bims-medica 2026-11-08 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–11–08
eighteen papers selected by
Brett Chrest, Wake Forest University

Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
Succinate promotes multiple myeloma cell proliferation through TCA cycle oxidation.
Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
Beyond ATP Synthesis: The Proton Motive Force as a Shared Energetic Resource in Mammalian Mitochondria.
Fumarate hydratase deficiency triggers disulfidptosis under glucose deprivation.
Lactate charging of tRNAs "brakes" the ribosome.
A low-populated helical region of the mitochondrial inhibitor IF1 drives interaction with the ATP synthase OSCP subunit.
Quaternary structure and activity of glutamate dehydrogenase are regulated by reversible S-palmitoylation and mitochondrial acyl-protein thioesterases.
An inhibitor of the mitochondrial respiratory chain exerts synergistic anti-tumour effects when combined with alkylating agents.
Human adenine nucleotide translocator isoforms mediate functionally redundant mitochondrial ADP/ATP exchange.
Cancer cells acquire cysteine directly from a reduced tumor microenvironment.
Therapy-related T-lymphoblastic lymphoma following acute myeloid leukemia remission with IDH2 mutation persistence.
Fatty acid oxidation of dietary lipids from ketogenic diets promotes intestinal tumorigenesis independently from ketone bodies.
A Phase 1 Trial of Low-dose Gemcitabine Combined with ATR Inhibitor Elimusertib for Advanced Solid Tumors.
Regulation of ketone body metabolism: biochemical mechanisms controlling ketogenesis and ketolysis.
Continuous measurement of oxygen consumption rate in hypoxic conditions with adherent cells using an oxygen-sensitive optode.
Whole-body glucose tolerance is impaired in male and female congenic mice lacking nicotinamide nucleotide transhydrogenase (NNT).
Balancing de novo and salvage pathways in cellular nucleotide synthesis.

J Biol Chem. 2026 Nov 04. pii: S0021-9258(26)02591-3. [Epub ahead of print] 113719

Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.

Sherry X Zhou, Benjamin Madden, M Cristine Charlesworth, Taro Hitosugi, Judith Favier, Louis James Maher.

  The tricarboxylic acid (TCA) cycle and electron transport chain (ETC) are key metabolic pathways required for cellular ATP production. Though loss of these components impairs cell survival, such defects can paradoxically promote tumorigenesis. One example is loss of succinate dehydrogenase (SDH), which functions in both the TCA cycle and as Complex II of the ETC. Mutations in SDH subunits can cause pheochromocytoma and paraganglioma (PPGL), rare hereditary neuroendocrine tumors of chromaffin cells in the adrenal gland and the nerve ganglia. Why tumor formation upon SDH loss is limited to certain tissues remains unclear. We hypothesized that the metabolic and proteomic perturbations resulting from SDH loss are cell-type specific, favoring survival of chromaffin cells. We comprehensively examined the proteomic, acetylproteomic, and succinylproteomic effects of SDH loss in two cell models, immortalized mouse chromaffin cells (imCCs) and immortalized mouse embryonic fibroblasts (iMEFs). Perturbations in metabolite levels were determined by mass spectrometry. Effects of SDH loss on fatty acid β-oxidation (FAO) were assessed by stable isotope tracing and pharmacologic inhibition. SDH-loss imCCs show significant upregulation of mitochondrial proteins, including TCA cycle and FAO enzymes, with pronounced downregulation of nuclear proteins. Both imCCs and iMEFs demonstrate significant energy deficiency upon SDH loss, but FAO activity is uniquely increased in SDH-loss imCCs. While SDH loss increases both lysine-reactive acetyl-CoA and succinyl-CoA, SDH-loss imCCs and iMEFs show disproportionate hyperacetylation but mixed succinylation. Surprisingly, SDH-loss imCCs, but not iMEFs, display disproportionate hypoacetylation and hyposuccinylation of mitochondrial proteins.

Keywords:  acetylation; energy deficiency; energy metabolism; fatty acid oxidation; paraganglioma; pheochromocytoma; protein acylation; proteomics; succinate dehydrogenase; succinylation

DOI:  https://doi.org/10.1016/j.jbc.2026.113719
Cell Rep. 2026 Nov 06. pii: S2211-1247(26)01346-X. [Epub ahead of print]45(11): 118267

Succinate promotes multiple myeloma cell proliferation through TCA cycle oxidation.

Nancy Gudgeon, Taylor Fulton-Ward, Victoria Stavrou, Aidan Haslam, Graham McIlroy, Hannah Giles, Guy Pratt, Sarah Dimeloe.

  Multiple myeloma is a plasma cell malignancy that develops within the bone marrow. The bone marrow metabolome is altered in myeloma, with implications for malignant cell growth. Here, the impact of elevated bone marrow levels of the tricarboxylic acid (TCA) cycle metabolite, succinate, was interrogated. Succinate was found to promote proliferation of several myeloma cell lines. This was linked to its uptake and oxidation in the TCA cycle, as indicated by increased ATP-coupled mitochondrial respiration and incorporation of succinate-derived carbons into downstream TCA cycle intermediates, which also occurs in primary myeloma cells. Succinate-driven proliferation was dependent upon mitochondrial oxidative phosphorylation and abrogated by ATP synthase inhibition. Furthermore, interrogation of large-scale transcriptomic data identified that elevated expression of a mitochondrial succinate transporter associates with accelerated disease progression in myeloma, indicating this mechanism may promote plasma cell growth in vivo and highlighting a target for therapeutic intervention.

Keywords:  CP: cancer; CP: metabolism; anti-tumour immunity; cancer; cancer metabolism; immunometabolism; metabolism; metabolites; mitochondria; multiple myeloma; succinate

DOI:  https://doi.org/10.1016/j.celrep.2026.118267
Elife. 2026 Nov 04. pii: RP107123. [Epub ahead of print]14

Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.

Sarah M Chang, Muhammad Bin Munim, Sonia E Trojan, Huel Cox, Anna Shevzov-Zebrun, Keene L Abbott, Renee Chang, Matthew G Vander Heiden.

  The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine-limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine-depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affect cancer cell proliferation.

Keywords:  NAD+/NADH ratio; biochemistry; cancer biology; cancer metabolism; chemical biology; human; lipid depletion; mitochondria; serine

DOI:  https://doi.org/10.7554/eLife.107123
Am J Physiol Cell Physiol. 2026 Nov 06.

Beyond ATP Synthesis: The Proton Motive Force as a Shared Energetic Resource in Mammalian Mitochondria.

Jarrod A Call, Junwon Heo, Edmund R S Kunji, Kelsey H Fisher-Wellman.

  The proton motive force (PMF) across the inner mitochondrial membrane drives ATP synthesis. Biochemistry textbooks give a maximum yield of 30-32 ATP per glucose, but this is a theoretical ceiling, reached only under complete coupling with ATP synthase as the sole consumer of the gradient. No living cell operates there. The PMF is a shared resource, and its allocation among consumers sets the mitochondrion's effective output: the gap between theoretical and effective yield is a reallocation to transport, redox maintenance, and biogenesis. This review re-examines the textbook yield, including the c-ring stoichiometry of ATP synthase, and catalogs the major PMF consumers and their proton costs. The widely quoted figure corresponds to no measured or structurally determined stoichiometry, a mismatch noted previously and consolidated here, and the c-ring subunit count is an upper bound on synthase efficiency under ideal coupling. We assemble these costs into a consolidated proton budget: a range whose upper limit is the ceiling at which the PMF drives ATP synthesis alone. Its lower limit cannot yet be calculated, because the resting flux through most PMF consumers has never been measured; we therefore list every term that this calculation would require and mark those still missing. The result is a framework for reasoning, not a closed set of numbers. Practical consequence: the PMF and membrane potential are composite quantities, so a change in membrane potential should not be read as a change in ATP synthesis, nor the non-phosphorylating residual as passive leak.

Keywords:  P/O ratio; membrane potential; molecule and ion transport; oxidative phosphorylation

DOI:  https://doi.org/10.1152/ajpcell.90010.2026
Nat Commun. 2026 10 05. pii: 11353. [Epub ahead of print]17(1):

Fumarate hydratase deficiency triggers disulfidptosis under glucose deprivation.

Peng Dou, Xin Lu, Pengyu Geng, Yasemin Cole, Miao Bao, Xin Ge, Siming Pu, Lina Zhou, Xinyu Liu, Hang Li, Jinhui Zhao, Hang Gao, Fating Chen, Zhikun Lin, Ting Wang, Qi Li, Jianwen Hu, Jie Dai, Xu Qian, Zhengping Zhuang, Guowang Xu.

Disulfidptosis is cell death caused by abnormal disulfide bonds, previously observed in cells with high SLC7A11 expression under glucose starvation. Whether other conditions can induce disulfidptosis remains unclear. However, we demonstrate that fumarate hydratase (FH)-deficient cells undergo disulfidptosis under glucose starvation. FH deficiency drives abnormal disulfide accumulation, promotes actin contraction, and consequently leads to cytoskeleton-plasma membrane dissociation. Under glucose starvation conditions, impaired oxidative tricarboxylic acid (TCA) cycle function in FH-deficient cells compromises NAD(P)H (the reduced forms of nicotinamide adenine dinucleotide and its phosphate) homeostasis, leading to redox system collapse. We find that targeting mitochondrial complex I enhances the reductive TCA cycle activity driving NADPH consumption while simultaneously suppressing the oxidative TCA cycle, thereby inducing disulfidptosis in the presence of glucose. Our findings establish a mechanistic link between FH deficiency and disulfidptosis, and define a therapeutically actionable vulnerability in FH-deficient tumors.

DOI: https://doi.org/10.1038/s41467-026-78274-6
Cell Metab. 2026 Nov 03. pii: S1550-4131(26)00438-9. [Epub ahead of print]38(11): 2167-2169

Lactate charging of tRNAs "brakes" the ribosome.

Hyo Min Cho, Raul Mostoslavsky.

Lactate has been recast from a waste product to a fuel and signaling molecule, yet why aggressive tumors invest so heavily in exporting it has remained unexplained. In a recent study in Molecular Cell, Wang et al. show that upon excess lactate production, AARS1 charges lactate onto tRNAs, generating dead-end lactyl-tRNAs that obstruct translation elongation to re-balance metabolism, a molecular "brake" that cancer cells avoid through upregulation of lactate exporters.

DOI: https://doi.org/10.1016/j.cmet.2026.10.002
Protein Sci. 2026 Dec;pii: e70844. [Epub ahead of print]35(12):

A low-populated helical region of the mitochondrial inhibitor IF1 drives interaction with the ATP synthase OSCP subunit.

Simone Fabbian, Galo Ezequiel Balatti, Marco Carrello, Celeste Quaggia, Lorenzo Cracco, Maria Ludovica Macchia, Stefano Mammi, Valentina Giorgio, Marta De Zotti, Alice Sosic, Sebastian Fernandez Alberti, Massimo Bellanda.

  The upregulation of mitochondrial IF1 is associated with the progression of several cancer types. In HeLa cells, naturally overexpressing this protein, IF1 binds to the ATP synthase OSCP subunit, resulting in inhibition of permeability transition-dependent apoptosis. This newly identified protein-protein interaction represents a promising therapeutic target in tumors characterized by IF1 overexpression. However, the rational design of targeted molecules is currently limited by a lack of structural data on the binding mechanism. Here we employed native mass spectrometry and NMR spectroscopy to identify the minimal IF1 segment required to target the OSCP subunit. NMR revealed that the interaction is weak in solution, with an affinity KD in the low millimolar range, consistent with a binding event occurring exclusively when IF1 is overexpressed in cancer cells. These findings guided the design of a model peptide containing the IF1 binding epitope, which was used in molecular dynamics simulations (MD) aimed at investigating its binding mechanism to the OSCP subunit. NMR and MD converged to show that the IF1 binding epitope requires a helical folding for OSCP engagement, consistent with a helical Molecular Recognition Feature (αMoRF) mechanism. Helicity of the epitope is strictly necessary for productive binding, with key contacts involving IF1 residues E30, E31, Y33, F34, and Q37 packing against OSCP helix H3. Structural analysis of the binding complex provided a first molecular framework to inspire the design of molecules capable of displacing IF1 from the OSCP subunit and potentially exerting anticancer activity.

Keywords:  IF1; NMR; OSCP; binding mechanism; cancer; molecular dynamics; native MS; peptides; protein–protein interaction (PPI); therapeutic target

DOI:  https://doi.org/10.1002/pro.70844
Protein Sci. 2026 Dec;pii: e70852. [Epub ahead of print]35(12):

Quaternary structure and activity of glutamate dehydrogenase are regulated by reversible S-palmitoylation and mitochondrial acyl-protein thioesterases.

Michael Salsaa, Huu Tram Anh Huynh, Charneal L Dixon, Jonathan St-Germain, Haggag S Zein, Ella M Potvin, David N Langelaan, Brian Raught, Gregory D Fairn.

  Glutamate dehydrogenase (GDH) is a mitochondrial enzyme that links amino acid and carbohydrate metabolism through the reversible conversion of glutamate to α-ketoglutarate. GDH functions as a hexamer and is subject to extensive allosteric regulation. Here, we demonstrate that GDH undergoes auto-palmitoylation in the presence of palmitoyl-CoA, accompanied by concentration-dependent inhibition of both reductive amination and oxidative deamination. Acyl-PEG exchange assays indicated predominantly one palmitoyl modification per GDH subunit, while mass spectrometry identified Cys55, Cys115, and Cys197 as putative modification sites. Blue native PAGE revealed that palmitoylation promotes dissociation of GDH hexamers into species consistent with dimers. Treatment with acyl-protein thioesterase 1 (APT1) restored both hexameric assembly and enzymatic activity, whereas α/β-hydrolase domain-containing protein 10 (ABHD10) restored activity less efficiently under the conditions tested. Acyl-resin-assisted capture also detected endogenous S-acylated GDH in three human cell lines, and treatment with the APT1 inhibitor ML348 increased GDH S-acylation in HepG2 cells. Together, these findings identify reversible S-palmitoylation as a mechanism regulating GDH assembly and activity, with the potential to couple mitochondrial lipid metabolism to amino acid catabolism.

Keywords:  S‐palmitoylation; acyl‐protein thioesterases; auto‐acylation; enzyme regulation; glutamate dehydrogenase; protein oligomerization

DOI:  https://doi.org/10.1002/pro.70852
Br J Pharmacol. 2026 Nov 06.

An inhibitor of the mitochondrial respiratory chain exerts synergistic anti-tumour effects when combined with alkylating agents.

Emiri Omori Takaki, Yuya Hidoh, Yutaka Obuchi, Yoko Nagai, Shingo Nishikori, Yuki Kuniyoshi, Yasuhiro Sawai, Naoto Ohi.

   BACKGROUND AND PURPOSE: Cancer cells exhibit the Warburg effect, but oxidative phosphorylation (OXPHOS) is also important for cancer cell proliferation. Metabolic reprogramming from glycolysis to OXPHOS is one mechanism of resistance to anti-tumour drugs. Here, we have synthesized and characterized OPB-111077, a novel, first-in-class orally available small-molecule compound, and investigated its anti-tumour activity and therapeutic potential in combination with alkylating agents.
EXPERIMENTAL APPROACH: Inhibition of mitochondrial function by OPB-111077 were assessed by measuring the oxygen consumption rate, ATP production and Complex I enzymatic activity. anti-tumour effects were evaluated in human haematological and solid tumour cell lines and in cell line-derived xenograft and lymphoma patient-derived xenograft models. Mechanistic studies included CRISPR screening, metabolomic analyses, and measurements of the oxygen consumption and extracellular acidification rates. Effects of OPB-111077 combined with alkylating agents were also assessed in mice.
KEY RESULTS: OPB-111077 inhibited mitochondrial respiratory chain Complex I, suppressed OXPHOS, and exerted anti-tumour effects in several models. OPB-111077 demonstrated synergism with the alkylating agent bendamustine, with simultaneous inhibition of both OXPHOS and glycolysis. Bendamustine reprogrammed cancer cells into an OXPHOS-dominant state, thereby enhancing the efficacy of OPB-111077.
CONCLUSION AND IMPLICATIONS: Based on these findings, we propose a novel anticancer therapeutic strategy of combining OXPHOS inhibitors with alkylating agents. OPB-111077 has demonstrated potential in combination therapy and was recently evaluated with bendamustine and rituximab in a Phase 1 clinical trial for patients with relapsed/refractory diffuse large B-cell lymphoma (NCT04049825).

Keywords:  DLBCL; OXPHOS inhibitor; metabolic reprogramming; synergistic anti‐tumour effect

DOI:  https://doi.org/10.1111/bph.70719
J Biol Chem. 2026 Nov 04. pii: S0021-9258(26)02600-1. [Epub ahead of print] 113728

Human adenine nucleotide translocator isoforms mediate functionally redundant mitochondrial ADP/ATP exchange.

Macie S Sheridan, John Z Chan, Steven M Claypool, Nanami Senoo.

  The adenine nucleotide translocator (ANT) is essential for cellular energy metabolism, mediating the exchange of ADP and ATP across the inner mitochondrial membrane. While mammals express multiple ANT isoforms, it remains unclear whether they possess distinct properties or whether their diverse expression patterns reflect functional specialization as widely posited. In this study, we employed a controlled human cell system to directly compare the transport kinetics and bioenergetic contributions of individual human ANT isoforms. By evaluating endogenous knockout cells and systematically re-expressing each isoform, we demonstrate that ANT1, ANT2, and ANT3 are functionally redundant. The three ANT isoforms exhibited near-identical transport rates in both forward (ADPin/ATPout) and reverse (ATPin/ADPout) exchanges. While transport kinetics were equivalent, cells solely expressing ANT2 or ANT3 exhibited slightly different resilience to respiratory inhibition, suggesting isoform-specific roles that may be related to non-transport functions. Our findings provide a refined view of ANT-mediated mitochondrial nucleotide flux and suggest that ANT isoform-specific differences, if they exist, are likely subtle and not innately tied to ADP/ATP exchange.

Keywords:  ADP; ATP; bioenergetics; exchanger; mammal; membrane protein; mitochondria; mitochondrial transport

DOI:  https://doi.org/10.1016/j.jbc.2026.113728
bioRxiv. 2026 Oct 27. pii: 2026.10.25.761647. [Epub ahead of print]

Cancer cells acquire cysteine directly from a reduced tumor microenvironment.

Feroza K Choudhury, