bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–10–04
twenty papers selected by
Brett Chrest, Wake Forest University
  1. Acanthamoeba ATP synthase structure reveals the TCA cycle is tethered to OXPHOS.
  2. Hypoxia? NNoT a PROblem!
  3. Ketone-targeting Approaches in Glioma.
  4. Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition.
  5. Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
  6. Loss of TCA cycle turning promotes stem cell function.
  7. ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesis and fatty acid oxidation in colorectal cancer.
  8. β-Hydroxybutyrate Maintains Energetically Demanding Neural Functions During Exogenous Glucose Deprivation.
  9. Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
  10. A genetically encoded redox bottleneck constrains human developmental rate.
  11. Targeting ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia.
  12. GTP biosynthesis is a therapeutic vulnerability in Rac1-mutant melanoma.
  13. α-KG conformationally stabilizes nuclear GLUD1-SNAIL complex to fuel trans-endothelial migration in metastasis.
  14. Depletion of the isocitrate dehydrogenase 3 subunit IDHA-1 licenses germ cell-to-neuron direct reprogramming.
  15. SurpHer: A genetically encoded ratiometric biosensor for dynamic extracellular pH imaging.
  16. Quality over Quantity: Dietary Fatty Acid Composition Shapes Pancreatic Tumorigenesis.
  17. A mitochondrial carrier turns on the heat.
  18. Structural insights into DHODH-mediated catalysis and drug resistance.
  19. Alpha-Ketoglutarate Dehydrogenase and Citric Acid Cycle Flexibility in Heart Disease and Failure.
  20. Glucosylceramide synthase is required for C6-ceramide nanoliposome-induced organelle stress and cell death.
  1. Cell. 2026 Oct 01. pii: S0092-8674(26)01068-8. [Epub ahead of print]189(20): 6307-6324.e7
    Acanthamoeba ATP synthase structure reveals the TCA cycle is tethered to OXPHOS.
    MitoCarta Tree of Life Consortium
      Oxidative phosphorylation (OXPHOS) is a key metabolic process that couples redox energy to ATP production. While some core OXPHOS complex subunits are found across all domains of life, many have diverged or expanded across evolution-as seen in the protozoan pathogen Acanthamoeba castellanii. By integrating cryo-electron microscopy of unenriched mitochondrial lysate with mass spectrometry proteomics, we resolved the structures of endogenous mitochondrial ATP synthase (complex V), Hsp60, and respiratory complex III from Acanthamoeba. We capture Acanthamoeba ATP synthase in an IF1-inhibited state and reveal how Acanthamoeba-specific subunits and extensions stabilize the molecular machine, which includes a β subunit extension that interfaces with the peripheral stalk. Additionally, we characterize an active malate dehydrogenase (MDH) dimer structurally integrated within the ATP synthase peripheral stalk, thus revealing a direct protein tether between OXPHOS and the tricarboxylic acid cycle. Together, these findings provide structural insight into lineage-specific adaptations in Acanthamoeba that may tune protozoan metabolism.
    Keywords:  ATP synthase; Acanthamoeba; complex V; cryo-EM; crystallography; malate dehydrogenase; mitochondria; oxidative phosphorylation; respiratory complexes; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.cell.2026.08.057
  2. Mol Cell. 2026 Oct 01. pii: S1097-2765(26)00627-1. [Epub ahead of print]86(19): 3862-3863
    Hypoxia? NNoT a PROblem!
    Ningning Liang, Costas A Lyssiotis, Daniel R Wahl.
      Glioma cells experience profound metabolic stress in hypoxic tumor regions, where mitochondrial respiration is constrained and redox balance becomes difficult to maintain. A recent study by Vettore and colleagues1 in Molecular Cell identifies nicotinamide nucleotide transhydrogenase as a key mitochondrial enzyme that connects NADH oxidation to NADPH production, thereby supporting proline synthesis and growth under hypoxia. This work highlights how distinct redox pools are coordinated in cancer cells and suggests that NNT-dependent metabolism may represent a vulnerability in hypoxic tumors.
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.007
  3. Hematol Oncol Clin North Am. 2026 Sep 29. pii: S0889-8588(26)00110-3. [Epub ahead of print]
    Ketone-targeting Approaches in Glioma.
