 117618
    The Gibbs free energy landscape based on liver metabolome revealed thermodynamic robustness against fasting and obesity.
    Takumi Abekawa, Satoshi Ohno, Akiyoshi Hirayama, Tomoyoshi Soga, Shinya Kuroda.
      Mammalian liver metabolism shifts substantially during fasting, yet the Gibbs free energy change of reaction (Δ r G'), a fundamental thermodynamic quantity that defines reaction driving force and constrains metabolic directionality, remains poorly characterized in intact organs. Here, we mapped the Δ r G' landscape of mouse liver glucose metabolism during fasting using absolute metabolite concentrations and GLEAM (Gibbs free energy of reaction landscape estimation from metabolome assisted by variance-covariance matrix), a computational method developed here. Despite metabolite fluctuations, Δ r G' landscapes remained robust, changing only modestly, even for reactions reversing direction between glycolysis and gluconeogenesis. Thermodynamically inferred potential rate-limiting steps were maintained during fasting. Enzyme-cost analysis further suggested a trade-off between thermodynamic robustness and enzyme requirements during glycolytic switching. Obese mouse liver also showed thermodynamic robustness despite metabolic disruption. Our framework provides a novel thermodynamic perspective on intact organ metabolism, revealing preservation of key thermodynamic characteristics across fasting and obesity.
    Keywords:  Gibbs free energy; enzyme kinetics; metabolome; thermodynamics
    DOI:  https://doi.org/10.1016/j.isci.2026.117618
  26. Nat Rev Genet. 2026 Oct 07.
    Histone acetylation finds its link to transcription.
    Liling Wan.
      
    DOI:  https://doi.org/10.1038/s41576-026-01024-3
  27. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2618654123
    A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models.
    Hong Wang, Eizo Marutani, Luca Zazzeron, Marissa Menard, Laura Volpicelli-Daley, Fumito Ichinose, Vamsi K Mootha.
      A growing body of preclinical research is demonstrating the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for rare and common diseases. However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small-molecule, "hypoxia-in-a-pill" combining a hemoglobin affinity enhancer (GBT440) to limit oxygen delivery with a HIF-2α inhibitor (PT2399) to prevent detrimental compensatory erythropoiesis. Although this small-molecule regimen extended the lifespan of the Ndufs4 knockout (KO) mouse model of mitochondrial complex I deficiency and Leigh syndrome, its efficacy did not match chronic 11% FIO2. Here we optimize this regimen using GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, and show it rescues key neurodegenerative phenotypes in multiple models. When we initiate therapy in 50 d old Ndufs4 KO mice with advanced disease, GBT601 monotherapy alleviated neurological disease phenotypes and extended median lifespan from 62 to 105 d, while dual therapy with the GBT601/PT2399 combination extended median lifespan to 158 d. When initiated after onset of advanced disease in a mouse model of Friedreich's ataxia, the combination halted further progression of motor phenotypes. In a mouse model of Parkinson's disease due to α-synuclein toxicity, initiating the GBT601/PT2399 combination after onset of motor dysfunction attenuates brain hyperoxia and lipid peroxidation and reverses motor phenotypes. Importantly, the combination maintained body weight without inducing any signs of pulmonary hypertension. Our findings motivate further preclinical and clinical evaluation of our "hypoxia in a pill" approach for diseases with high unmet need.
    Keywords:  HIF-2α; hemoglobin; hyperoxia; hypoxia; neurodegeneration
    DOI:  https://doi.org/10.1073/pnas.2618654123
  28. Front Mol Biosci. 2026 ;13 1816622
    H+ exchange and pH profiling of select non-glycolytic cytosolic phosphate transfer and oxidation-reduction reactions.
    Robert Robergs, Marek Nalos, Petr Kelbich, Adela Jizerová, Ivana Mervartová, Michal Vostrý, Milan Štengl, Vaclav Babuška.
       Background: Despite animal research of cellular and systemic acidosis for more than 100 years, there is no dominant evidence-based understanding of the cause of metabolic acidosis. Embedded in this crisis state is the understanding that the hydrogen ion (H+) involved in some chemical reactions, either as a substrate or product (H+ exchange (H+ e)), does not change the pH of biological solutions. This research documents the direct roles of the H+ e of a selection of non-glycolytic cytosolic chemical reactions in changing the pH of an unbuffered aqueous solution.
    Methods: Reagents were prepared using deionized water, substrates at known concentrations, enzymes and needed activator chemicals. The chemical reactions studied were creatine kinase (CKase) (to ATP and CrP), ATPase, hexokinase (HKase), and glucose-6-phosphate dehydrogenase (G6PDHase). Each reaction was started by addition of the enzyme, and reagent pH was measured intermittently using a pH electrode. Samples of reagent (200 μL) were acquired for product measurement by spectrophotometry.
    Results: Results are presented as start pH:end pH; [Product], mmol·L-1; pH:[Product] slope, pH.mmol-1.L-1: CKase to ATP (7.49:9.51; [1.95]; 1.289); CKase to CrP (8.29:7.89; [0.64]; -1.35); ATPase (8.94:8.23; [0.84]; -0.9385); HKase (8.59:6.55; [2.36];-1.596), G6PDHase (7.53:6.89; [1.46]; -0.8006). All chemical reactions that produced carboxylic acids did so as anions, and all resulted in pH responses consistent with the role of the H+ as a substrate or product. The sequencing or summing of the CKase, ATPase, HKase and G6PDHase reactions revealed potential for summative computational modelling.
    Conclusions: The evidence opposes traditional theories as the sole cause of cellular or systemic acidosis.
    Keywords:  acidosis; alkalosis; bioenergetics; buffering; enzymology; metabolism
    DOI:  https://doi.org/10.3389/fmolb.2026.1816622
  29. ACS Sens. 2026 Oct 07.
    Genetically Encoded Glucosensor for Multiplexed 129Xe NMR.
    Jiayi He, Nathan A Rudman, Giulia Nisita, Ivan J Dmochowski.
      Hyperpolarized 129Xe NMR provides a non-optical platform for molecular, multiplexed detection. Genetically encoded protein reporters are attractive for biological sensing, but creating new 129Xe NMR sensors remains challenging because productive xenon binding is difficult to engineer into protein scaffolds. Here, we use glucose/galactose-binding protein (GGBP) as a ligand-responsive model protein to examine how molecular dynamics (MD)-derived cavity descriptors can guide the design of a xenon-binding protein sensor. Direct transfer of cavity-forming mutation from a related periplasmic binding protein (PBP) did not produce a well-resolved 129Xe response, motivating a broader analysis of candidate cavities by MD simulations. Among the GGBP variants examined, I24F/F90A combined an appropriate cavity volume, high pocket persistence, solvent exclusion, and high hydrophobicity density within the mutant series. The resulting glucosensor, GS, bound glucose with low-micromolar affinity and produced a distinct glucose-dependent 129Xe@GS hyper-CEST resonance shifted 30 ppm upfield from the aqueous xenon signal. This upfield resonance expands the chemical-shift window for genetically encoded protein-based 129Xe sensors to 125 ppm, highlighting an additional cavity-engineering route for modulating 129Xe NMR chemical shifts. GS enabled quantification of micromolar glucose concentrations in E. coli lysate, with results comparable to an enzymatic glucose assay. The upfield-shifted 129Xe NMR signal also allowed 129Xe@GS to be spectrally resolved from other PBP-based 129Xe sensors, enabling simultaneous detection of glucose-, ribose-, and maltose-responsive signals in a single hyper-CEST experiment. Finally, fusion of GS to the "always-on" 129Xe NMR contrast agent TEM-1 β-lactamase generated a ratiometric sensor. These results establish GGBP as a new scaffold for ligand-responsive 129Xe biosensing and introduce an MD-informed strategy for developing multiplexed and self-referenced genetically encoded 129Xe NMR sensors.
    Keywords:  glucose sensing; hyper-CEST; hyperpolarized 129Xe; molecular dynamics simulations; multiplexed sensing; ratiometric sensing; xenon-binding protein cavities
    DOI:  https://doi.org/10.1021/acssensors.6c02887
  30. Clin Pharmacol Ther. 2026 Oct 06.
    Dihydropyrimidine Dehydrogenase Genotype-Phenotype Correlations in Plasma and Peripheral Blood Mononuclear Cells.
    Brianna M Bembenek, Seid Hamzic, Kelly J Bouchonville, Carlo R Largiadèr, Steven M Offer.
      The chemotherapeutic 5-fluorouracil (5-FU) is commonly used to treat solid tumors, especially colorectal cancer. Deleterious variants in DPYD, which encodes dihydropyrimidine dehydrogenase (DPD), are strongly associated with severe and potentially lethal 5-FU toxicity. Phenotypic assays for DPD function have been proposed as alternative or complementary approaches to identify DPD deficiencies with the rationale that they may capture unrecognized causes. These assays include the direct measurement of DPD activity in peripheral blood mononuclear cell (PBMC) lysates and measuring plasma metabolites uracil (U), dihydrouracil (UH2), and the dihydrouracil/uracil (UH2:U) ratio. We evaluated correlations between PBMC DPD activity and plasma metabolite measures in matched samples from 203 patients with available DPYD exome sequencing data. We also compared the ability of phenotypic measures to identify carriers of deleterious DPYD variants. In addition to established high-risk variants, we identified three rare DPYD variants predicted to be deleterious: c.274C>G, c.966C>A, and c.1435G>A. Collectively, these variants were associated with impaired DPD function with effect sizes comparable to well-studied toxicity-associated variants. At the population level and within carriers of specific genotypes, weak but significant correlations were observed between PBMC DPD activity and either UH2:U ratio or U level. These findings suggest that although phenotypic assays can detect severe DPD deficiency, high variability limits their utility as standalone diagnostic tools. Integration with genetic testing may provide a more robust pretreatment risk assessment strategy.
    DOI:  https://doi.org/10.1002/cpt.70511
  31. J Lipid Res. 2026 Oct 08. pii: S0022-2275(26)00199-9. [Epub ahead of print] 101169
    Tafazzin catalyzes transacylation and hydrolysis with inverse acyl specificities.
    Michael Schlame, Yang Xu, Mindong Ren, Julio Lopes Sampaio, Daniel Levy.
      Tafazzin is a phospholipid-lysophospholipid acyltransferase that remodels fatty acids of mitochondrial phospholipids. To study the tafazzin mechanism, we expressed and purified the enzyme, measured its kinetics with different pairs of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) species, and simulated the reactions in a mathematical model based on the mass-action law. Variations in chain length and PC:LPC ratio showed that tafazzin reacts with micelles but not with bilayers. In the presence of micellar substrates (LPC + short-chain PC), transacylation rates measured at different substrate ratios suggested similar affinities for PC and LPC. Surprisingly, tafazzin catalyzed both transacylation and hydrolysis of fatty acids, the former preferring oleoyl over palmitoyl and the latter preferring palmitoyl over oleoyl groups. To study the remodeling of cardiolipin, we measured the reaction of trilinoleoyl-monolyso-cardiolipin with palmitoyl-oleoyl-PC and simulated it in a mathematical model. Simulations predicted and measurements confirmed a large number of bidirectional transacylations between the initial substrates, between substrates and products, and between different products. This led to a gradual diversification of the lipid composition from 2 to more than 15 species. Discrepancies between observed and simulated compositions demonstrated transacylation preference for oleoyl over palmitoyl groups. The data are consistent with a bidirectional ping-pong mechanism that operates through a single low-affinity binding site and suggest that transacylation specificity can at least in part be explained by selective loss of fatty acids through hydrolysis.
    Keywords:  Cardiolipin; enzymology/enzyme mechanism; fatty acid remodeling; glycerophospholipids; lipolysis and fatty acid metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.jlr.2026.101169
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒11 at 15:15.