bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–10–25
24 papers selected by
Brett Chrest, Wake Forest University
  1. Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
  2. A Liquid Chromatography-Mass Spectrometry Method to Quantify Total Coenzyme A Concentration and Isotopic Labeling.
  3. Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
  4. Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
  5. Lung cancer metabolism: a dynamic and adaptive network.
  6. Primary tumor-derived lactate primes prostate cancer cells for a dormant fate.
  7. Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.
  8. Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia.
  9. Putting glucose metabolism under electronic control.
  10. Constitutive UCP1 expression is associated with a glucose-dependent phenotype in murine mesenchymal stem cells.
  11. MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.
  12. Elucidation of the Hydroxylation Sequence in 1-DNJ Biosynthesis through Stable Isotope Tracing and Enzymatic Characterization.
  13. Development of Next-Generation ALDH1B1 Inhibitors with Enhanced Pharmacological and Functional Properties.
  14. Structure bioinformatics of eight human ATP synthase F0 subunits and their AlphaFold3-predicted reduced-hydrophobicity QTY analogues.
  15. HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
  16. Validation of targets linked to weight gain in C57BL/6 mice and translational aspects in humans.
  17. Should mitochondrial membrane potential be reconsidered as a criterion of cell death?
  18. On the interpretation of diet-specific metabolic effects following weight loss.
  19. Structural Snapshots of F1-ATPase Catalysis in Drug Resistant Acinetobacter baumannii Reveal Novel Therapeutic Targets.
  20. mechanoLight: A genetically encoded fluorescent biosensor for visualizing 5-HT2AR mechanotransduction in live cells.
  21. A Micropeptide Component of the OGDH Complex Modulates ATP Production in the TCA Cycle.
  22. Putting the Warburg effect in reverse.
  23. Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
  24. A cell death ballet in two acts.
  1. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123
    Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
    Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.
      When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.
    Keywords:  GLS; P5CS; metabolism; mitochondria; mtDNA
    DOI:  https://doi.org/10.1073/pnas.2613074123
  2. J Am Soc Mass Spectrom. 2026 Oct 07. 37(10): 2453-2462
    A Liquid Chromatography-Mass Spectrometry Method to Quantify Total Coenzyme A Concentration and Isotopic Labeling.
    Amelia L Taylor, Nathaniel W Snyder, Caroline R Bartman.
      Coenzyme A is an essential cofactor synthesized from pantothenate, which carries activated acyl groups in cellular metabolic reactions. Coenzyme A participates in catabolism of carbohydrates, fats, and amino acids; biosynthesis of fatty acids, cholesterol, and heme; and protein modification, including acetylation and 4-phosphopantetheinylation. Despite CoA's critical functions, the regulation of CoA levels and the rate of CoA synthesis in different cell types and disease states are not well understood. Acyl-CoA species are challenging to measure due to instability, poor ionization, and the wide range of biochemical properties conferred by different acyl chain lengths; moreover, most current methods cannot measure CoA isotopic labeling, required to quantify the CoA synthesis rate or to measure concentration using isotope-labeled internal standards. Here, we describe a method to quantify the concentration and isotopic labeling of total CoA, defined as the sum of CoASH plus all acyl-CoA species. Acyl-CoA species are hydrolyzed using sodium hydroxide to remove acyl chains; then, CoA is derivatized with N-ethylmaleimide (NEM). Following protein precipitation and solid-phase extraction, samples are analyzed by liquid chromatography-mass spectrometry. This method is linear in a wide range that captures mouse tissue CoA levels, with accuracy within 15% error and precision below 15% relative standard deviation for standards and tissue samples. We applied this method to measure total CoA concentration in five mouse tissues and the total CoA synthesis rate in mouse liver via infusion of 13C-15N-pantothenate. Overall, this method offers a tractable approach to measure total CoA concentration and synthesis rate in health and disease.
    DOI:  https://doi.org/10.1021/jasms.6c00206
  3. Leukemia. 2026 Oct 19.
    Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
    Xiqin Tong, Guopeng Chen, Yuzhe Pan, Yanling Chen, Yuxin Tan, Hongqiang Jiang, Qian Wang, Linlu Ma, Ruihang Li, Yuxing Liang, Xiaoyan Liu, Fuling Zhou.
      Acute myeloid leukaemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) frequently relapses after FLT3 tyrosine kinase inhibitor (TKI) therapy, highlighting the need to define mechanisms of drug tolerance. Here, we identify the mitochondrial complex I core subunit NDUFS2 as a determinant of FLT3 TKI tolerance in FLT3-ITD AML. A metabolism-focused CRISPR-Cas9 sensitiser screen, integrated with transcriptomic profiling of gilteritinib-resistant cells and primary samples, identified NDUFS2 as upregulated in acquired resistance and preferentially expressed in FLT3-ITD AML. NDUFS2 knockdown impaired complex I activity, oxidative phosphorylation, mitochondrial membrane potential and ATP production, thereby promoting apoptosis and sensitising FLT3-ITD AML cells to gilteritinib. Pharmacologic complex I inhibition with IACS-010759 similarly enhanced gilteritinib activity in FLT3-ITD AML cell lines and primary FLT3-ITD samples, activated AMPK-PERK-ATF4-CHOP stress signalling, promoted apoptosis, and reduced leukaemia burden in a patient-derived xenograft model. Genetic NDUFS2 knockdown also prolonged survival in a xenograft model. A preliminary murine safety assessment showed no overt toxicity under the tested short-term dosing schedule. These findings identify NDUFS2-dependent complex I activity as an adaptive metabolic dependency supporting FLT3 inhibitor tolerance and provide mechanistic insight for further preclinical evaluation.
    DOI:  https://doi.org/10.1038/s41375-026-03170-3
  4. Gastroenterology. 2026 Oct 21. pii: S0016-5085(26)07348-8. [Epub ahead of print]
    Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
    Alica K Michels, Sabrina Calderon, Ethan Nghiem, Eleni Zimmer, Leonor Schubert Santana, Rima Singh, Tim Eiseler, Chantal Allgöwer, Gregory Tong, Sharon Wu, Kevin Gulay, Mumina Sadullozoda, Austin Silva, Cecily Anaraki, Natalie Yousefian, Devon F Pendlebury, Cameron Geller, Alina Chao, Dennis Juarez, Thomas Seufferlein, Cholsoon Jang, Aimee L Edinger, Marcus Seldin, Alexander Muir, Thomas F Martinez, Alexander Kleger, David K Chang, Herve Tiriac, Jennifer B Valerin, David A Fruman, Christopher J Halbrook.
       BACKGROUND & AIMS: Gemcitabine remains a cornerstone of systemic therapy for pancreatic ductal adenocarcinoma (PDAC) but acquired resistance limits its efficacy. While both microenvironment-derived metabolites and intrinsic metabolic reprogramming have been implicated in gemcitabine resistance, the relationship between these mechanisms remains poorly understood. We investigated the metabolic adaptations accompanying acquired gemcitabine resistance and identified therapeutically actionable vulnerabilities.
    METHODS: Acquired gemcitabine-resistant PDAC models were generated and characterized. The effects of physiological pyrimidines on gemcitabine response were evaluated alongside changes in pyrimidine metabolism. Sensitivity to inhibition of the mevalonate pathway was assessed in vitro and in immunocompetent mouse models. Metabolite rescue experiments were performed to identify critical downstream mediators of statin activity and HMGCR expression was analyzed for its association with clinical response to gemcitabine.
    RESULTS: PDAC cells with acquired gemcitabine resistance exhibited diminished sensitivity to physiological extracellular pyrimidines due to suppression of the pyrimidine salvage pathway. This metabolic rewiring created a selective dependency on the mevalonate biosynthesis pathway, rendering gemcitabine resistant cells highly sensitive to statins. Statin treatment selectively inhibited the growth of gemcitabine-resistant tumors in mice. Metabolite rescue studies identified geranylgeranyl pyrophosphate depletion, not cholesterol limitation, as a principal mediator of statin sensitivity. HMGCR expression declined progressively during the acquisition of gemcitabine resistance and low HMGCR expression levels predicted poor response to gemcitabine-based therapy in PDAC patients.
    CONCLUSIONS: Acquired gemcitabine resistance drives metabolic reprogramming that suppresses pyrimidine salvage while creating a therapeutically exploitable dependence on the mevalonate pathway. These findings identify pharmacological inhibition of HMGCR as a metabolic vulnerability in gemcitabine resistance and support HMGCR expression as a candidate biomarker for treatment stratification in PDAC patients.
    Keywords:  3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR); Chemotherapy resistance; Pancreatic ductal adenocarcinoma; Statin
    DOI:  https://doi.org/10.1053/j.gastro.2026.09.027
  5. Cell Mol Life Sci. 2026 Oct 19. pii: 389. [Epub ahead of print]83(1):
    Lung cancer metabolism: a dynamic and adaptive network.
    Sara Gholamhosseinian-Najjar, Christian Frezza.
      Lung cancer remains the leading cause of cancer-related mortality worldwide. Although substantial progress has been made in defining the genetic, epigenetic, and molecular drivers of this heterogeneous disease, metabolic reprogramming has only recently emerged as a major determinant of tumour progression and therapeutic response. Cumulative evidence demonstrates that rather than relying on a single nutrient source or pathway, cancer cells integrate glucose and glutamine, fatty acid and one-carbon metabolism, as well as nucleotide biosynthesis, and redox-supporting circuits in a highly context-dependent manner. These programs vary across histological and molecular subtypes, reflecting the influence of lineage identity and oncogenic state on metabolic organisation. In both non-small cell lung cancer and small cell lung cancer, subtype-specific constraints shape distinct metabolic states, yet a common feature is the ability to rapidly shift between alternative nutrients and biosynthetic routes. This adaptability supports continued growth under nutrient limitation, maintains redox homeostasis, and contributes to resistance against conventional and targeted therapies. By summarising current mechanistic evidence, this review presents lung cancer metabolism as an integrated and adaptable system rather than a collection of isolated pathways, and identifies metabolic dependencies that may be leveraged for therapeutic intervention.
    Keywords:  Glucose metabolism; Glutamine metabolism; Lung cancer metabolism; Metabolic plasticity; Nucleotide metabolism; Sulphur metabolism.
    DOI:  https://doi.org/10.1007/s00018-026-06417-5
  6. Sci Adv. 2026 Oct 23. 12(43): eaeb8595
    Primary tumor-derived lactate primes prostate cancer cells for a dormant fate.
    Luigi Ippolito, Erica Pranzini, Giulia Gangarossa, Marta Iozzo, Giuseppina Comito, Giacomo Venditti, Sara Roccabianca, Elisa Pardella, Matteo Lulli, Alice Santi, Gabriella Nesi, Elisa Giannoni, Paola Chiarugi.
      The metastatic outcome depends on the state of disseminated cancer cells (DCCs) leading to overt metastasis or undergoing dormancy. Before distant organ colonization, primary tumor microenvironment may shape the decision between proliferation and dormancy. Here, we identify lactic acid (LA), a highly abundant environmental metabolite at the primary site in prostate cancer (PCa), as a key inducer of dormant state. LA-uploading PCa cells undergo a proliferation delay, associated with stemness, therapy tolerance, and invasiveness through the nuclear receptor subfamily 2 group F member 1 (COUP-TF1/NR2F1) activation. These traits rely on LA-driven accumulation of lipid droplets (LDs), which serve as reservoirs of lipid-derived acetyl moieties essential for histone acetylation. Notably, the epigenetic reader BRD4 is essential for COUP-TF1 expression and for establishing and maintaining dormancy. In metastatic sites, where LA levels are low, dormant features are lost, allowing DCCs to support metastatic growth. Last, targeting LA-mediated LD formation or BRD4 activation prevents dormancy entry, reducing PCa cell adaptability and increasing vulnerability to antiproliferative therapies.
    DOI:  https://doi.org/10.1126/sciadv.aeb8595
  7. Nat Chem Biol. 2026 Oct 22.
    Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.
    Dina Y Bass, Ekaterina S Potekhina, Alexander V Ivanenko, Aleksandr A Moshchenko, Dmitry A Korzhenevskiy, Alexey M Nesterenko, Evgeny K Shevchenko, Anastasia E Karnaeva, Natalia F Zakirova, Alexander V Ivanov, Liubov E Shimolina, Marina V Shirmanova, Olga V Lyang, Olga I Patsap, Olga M Kudryashova, Guzel R Gazizova, Elena I Shagimardanova, Sofia S Mariasina, Vasiliy A Ivlev, Ivan Bogeski, Oleg A Gusev, Vsevolod V Belousov.
      Upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation, termed as the Warburg effect, is characteristic of tumor cells. Restriction of pyruvate flux into the mitochondrial matrix is one of the major mechanisms underlying this phenomenon. Warburg metabolism is beneficial for rapidly proliferating cells; however, the metabolic consequences of activation of mitochondrial respiration in such cells remain unclear. Here we created a chemogenetic instrument, Grubraw, that generates pyruvate from ᴅ-alanine directly in the mitochondrial matrix, bypassing restricted pyruvate influx. In cancer cells, Grubraw-produced mitochondrial pyruvate increased oxidative metabolism. Chemogenetic activation of mitochondria slowed the growth rate of human melanoma xenografts. Moreover, activation of cancer cell mitochondria suppressed the transcription of genes that control cell-cycle progression, cell proliferation and DNA replication. Surprisingly, we found that cancer cells with Warburg metabolism control carbon flux by disposing of excess mitochondrial pyruvate produced by Grubraw and exporting it out of the cell.
    DOI:  https://doi.org/10.1038/s41589-026-02350-7
  8. Nat Commun. 2026 09 18. pii: 10949. [Epub ahead of print]17(1):
    Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia.
    Blanca Majem, Min-Sik Lee, Kyung Cheul Shin, Insia Naqvi, Courtney Dennis, Lucas Dailey, Sarah Jeanfavre, Mari Mino-Kenudson, Joao B Xavier, Clary B Clish, Deepti Mathur, Nada Y Kalaany.
      Cachexia or body wasting is a significant contributing factor to the morbidity and mortality of pancreatic cancer. Despite an unmet need, its metabolic underpinnings remain poorly understood. Here, we characterize a mouse model that recaptures the longitudinal progression of human cachexia during pancreatic cancer development. We profile the metabolomes of pre-, early- and late-stage cancer-associated cachexia in male and female pancreas, its interstitial fluid (IF), plasma, liver, adipose tissue and skeletal muscle. We find that each tissue has a unique metabolome and trajectory across stages and reveal a marked lipid enrichment in the tumor IF. Using mathematical modeling, we identify metabolites participating in cross-tissue networks and in vivo validate a lactate-glucose conversion. We find systemic metabolic changes prior to weight loss and use feature selection algorithms to identify early detection markers. Our study provides a resource for system-wide metabolic evolution of pancreatic cancer and associated cachexia, highlighting the potential for timely diagnostics and interventions.
    DOI:  https://doi.org/10.1038/s41467-026-77745-0
  9. Science. 2026 Oct 22. 394(6822): 382-383
    Putting glucose metabolism under electronic control.
    W E Bentley, G F Payne.
      An electronic device controls the redox mechanisms that regulate glucose concentrations in mice.
    DOI:  https://doi.org/10.1126/science.aem0762
  10. Cell Tissue Res. 2026 Oct 19. pii: 15. [Epub ahead of print]405(3):
    Constitutive UCP1 expression is associated with a glucose-dependent phenotype in murine mesenchymal stem cells.
    Ulises Edgardo De-Leon-Covarrubias, Jose Juan Perez-Trujillo, Maria de Jesus Loera-Arias, Aracely Garcia-Garcia, Odila Saucedo-Cardenas, Roberto Montes-de-Oca-Luna.
      Mesenchymal stem cells (MSCs) possess significant metabolic plasticity, enabling them to adapt dynamically to environmental stressors during tissue repair. Although UCP1 is associated with nonshivering thermogenesis in brown adipose tissue (BAT) through the uncoupling of oxidative phosphorylation, its impact on MSCs metabolism remains unexplored. Herein, we evaluated the ectopic expression of UCP1 in MSCs and its effects on classical surface markers, the redox state and glucose metabolism. MSCs were genetically modified to constitutively overexpress UCP1 using a lentiviral construct. Transduction efficiency was evaluated by direct UCP1 expression and the co-expressed EGFP fluorescent tag. Surface marker phenotype and proliferation were evaluated by expression of multipotency markers and metabolic activity, respectively. Metabolic phenotypes were assessed by measuring mitochondrial membrane potential (ΔΨm), quantifying cytoplasmic and mitochondrial reactive oxygen species (ROS), and evaluating glucose uptake via the 2-NBDG assay, while key glycolytic markers were evaluated by qPCR and immunoblot. UCP1-overexpressing MSCs showed a marked reduction in ΔΨm; however, normalized intracellular ATP levels remained stable across varying cell densities. Crucially, persistent UCP1 expression did not affect surface markers or cell metabolic activity, retaining their classical surface marker profile; furthermore, the engineered cells showed reduced baseline ROS levels compared with the parental line. Most notably, MSC-UCP1 cells showed increased glucose uptake and increased sensitivity to glucose deprivation, displaying increased expression of glycolytic markers. Our data indicate that constitutive UCP1 expression is associated with a shift in MSC metabolism towards a glucose-dependent state. This distinct metabolic profile highlights the plasticity of MSCs energetics and suggests a potential therapeutic application for genetically engineered MSCs in treating energy imbalance disorders such as obesity and type 2 diabetes.
    Keywords:  Glucose; Mesenchymal stem cells; Mitochondrial uncoupling; Obesity; UCP1
    DOI:  https://doi.org/10.1007/s00441-026-04100-6
  11. Cell. 2026 Oct 22. pii: S0092-8674(26)01205-5. [Epub ahead of print]
    MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.
    Shuke Xiao, Alan Sheng-Hwa Tung, Jan Spaas, Sipei Fu, Xudong Chen, Tuan Kiet Trinh, Maria Dolores Moya-Garzon, Veronica L Li, Hannah T Cessna, Kentaro Ito, Saranya C Reghupaty, Chao Lin, Xuchao Lyu, Steffen H Raun, Miles D W Tyner, Arthur Germakovski, Jacob Tondreau, Megan Yeckley, Wei Wei, Michael R Howitt, Mark D Parker, Jason A Sprowl, Stephen M Hinshaw, Jonathan Z Long.
      Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple local intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) as a model system, we identify the orphan transporter MCT6/SLC16A5 as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe in vitro, mediates Lac-Phe efflux in cells, and is required for maintaining normal circulating Lac-Phe levels in vivo, particularly following metformin treatment or high-intensity exercise. High-fat-diet-fed mice with global or intestinal epithelial-specific deletion of MCT6 exhibit resistance to metformin-associated weight loss. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-knockout (KO) mice. These data connect MCT6 to Lac-Phe and gut glycolytic flux and underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.
    Keywords:  Lac-Phe; MCT6; SLC16A5; circulating; lactate; metabolites; metformin; obesity; transporter; weight loss
    DOI:  https://doi.org/10.1016/j.cell.2026.09.058
  12. J Agric Food Chem. 2026 Sep 16. 74(36): 28558-28569
    Elucidation of the Hydroxylation Sequence in 1-DNJ Biosynthesis through Stable Isotope Tracing and Enzymatic Characterization.
    Jiahe Fan, Liyuan He, Yue Gao, Jingqiong Wan, Zhongyi Hua, Qishuang Li, Yuan Wei, Juan Guo, Zhen Ouyang.
      1-Deoxynojirimycin (DNJ) is the primary bioactive polyhydroxy alkaloid responsible for the antidiabetic properties of mulberry leaves. While the upstream biosynthesis is characterized, the downstream hydroxylation logic and transient intermediates remain elusive. Here, we combined stable isotope tracing with in vivo and in vitro enzymatic assays to delineate this hydroxylation sequence. Stable isotope feeding experiments identified piperidine as a key precursor and pinpointed C-7 as a critical secondary hydroxylation site. We demonstrated that (2R,4R)-2-methylpiperidine-4-ol (2) and (2S,4R)-2-(hydroxymethyl)piperidine-4-ol (4) are successive intermediates of the first two steps, occurring via sequential C-4 and C-7 hydroxylation. Furthermore, using mulberry leaf crude enzyme and recombinant C-5 hydroxylase, we deduced that 4 is subsequently converted to fagomine (FGM) via an endogenous C-3 hydroxylation activity, followed by C-5 modification to yield DNJ. Collectively, this study clarifies the sequential logic of the downstream hydroxylation (C-4→C-7→C-3→C-5), providing a foundational framework for the rational engineering and heterologous biosynthesis of DNJ.
    Keywords:  1-deoxynojirimycin; biosynthesis; hydroxylase; hydroxylation sequence; stable isotope tracing
    DOI:  https://doi.org/10.1021/acs.jafc.6c03778
  13. J Med Chem. 2026 Oct 22. 69(20): 23428-23448
    Development of Next-Generation ALDH1B1 Inhibitors with Enhanced Pharmacological and Functional Properties.
    A Kaan Tarhan, Zhiping Feng, Daniel Fernandez, Audrey Y Kim, Thomas E Bearrood, Andrew Hinman, Stefania Demuro, Adrianne M Kinsey, Nicholas R White, James K Chen.
      ALDH1B1 is a mitochondrial aldehyde dehydrogenase required for the survival of stem-like colorectal and pancreatic cancer cells. Isoform-selective guanidinyl antagonists of aldehyde dehydrogenases (IGUANAs) have been developed for ALDH1B1, and here we describe structure-activity relationship (SAR) studies of three scaffold components: the bicyclic guanidine core, a substituted aryl ring that engages the catalytic site, and a biaryl group that interacts with flanking residues. We further show that previously reported IGUANAs are metabolically labile and rapidly effluxed from intestinal epithelial cells. To address these limitations, we have explored bioisosteres of the biaryl moiety and modifications of the guanidine core. These investigations have yielded the aryl-alkyl ether derivative IGUANA-5, a potent ALDH1B1 inhibitor that selectively blocks the growth of colon and pancreatic cancer spheroids and exhibits enhanced in vitro and in vivo pharmacological properties. Our findings establish a new class of ALDH1B1 inhibitors that could inform the advancement of anti-cancer therapies.
    Keywords:  ALDH1B1; IGUANAs; aldehyde; biaryl; cancer stem cells; colorectal cancer; guanidine; pancreatic cancer
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c03612
  14. PLoS One. 2026 ;21(10): e0352911
    Structure bioinformatics of eight human ATP synthase F0 subunits and their AlphaFold3-predicted reduced-hydrophobicity QTY analogues.
    Ziyu Wang, Edward Chen, Shuguang Zhang.
      Human mitochondrial ATP synthase is an essential rotary motor enzyme that produces most of the cellular ATP through oxidative phosphorylation. Its membrane-embedded F0 sector contains highly hydrophobic transmembrane subunits that are challenging to study in aqueous environments without detergents. We applied the QTY code to eight human ATP synthase F0 subunits: ATP6, ATP8, ATPK, ATP68, ATPMK, AT5G1, AT5G2, and AT5G3. Hydrophobic amino acids leucine (L), isoleucine (I), valine (V), and phenylalanine (F) in transmembrane regions were systematically replaced with hydrophilic glutamine (Q), threonine (T), and tyrosine (Y). Four native subunits with available CryoEM structures from human ATP synthase (PDB: 8H9S) were superposed with their AlphaFold3-predicted QTY analogues. For subunits without complete CryoEM structures, AlphaFold3-predicted native structures were superposed with their AlphaFold3-predicted QTY analogues. Additional structural analyses were included, and key structural and functional regions, including ATP68 and the ATP6-c-ring interface, were modeled. The native ATP synthase F0 subunits superposed well with their respective QTY analogues. For the CryoEM-native comparisons, RMSD values ranged from 0.565 Å to 6.952 Å. For the AlphaFold3-native comparisons of subunits without CryoEM structures, RMSD values ranged from 0.204Å to 0.297Å. Considering all eight subunits, despite substantial QTY substitutions in the transmembrane regions, ranging from 38.89% to 50.79%, the QTY analogues retained similar overall folds, molecular weights, and isoelectric points. Hydrophobic surface analysis showed that the QTY analogues had reduced hydrophobic surfaces compared with their native counterparts. These structural bioinformatics studies suggest that the QTY code is applicable to ATP synthase F0 subunits to generate more hydrophilic, water-soluble analogues while preserving overall structural similarity. These results extend the application of the QTY code to the membrane-embedded F0 sector of ATP synthase and provide a foundation for future experimental studies for these QTY analogues expressed, purified, and evaluated for self-assembly.
    DOI:  https://doi.org/10.1371/journal.pone.0352911
  15. FASEB J. 2026 Oct 31. pii: e72407. [Epub ahead of print]40(20):
    HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
    Ko Suzuki, Jun-Ichiro Takahashi, Kiriko Kaneko, Kazumichi Furuyama.
      Intracellular energy metabolism is strictly regulated by hormones and intracellular metabolites for the appropriate use of energy resources such as carbohydrates and fatty acids. Mitochondria are essential organelles in eukaryotic cells since they contain several metabolic machineries required for oxidative phosphorylation, such as the tricarboxylic cycle, electron transport chain, and fatty acid β-oxidation (FAO). Previously, we reported that FAO activity is increased in CLPX-knockout HepG2 cells (CLPX-KO cells). CLPX is the substrate recognition subunit of the mitochondrial protease ClpXP that regulates intracellular heme levels through the degradation of ALAS1 in the mitochondrial matrix. ALAS1 is the rate-limiting enzyme for heme biosynthesis; thus, we examined whether heme regulates FAO activity. We found that the inhibition of heme synthesis in CLPX-KO cells decreased FAO activity; in contrast, hemin treatment increased FAO activity in wild-type HepG2 cells (CLPX-WT cells). Furthermore, pretreatment of CLPX-WT cells with a chemical inhibitor or specific siRNA targeting the heme degradation enzyme HMOX1 blocked FAO activation induced by hemin, indicating that heme catabolites rather than heme itself are responsible for FAO activation by heme. Among the heme catabolites, we identified carbon monoxide (CO) as an essential metabolite for FAO activation through the activation of the LKB1/AMPK signaling pathway. In this manuscript, we revealed the previously unknown role of CO as an intrinsic inducer of mitochondrial FAO activity and revealed that an excess amount of heme increases FAO activity via CO production by HMOX1.
    Keywords:  AMP‐activated kinase; carbon monoxide; fatty acid oxidation; heme; heme oxygenase; mitochondria
    DOI:  https://doi.org/10.1096/fj.202603280R
  16. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613776123
    Validation of targets linked to weight gain in C57BL/6 mice and translational aspects in humans.
    Yingga Wu, Agata M Rudolf, Lu Wang, Zhengjie Zhang, Chaoqun Niu, Fan Xia, Min Li, Anyongqi Wang, Sharon E Mitchell, Haoran Zhang, Yalin He, Chunyu Chen, John R Speakman.
      Obesity is linked to complex interactions between an organism's genetic background and its environment. Mouse models have been invaluable research tools to study obesity, with C57BL/6N being widely studied, given its propensity for weight gain on a high-fat diet (HFD). Despite this, the genetic basis of its susceptibility is poorly understood. In a partner paper we have identified SNP variants in 11 genes causing susceptibility to, or protection against, HFD-induced obesity in male C57BL/6N mice explaining 87% of the individual variation in fat gain. Surprisingly, most of them were maximally expressed outside the brain. In this study, we further validate some of these targets. We demonstrate that tissue-specific inhibition of Nova1 and Mchr1 in muscle, Nr1i3 in liver, and Ahr in lung and liver led to resistance to HFD-induced obesity or glucose intolerance. Further RNAseq analysis revealed that mTOR, Acox1, IL-15, and eIF2a signals are positioned downstream of these genes, potentially mediating their effects on obesity susceptibility. Importantly, variants in eight of the genes identified here have been previously implicated in human obesity, suggesting that a deeper understanding of the genetic/environment interactions of model systems can inform this complex human disease. Our work confirms that body fat regulation is likely more complex than current models which focus on the brain-adipose axis suggest.
    Keywords:  energy balance; food intake; genetics; mouse; obesity
    DOI:  https://doi.org/10.1073/pnas.2613776123
  17. Pharmacol Res. 2026 Oct 19. pii: S1043-6618(26)01611-7. [Epub ahead of print]233 109696
    Should mitochondrial membrane potential be reconsidered as a criterion of cell death?
    Petr Mlejnek.
      
    Keywords:  Cell death; Cell death criteria; Cell viability; Flow cytometry; Mitochondrial membrane potential; Plasma membrane permeabilization
    DOI:  https://doi.org/10.1016/j.phrs.2026.109696
  18. Cell Metab. 2026 Oct 22. pii: S1550-4131(26)00385-2. [Epub ahead of print]
    On the interpretation of diet-specific metabolic effects following weight loss.
    Faidon Magkos.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.09.010
  19. FASEB J. 2026 Oct 31. 40(20): e72385
    Structural Snapshots of F1-ATPase Catalysis in Drug Resistant Acinetobacter baumannii Reveal Novel Therapeutic Targets.
    Khoa C M Le, Jan K Marzinek, Vikneswaran Mathiyazakan, Peter J Bond, Gerhard Grüber.
      Gram-negative Acinetobacter baumannii, one of the most critical priority pathogens, has developed multiple defense mechanisms, including upregulation of drug efflux pumps powered by the proton-motive force (pmf) or ATP. As a nonfermenting bacterium, it relies on oxidative phosphorylation, in which the F-ATP synthase, composed of an F1-ATPase (α3:β3:γ:ε) and FO-domain (a:b2:c10), synthesizes ATP, the cell's currency of life. Here, we present cryo-electron microscopy structures of the F1-ATPase captured during ATP synthesis, revealing concerted conformational changes within the α3:β3-catalytic head that trigger structural transitions of subunit ε and twisting of the γ:ε central stalk, coupled with spontaneous ATP formation. Molecular dynamics simulations validate and expand the ensemble of structural rearrangements underlying the rotary mechanism. The resolved intermediate states of the ε subunit reveal its role as a molecular gear, regulating ATP synthesis while simultaneously inhibiting ATP hydrolysis, essential for the pathogen to prevent wastage of ATP. These structural snapshots identify novel therapeutic targets and pave the way for rational design of selective inhibitors.
    Keywords:   Acinetobacter baumannii ; ATP synthase; antibiotics; bacterial pathogenesis; bioenergetics; membrane protein
    DOI:  https://doi.org/10.1096/fj.202602735R
  20. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2610816123
    mechanoLight: A genetically encoded fluorescent biosensor for visualizing 5-HT2AR mechanotransduction in live cells.
    In-Yeop Baek, Hyunbin Kim, Duwan Kwon, Hahnbeom Park, Jihye Seong.
      G protein-coupled receptors (GPCRs) are pivotal sensors of the mechanical environment, yet how they sense and transduce physical stimuli into biochemical signals within live cells remains largely elusive. Here we introduce mechanoLight, a genetically encoded red fluorescent biosensor designed to report the mechanical activation of the 5-hydroxytryptamine 2A receptor (5-HT2AR). By incorporating a circularly permuted mApple (cp-mApple) into the third intracellular loop of 5-HT2AR with the optimized linker (m-linker), mechanoLight selectively detects conformational changes of 5-HT2AR in response to fluid shear stress while exhibiting minimal sensitivity to 5-HT. In sharp contrast, psychLight2, the previously developed green 5-HT2AR biosensor, primarily detects ligand-induced 5-HT2AR activation, suggesting that mechanoLight and psychLight2 capture distinct conformational modes of 5-HT2AR activation. Integrated analysis of linker-swapping experiments, structural modeling, and molecular dynamics simulations revealed that the flexibility of the m-linker underlies the mechanosensitivity of mechanoLight. We further extend this strategy to other mechanosensitive GPCRs, enabling visualization of their mechanoreactivity in live cells. The mechanoLight signal reflects the mechanosensitivity of 5-HT2AR, as shear stress-induced 5-HT2AR activation triggers Gαq-dependent signaling pathways, including phospholipase C (PLC) activation, intracellular Ca2+ mobilization, and ERK phosphorylation. Mutational analysis further identifies N-terminal glycosylation and helix 8 as structural determinants of 5-HT2AR mechanotransduction. Together, our findings establish 5-HT2AR as a mechanotransducer and introduce mechanoLight as a powerful tool for deciphering the molecular principles of GPCR mechanotransduction in live cells.
    Keywords:  5-HT2AR; G protein–coupled receptor; circular permutation; genetically encoded fluorescent biosensor; mechanobiology
    DOI:  https://doi.org/10.1073/pnas.2610816123
  21. Adv Sci (Weinh). 2026 Oct 18. e77242
    A Micropeptide Component of the OGDH Complex Modulates ATP Production in the TCA Cycle.
    Xinqiang Yin, Weiyan Qi, Lifen Lin, Huilin Zheng, Guoxiang Zhao, Quan Chen, Guoqiang Shao, Yifan Wu, Jialiang Hu, Hanmei Xu.
      Since its elucidation, the tricarboxylic acid (TCA) cycle has been regarded as a fully defined enzymatic pathway. Here, we report the discovery of a previously unrecognized micropeptide component of this central metabolic system. Through analyzing ribosome profiling data from the mouse sORFs.org database, we discovered APPM (ATP production-promoting micropeptide), a 29-amino acid peptide encoded by a non-canonical small open reading frame within the mouse Ctsb gene. APPM localizes to the mitochondrial matrix and inner membrane, where it directly binds to the E1 subunit (OGDH) of the α-ketoglutarate dehydrogenase complex (OGDHc). This interaction modulates OGDHc enzymatic activity, thereby regulating NADH and ATP production. We identified tyrosine-13 as the critical residue mediating the APPM-OGDH interaction and functional activation. Exogenous APPM administration increased ATP levels in vivo and, in a mouse model of heart failure, restored cardiac function, outperforming the reference drug trimetazidine. Collectively, our findings identify APPM as the first micropeptide regulator of the OGDH complex, expanding the known repertoire of the TCA cycle and presenting a potential therapeutic strategy for diseases characterized by bioenergetic insufficiency.
    Keywords:  APPM; ATP synthesis; OGDHc; TCA cycle; mitochondrial function
    DOI:  https://doi.org/10.1002/advs.77242
  22. Nat Chem Biol. 2026 Oct 22.
    Putting the Warburg effect in reverse.
    Valentin Cracan.
      
    DOI:  https://doi.org/10.1038/s41589-026-02343-6
  23. Leukemia. 2026 Oct 23.
    Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
    Ilias Sinanidis, Panagiotis Tsakiroglou, Benjamin Dubner, Rebecca Foertsch, Julia Gondek, InYoung Choi, Bogdan Paun, Teodora Supeanu, Liang Zhao, Gabriel Ghiaur, W Brian Dalton.
      Serine metabolism is of growing biologic and therapeutic interest in cancer. Upregulation of the serine synthesis pathway (SSP) can fuel tumor growth, and cancers with this phenotype are often sensitive to. SSP inhibitors. In parallel, dietary restriction of serine and glycine (SG) can suppress some cancers, but the determinants of sensitivity to. this approach are poorly understood. This is especially true in acute myeloid leukemia (AML), where serine metabolism has been less explored. We report that a subset of human AML cell lines and primary samples are completely dependent on external serine, known as serine auxotrophy. These leukemias consistently suppressed the SSP enzyme PSAT1, failed to. synthesize serine, responded to. SG restriction in vivo, and were rescued by restoring PSAT1. We also found that SG restriction synergized with venetoclax in serine auxotrophic AML, and that MECOM rearrangement was strongly associated with PSAT1 suppression and serine auxotrophy. These findings define a metabolically distinct AML subtype and nominate it for targeting by SG restriction.
    DOI:  https://doi.org/10.1038/s41375-026-03176-x
  24. Science. 2026 Oct 22. 394(6822): 383-384
    A cell death ballet in two acts.
    Cristina Muñoz-Pinedo, Seamus J Martin.
      Two proteins that permeabilize mitochondria promote cell death through distinct mechanisms.
    DOI:  https://doi.org/10.1126/science.aem1247
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