    Maria Ioannou, Karisa C Schreck.
      Metabolic dysregulation in gliomas creates a therapeutic vulnerability for interventions such as ketogenic metabolic therapies (KMTs). KMTs can take many forms, including fasting, ketogenic diet therapy, exogenous ketone supplementation, or a combination. Preclinical evidence suggests that these approaches can impair tumor growth, normalize the tumor microenvironment, and enhance sensitivity to cancer-directed therapies. Clinical studies highlight not only the safety of KMTs but also the challenges related to tolerability and biological effect. Here, we summarize preclinical and clinical data on ketone-targeting approaches in gliomas, as well as future directions toward improved implementation.
    Keywords:  Beta-hydroxybuterate; Fasting; Glioma; Ketone diet; Ketone supplement
    DOI:  https://doi.org/10.1016/j.hoc.2026.08.009
  4. Cancer Res. 2026 Sep 28.
    Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition.
    Thi Thinh Nguyen, Jane Ding, Mohit Bansal, Sunil Sudarshan, Han-Fei Ding.
      The mevalonate pathway generates sterols and isoprenoids essential for membrane biosynthesis and signaling. Increased activity of the mevalonate pathway is a common feature of cancer and has emerged as a potential therapeutic vulnerability. Here, we showed that the mevalonate pathway sustains de novo serine biosynthesis and aspartate production by maintaining NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impaired oxidative phosphorylation, lowered the NAD⁺/NADH ratio, suppressed serine and aspartate biosynthesis, and activated the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limited purine and pyrimidine biosynthesis. Genetic and pharmacological disruption of ubiquinone synthesis recapitulated the metabolic defects, whereas expression of the bacterial NADH oxidase LbNOX restored the NAD⁺/NADH ratio and reversed the metabolic and growth defects induced by statin treatment. Importantly, impairment of NAD⁺ regeneration reduced PHGDH-dependent de novo serine synthesis, thereby sensitizing neuroblastoma cells to PHGDH inhibition. Accordingly, simvastatin enhanced the anti-proliferative effects of the PHGDH inhibitor NCT-503 in vitro and exhibited elevated anti-tumor activity in combination with NCT-503 in neuroblastoma xenograft models. Together, these findings establish ubiquinone-dependent NAD⁺ regeneration as a key mechanism linking the mevalonate pathway to amino acid and nucleotide biosynthesis and provide a mechanistic rationale for combined targeting of the mevalonate pathway and serine biosynthesis in cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1063
  5. Science. 2026 Oct;394(6819): eadz4797
    Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
    Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Adam Chatoff, Andrea Andress Huacachino, Hannah J Richter, Meghna Birla, Sabina Chubanava, Yann Deleye, Rini Arianti, David Tandio, Sarah E Utzon, Zafir Kaiser, Yachen Shen, Ditte Neess, Hannes Embring, Dilip Menon, Olivia J Conway, Frederike Sass, Fabian Finger, Lidia Argemi-Muntadas, Tao Ma, Elahu G Sustarsic, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucińska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew P Gillum, Terry D Hinds, Raymond E Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Endre Kristóf, Susanne Mandrup, Brice Emanuelli, Nathaniel W Snyder, Daniel J Fazakerley, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.
      Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator-activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl-coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.
    DOI:  https://doi.org/10.1126/science.adz4797
  6. bioRxiv. 2026 Sep 22. pii: 2026.09.21.753355. [Epub ahead of print]
    Loss of TCA cycle turning promotes stem cell function.
    Yafeng Li, Joseph Rose, Edward O Kwarteng, Xiaotong Yang, Jacob Zielke, Li Li, Zhiyu Zhao, Ji Hyung Jun, Michalis Agathocleous.
      The citric acid cycle (TCA cycle) is the common terminal pathway for the oxidation of all nutrients. Citrate oxidation to oxaloacetate produces CO 2 , and citrate synthase (CS) uses nutrient-derived acetyl groups to regenerate citrate and fuel cycle turning. However, the essentiality of cycle fueling and turning in vivo remains unclear. Here, we use hematopoiesis, the most proliferative system in the body, as a model to show that, contrary to common assumptions, TCA cycle turning is dispensable for respiration, survival, and proliferation of stem and progenitor cells in vivo and its loss promotes stem cell function. Hematopoietic-specific Cs deletion in adult mice blocked citrate cycling without reducing the frequency of hematopoietic stem (HSC) and progenitor cells. HSCs and progenitor cells adapted to TCA cycle loss by markedly increasing nutrient consumption and biosynthesis. Disruption of cycle turning increased HSC regeneration, myeloid progenitor proliferation, and myelopoiesis in vivo. HSCs without a turning TCA cycle outcompeted wild-type HSCs within the same environment. The effect of CS deletion on HSC function was not phenocopied by genetic ablation of cytosolic citrate use and was rescued by ablation of glutamine use in biosynthesis. Therefore, TCA cycle turning restrains nutrient uptake, biosynthesis, cell proliferation, and stem cell function. These results suggest an explanation for the reduction in cycle activity observed in many normal proliferating cells and cancer cells.
    DOI:  https://doi.org/10.64898/2026.09.21.753355
  7. bioRxiv. 2026 Sep 25. pii: 2026.09.24.753323. [Epub ahead of print]
    ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesis and fatty acid oxidation in colorectal cancer.
    Zhiping Feng, Thomas E Bearrood, Sydney L Campbell, Adrianne M Kinsey, Nedas Matulionis, Che-Hong Chen, Takuya Seike, Logan Leak, A Kaan Tarhan, Scott J Dixon, Daria Mochly-Rosen, Heather R Christofk, James K Chen.
      Metabolic reprogramming is a hallmark of cancer cells, and stem-like populations often upregulate aldehyde dehydrogenases (ALDHs). Functional studies have established essential roles for individual ALDH isoforms in tumor initiation, progression, and metastasis; however, the mechanisms by which these enzymes promote malignancy remain poorly understood. Here we show that aldehyde dehydrogenase 1B1 (ALDH1B1), a mitochondrial enzyme highly expressed in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), generates γ-butyrobetaine (GBB) and γ-aminobutyric acid (GABA) in CRC cells. The biosynthesis of both aminocarboxylic acids has been attributed to the cytosolic enzyme ALDH9A1, and we demonstrate that mitochondrial GBB and GABA are functionally distinct from the cytosolic pools of these metabolites. We further demonstrate that mitochondrial GBB can function as an antiport substrate of carnitine-acylcarnitine translocase (CACT), the transporter that mediates fatty acid uptake into the mitochondrial inner matrix. This activity complements the role of cytosolic GBB as the biosynthetic precursor to carnitine. Accordingly, ALDH1B1 can markedly enhance mitochondrial fatty acid oxidation (FAO), a catabolic process that has been linked to CRC and PDAC stemness, progression, and metastasis. Our findings reveal an unexpected role for ALDH1B1 in carnitine metabolism, GABA biosynthesis, and FAO and illustrate how the compartmental reprogramming of metabolic pathways can promote tumor growth.
    DOI:  https://doi.org/10.64898/2026.09.24.753323
  8. Cell Mol Neurobiol. 2026 Oct 02. pii: 147. [Epub ahead of print]46(1):
    β-Hydroxybutyrate Maintains Energetically Demanding Neural Functions During Exogenous Glucose Deprivation.
    Rachel L Ricks, Dallin S Nevers, Tyler Poulos, T Luke Shafer, Clayton Dunford, Jason M Hansen, Paul R Reynolds, Benjamin T Bikman, R Ryley Parrish.
      Ketone bodies are a major source of cerebral energy during fasting and the ketogenic diet, but whether they can sustain brain tissue metabolism when glucose is absent remains uncertain. This question is difficult to resolve in vivo because circulating glucose is maintained, even during starvation, through endogenous production. We therefore used an ex vivo brain preparation to examine the metabolic capacity of tissue following incubation with β-hydroxybutyrate (BHB) as the only exogenous fuel, isolating brain tissue from its primary endogenous glucose sources. Mitochondrial respiration was monitored following 4-hour incubation in glucose-free, BHB-rich artificial cerebrospinal fluid, and tissue resilience was tested by inducing spreading depolarization, a severe energetic challenge that requires rapid restoration of ionic and metabolic homeostasis. Following acute reliance on exogenous BHB, in addition to endogenous energy reserves, mitochondrial electron transfer system function persisted, with lower O2 flux than following incubation with exogenous glucose. BHB-supported tissue maintained sufficient energetic capacity to generate and recover from repeated spreading depolarizations. In contrast, tissue relying solely on endogenous energy reserves failed to undergo repeated spreading depolarizations, suggesting that exogenous BHB provided the needed short-term energetic support beyond that available from endogenous substrates in the complete absence of exogenous glucose. The results broaden our understanding of cerebral fuel flexibility and provide evidence that BHB can support highly energetic neural function in the absence of exogenous glucose.
    Keywords:  Brain metabolism; Energetics; Ketones; Spreading depolarization; Spreading depression
    DOI:  https://doi.org/10.1007/s10571-026-01834-3
  9. Sci Adv. 2026 Oct 02. 12(40): eaei2831
    Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
    Nancy T Santiappillai, Andrew Cho, Georg Verch, Ana C Codo, Achuth Nair, Ya-Ting Wang, Allie Lipshutz, Celia Martínez de la Torre, Eric Minwei Liu, Marjan Berishaj, Alissa J Trzeciak, Zhaoquan Wang, Michelle Saoi, Waleska Saitz Rojas, Justin R Cross, Ed Reznik, Justin S A Perry, Kayvan R Keshari.
      Triple-negative breast cancer (TNBC) develops in hypoxic, nutrient-limited tumors enriched with macrophages and cell death. We show that metabolically distinct TNBCs differentially exploit macrophage-derived nutrients, influencing tumor growth and therapeutic response. Prolonged hypoxia reprogrammed mouse and human macrophages, enabling them to release metabolites that rescued the growth of select TNBC cell lines during glutamine deprivation or glutamine metabolism inhibition. Hypoxic macrophages reduced glutamine consumption, increased arginine utilization, and secreted higher levels of ornithine, an intermediate of arginine metabolism. Exogenous ornithine, but not arginine, restored the growth of responsive TNBC cells. Mechanistically, TNBC cells diverted ornithine into proline biosynthesis, supporting oxidative pentose phosphate pathway activity. In vivo, depletion of tumor-associated myeloid cells reduced tumor growth and impaired proline synthesis in glutaminase inhibitor-resistant TNBC. These findings identify hypoxia-driven metabolic cross-talk between macrophages and TNBC cells, revealing ornithine-dependent proline metabolism as a mechanism by which macrophages sustain tumor growth under nutrient stress and contribute to resistance to glutamine-targeted therapies.
    DOI:  https://doi.org/10.1126/sciadv.aei2831
  10. bioRxiv. 2026 Sep 13. pii: 2026.09.10.750701. [Epub ahead of print]
    A genetically encoded redox bottleneck constrains human developmental rate.
    Gabriel E Valdebenito, Jack P Madden, Carolina Mendez, Leslie M Azurdia, Xintao Zhu, Siyu Chen, Diana Atlas, Katherine Introcaso, Hao Zhang, Yahui Wang, Fangcong Dong, Rohit Sharma, Vamsi K Mootha, Gary J Patti, Margarete Diaz-Cuadros.
      The intrinsically slow pace of human development poses challenges for regenerative medicine and disease modeling. This trait is attributed to low metabolic rates, yet the endogenous mechanisms determining species-specific metabolic flux remain unknown. Here, we identify coupling between glycolytic NADH production and mitochondrial oxidation through the glycerol-3-phosphate (G3P) shuttle as a genetic bottleneck constraining human developmental tempo. Using stem cell-derived models of the segmentation clock, an oscillator whose period reflects developmental rate, we show that low expression of the G3P shuttle enzyme GPD1L limits NADH oxidation in human progenitors compared to mouse. Overexpressing GPD1L boosts metabolic flux, accelerating the segmentation clock, cell cycle, and differentiation across germ layers. G3P-mediated redox coupling is thus a genetically encoded, rate-limiting mechanism that sets the tempo of human development.
    DOI:  https://doi.org/10.64898/2026.09.10.750701
  11. Cancer Res. 2026 Sep 28.
    Targeting ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia.
    Xinrong Xiang, Baozhu Luo, Lei Zhao, Jing Sui, Yi Wu, Jiasheng Huang, Song Liu, Hexian Li, Fangfang Wang, Mengran Chen, Ying Qu, Aiping Tong, Chong Chen, Yu Wu, Youfu Luo.
      Acute myeloid leukemia (AML) critically depends on oxidative phosphorylation (OXPHOS). Mitochondrial targeted therapies are advancing into clinical trials, but metabolic vulnerabilities have been primarily explored from a tumor-intrinsic perspective. Leukemic cells can actively reshape an immunosuppressive tumor microenvironment through metabolic competition, highlighting the importance of evaluating the impact of mitochondrial targeted therapies on antitumor immunity. Here, we showed that elevated expression of the mitochondrial caseinolytic protease P (ClpP) is associated with advanced AML. Development of IMP125, a potent ClpP agonist, enabled dual targeting of AML to elicit robust anti-leukemic activity. In addition to direct cytotoxicity, IMP125 induced immunometabolic reprogramming of AML models. Owing to differential ClpP expression, IMP125 preferentially suppressed mitochondrial respiration and oxygen consumption in AML cells while exerting minimal direct effects on T-cell respiration. By reducing AML oxygen consumption and metabolic demand, IMP125 alleviated hypoxia and metabolic competition within the leukemic niche. In this remodeled microenvironment, T cells exhibited recovery of OXPHOS, effector function, and memory-associated features, consistent with an indirect mechanism mediated through metabolic suppression in AML cells. The anti-leukemic efficacy of IMP125 was dependent on T cells and was synergistically enhanced by PD-1 blockade. Collectively, this work reframes ClpP agonism from a tumor-intrinsic therapy to a strategy that actively induces metabolic-immune rewiring, bridging ClpP-targeted and immunotherapeutic approaches for mitochondrial-dependent AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0477
  12. bioRxiv. 2026 Sep 24. pii: 2026.09.23.753957. [Epub ahead of print]
    GTP biosynthesis is a therapeutic vulnerability in Rac1-mutant melanoma.
    Samson Eugin Simon, Tiannan Wang, Arsha Sreekumar, Zaria Yearby, Isha Patel, Varsha Tandra, Catherine C Hedrick, Jie Li, David W Wolff.
      Metastatic melanoma remains highly lethal despite advances in immunotherapy and MAPK-targeted therapy. The Rac1 P29S mutation, present in 4-9% of cutaneous melanomas, confers intrinsic resistance to BRAF and MEK inhibitors. Like other small GTPases, Rac1 lacks suitable pockets for small molecule inhibitor binding, motivating indirect approaches to suppressing its activity. We have previously shown that wild-type Rac1 is sensitive to inhibition of de novo GTP biosynthesis in cancer cells, particularly suppression of the rate-limiting inosine monophosphate dehydrogenase (IMPDH) enzymes. Therefore, we asked whether IMPDH inhibition could suppress Rac1 P29S and its associated phenotypes in melanoma. We found that IMPDH inhibition reduced Rac1 activity, impaired Rac1-dependent phenotypes, and induced S-phase arrest in Rac1 P29S -harboring cells. Moreover, IMPDH inhibition synergized with the BRAF inhibitor vemurafenib and the MEK inhibitor trametinib in Rac1 P29S melanoma cells. Dual BRAF and IMPDH inhibition also resulted in enhanced suppression of MEK and ERK phosphorylation in vitro. In syngeneic mouse models, the FDA-approved IMPDH inhibitor mycophenolate mofetil sensitized Rac1 P29S -expressing melanoma tumors to trametinib, including tumors made refractory by prior trametinib exposure. We further identified a feed-forward circuit in which Rac1 sustains IMPDH2 expression levels through JNK and c-Jun/AP1 signaling, potentially coupling the GTPase to its own nucleotide supply. These findings establish GTP biosynthesis as a targetable vulnerability in Rac1 P29S melanoma and support IMPDH inhibition as a rational partner for MAPK-targeted therapy.
    DOI:  https://doi.org/10.64898/2026.09.23.753957
  13. Nat Commun. 2026 08 31. pii: 10377. [Epub ahead of print]17(1):
    α-KG conformationally stabilizes nuclear GLUD1-SNAIL complex to fuel trans-endothelial migration in metastasis.
    Jiawen Cui, Nuo Xu, Rongyu Cao, Ruqi Zhang, Ying Yu, Luyao Ao, Feiyi Wang, Qixing Gong, Le Zhen, Yantong Li, Qingqing Zhou, Yue Dang, Guangji Wang, Fang Zhou, Jiali Liu.
      Trans-endothelial migration (TEM) is a critical rate-limiting barrier in tumor metastasis, yet its mechanistic basis remains poorly defined. Here we show that α-ketoglutarate (α-KG) and its metabolic enzyme glutamate dehydrogenase 1 (GLUD1) constitute a pivotal regulatory axis governing this process. Mechanistically, GLUD1 translocates to the nucleus, where α-KG binds to its non-catalytic site (K147) to induce a conformational change that stabilizes the GLUD1-SNAIL interaction, promoting assembly of a nuclear ternary complex. Notably, this complex is preferentially enriched in tumors, and specific blockade of K147 disrupts this assembly and abrogates metastatic effects. Our findings reveal a non-canonical role for GLUD1 and α-KG in transcriptional regulation and propose a therapeutic paradigm that selectively interferes with metabolite-dependent complex formation rather than enzymatic activity, offering a precise strategy to target TEM-driven metastatic cells.
    DOI:  https://doi.org/10.1038/s41467-026-77149-0
  14. bioRxiv. 2026 Sep 23. pii: 2026.09.22.753437. [Epub ahead of print]
    Depletion of the isocitrate dehydrogenase 3 subunit IDHA-1 licenses germ cell-to-neuron direct reprogramming.
    Nida Ul Fatima, Anna Reid, Amin Shadfar, Alexander Blume, Tobias Opialla, Stefan Kempa, Baris Tursun.
      Direct reprogramming (DR) converts one differentiated cell identity into another and is a promising strategy for regenerative approaches when cells are lost because of injury or disease. Transcription factors (TFs) that specify a given cell type can drive DR, but inhibitory mechanisms restrict this conversion in most cell types. To identify such barriers in vivo , we use Caenorhabditis elegans and the zinc finger TF CHE-1, which is required to specify the glutamatergic taste neuron fate of ASE neurons. Ectopic CHE-1 expression can induce DR of different cell types to ASE neurons upon RNAi-mediated depletion of barrier genes. Here we characterize the α subunit of the mitochondrial isocitrate dehydrogenase 3 complex (IDH3), IDHA-1, as a barrier to DR of germ cells into neurons. RNAi against idha-1 produced consistent ASE fate reporter expression, accompanied by morphological changes to neuron-like structures in the germline upon ectopic CHE-1 expression. Using different neuronal gene expression reporters, single-molecule FISH, and antibody staining, we confirm that this germ cell conversion (GeCo) produces neuron-like cells. We found that loss of IDH3 activity causes metabolic perturbations that result in a variety of direct and indirect effects on DR of germ cells. One arm implicates the hypoxia-inducible factor HIF-1, which promotes GeCo. Its loss causes a significant decrease, while the vhl-1 mutant background, in which HIF-1 protein is stabilized, leads to enhanced GeCo. Another arm implicates epigenetic changes leading to a detectable loss of the repressive histone marks H3K27me3 and H3K9me3 upon idha-1 depletion. Furthermore, stable-isotope-resolved metabolomics shows strong citrate accumulation without a noteworthy drop in α-Ketoglutarate (αKG) levels, indicating that compensatory pathways maintain αKG levels. Genetics and metabolomics analyses confirmed that Glutamate anaplerosis contributes to compensating for the loss of IDHA-1. Additionally, we found that depletion of glucose transporter FDGT-2 nearly doubles GeCo efficiency. Overall, our findings define the TCA cycle as an in vivo safeguard of germ cell identity and show that multiple metabolic inputs converge to keep germ cells refractory to TF-induced DR to neuronal cells.
    DOI:  https://doi.org/10.64898/2026.09.22.753437
  15. Cell Rep Methods. 2026 Sep 29. pii: S2667-2375(26)00314-0. [Epub ahead of print] 101613
    SurpHer: A genetically encoded ratiometric biosensor for dynamic extracellular pH imaging.
    Sofie Cens Holste, Leïla Dos Santos, Mahdi Rezayati Charan, Oline Nyhegn-Eriksen, Roxane Crouigneau, Birthe B Kragelund, Rodolphe Marie, Albin Sandelin, Jamie Yam Auxillos, Stine Falsig Pedersen.
      Extracellular pH is a critical regulator of cell function in health and disease, yet tools for dynamic monitoring of pericellular pH at single-cell resolution remain limited. We report SurpHer, a genetically encoded, ratiometric extracellular pH biosensor identified through screening of a modular library of membrane-targeted designs. SurpHer combines the pH-sensitive fluorophore SEpHluorin with the reference fluorophore mKate2 and a CD59-derived GPI anchor, enabling robust plasma membrane localization, quantitative ratiometric imaging, and stable long-term expression. Unlike non-ratiometric membrane-targeted reporters, SurpHer corrects for variation in sensor abundance and imaging conditions, while avoiding the complexity and confounding sensitivities of FRET-based designs. SurpHer responds rapidly and reversibly across the physiologically relevant extracellular pH range of 6.0-7.8 and performs consistently in several human cell lines. Stable genomic integration enabled longitudinal imaging of extracellular pH gradients in a microfluidic tumor microenvironment model. SurpHer provides a versatile platform for investigating extracellular pH dynamics in complex biological systems.
    Keywords:  CP: cell biology; CP: imaging; acid-base homeostasis; extracellular pH; genetically encoded biosensor; live-cell imaging; microfluidics; pericellular pH; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101613
  16. Cancer Discov. 2026 Oct 01. 16(10): 1961-1963
    Quality over Quantity: Dietary Fatty Acid Composition Shapes Pancreatic Tumorigenesis.
    Yu-Jin Jeong, Evan C Lien.
      Obesity and high dietary fat consumption are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC), and Ruiz and colleagues show that in addition to total fat consumption, distinct types of dietary fat contribute differently to tumor initiation in murine PDAC models. Diets rich in monounsaturated fatty acids enhance tumor progression, whereas dietary polyunsaturated fatty acids suppress tumorigenesis by increasing pancreatic cell susceptibility to lipid peroxidation and ferroptosis. See related article by Ruiz et al., p. 2108.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1528
  17. Science. 2026 Oct;394(6819): 29-30
    A mitochondrial carrier turns on the heat.
    Martin van der Laan.
      An orphan protein integrates circadian, dietary, and environmental signals to control brown fat metabolism.
    DOI:  https://doi.org/10.1126/science.ael7271
  18. bioRxiv. 2026 Sep 24. pii: 2026.09.23.753858. [Epub ahead of print]
    Structural insights into DHODH-mediated catalysis and drug resistance.
    Ruchika Pokhriyal, Hyuk-Soo Seo, Mio Murakoso, Sonia E Trojan, Laura Evans, Jillian K O'Neil, Komal Chauhan, Shakchhi Joshi, Hanna Meyer, Anders Friberg, Judith Günther, Sven Giese, Sven Christian, Xiaoping Yang, Robert E Lintner, David E Root, Marcia C Haigis, Matthew Vander Heiden, Marco Mravic, Sirano Dhe-Paganon, Julie-Aurore Losman.
      Dihydroorotate dehydrogenase (DHODH), which catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, is a validated therapeutic target in cancer, autoimmune disorders and infectious diseases. DHODH is hypothesized to utilize a 'ping-pong' catalytic mechanism. However, available crystal structures of DHODH in complex with small molecule inhibitors are irreconcilable with this model, showing simultaneous occupancy of both substrate binding sites. To elucidate the structural basis for DHODH-mediated catalysis, we resolved the structures of two DHODH holoenzymes. These structures capture novel conformational states that show mutually exclusive substrate binding. The holoenzyme structures also suggest that conformational changes in the catalytic loop of DHODH play a critical role in regulating enzyme activity. To map the functional landscape underlying DHODH inhibitor resistance, we performed deep mutational scanning drug-resistance screens with two clinically-relevant structurally distinct DHODH inhibitors, BAY2402234 and brequinar. Resistance variants cluster in the inhibitor binding site and at a previously unappreciated surface pocket on DHODH that allosterically regulates ubiquinone binding. Together, our findings provide structural evidence for the 'ping pong' model of catalysis, define the mutational landscape governing inhibitor resistance, and reveal novel structural vulnerabilities in DHODH that can be utilized for future drug development.
    DOI:  https://doi.org/10.64898/2026.09.23.753858
  19. Am J Physiol Heart Circ Physiol. 2026 Sep 29.
    Alpha-Ketoglutarate Dehydrogenase and Citric Acid Cycle Flexibility in Heart Disease and Failure.
    Nadia Martinez Naya, Abigail R Heath, Gustavo Adolfo Gámez de Armas, Keith A Webster, Lina A Shehadeh.
      Tricarboxylic acid cycle (TCA) enzymes, mitochondrial isocitrate dehydrogenase (IDH2), α-ketoglutarate dehydrogenase (AKGDH), and succinyl-CoA synthetase (SCS) catalyse the conversion of isocitrate to succinate generating reducing equivalents for mitochondrial complex I and ATP by substrate level phosphorylation. Because of their central roles in energy metabolism, TCA enzymes and their metabolites distribute extensively across cellular compartments coordinating intermediary metabolism, cellular redox, and nuclear gene expression. AKGDH activity is regulated by acylation, oxidation, energy charge, substrates, and product succinyl-CoA. Global TCA dysfunction is both a consequence and cause of the adverse metabolic remodelling that underlies contractile decline and ultimately heart failure (HF). This narrative review focuses on the potential for therapeutic enhancement of TCA function by augmenting AKG and/or AKGDH in the settings of cardiovascular disease and HF. The results support significant reversibility of TCA dysfunction and multiple clinical contexts wherein AKG supplementation confers benefit by mechanisms that include enhanced antioxidant defence as well as anaplerosis with improved bioenergetics and segmental TCA flux despite coincident dysfunction of other TCA enzymes. Elevated systemic AKG, recently identified as a biomarker of HF, is associated with worse outcomes of heart disease and, in preclinical models, with hypertrophy, fibrosis, and neurotoxicity, such that the success of therapeutic manipulation may be critically determined by the disease stage and context.
    Keywords:  AKGDH; Cardiac Metabolism.; Heart Failure; Metabolic Dysfunction; Succinate; α-Ketoglutarate
    DOI:  https://doi.org/10.1152/ajpheart.00428.2026
  20. bioRxiv. 2026 Sep 22. pii: 2026.09.21.753214. [Epub ahead of print]
    Glucosylceramide synthase is required for C6-ceramide nanoliposome-induced organelle stress and cell death.
    Luke R Vass, Ella W Smith, Jayda M Cavanaugh, Summer L Johnson, Ariana Sabzevari, Pedro Costa-Pinheiro, Jeremy J P Shaw, Thomas P Loughran, Todd E Fox.
      Sphingolipids are bioactive lipids that regulate key signaling pathways both directly as ligands and through membrane re-organization. Ceramide sits at the center of this network and is considered pro-death in many contexts, making ceramide accumulation an attractive therapeutic strategy. Given the wide-ranging regulation of cellular responses this network exerts, better understanding ceramide metabolism may promote therapeutic efficacy of sphingolipid-based therapeutics. Ceramide glycosylation, catalyzed by glucosylceramide synthase (GCS; UGCG), is in turn widely regarded as a detoxification route thus limiting efficacy of ceramide-based therapeutics. Here we show the opposite. Delivery of short-chain C6-ceramide via a ceramide nanoliposome (CNL) induced organelle stress and cell death in chronic lymphocytic leukemia (CLL) via the accumulation of glycosphingolipids (GSLs), rather than through ceramide itself. Pharmacologic and genetic blockade of GCS protected B-cell leukemia, breast carcinoma, glioblastoma, lung adenocarcinoma, and non-malignant embryonic kidney cells from CNL-induced death. Conversely, exogenous C8-glucosylceramide was sufficient to kill cells that cannot degrade it. We show that GSL accumulation drives an ordered organelle response beginning with lysosomal deacidification, endoplasmic reticulum stress, followed by mitochondrial respiratory capacity decline, each attenuated by inhibition of GSL synthesis. These effects were accompanied by MLKL phosphorylation, increased activity of the stress sensor JNK and CHOP induction, with JNK inhibition partially protecting from death. These findings invert the prevailing view of ceramide glycosylation as a resistance mechanism and identify glycosphingolipid flux as a required effector arm of ceramide-directed therapy.
    DOI:  https://doi.org/10.64898/2026.09.21.753214
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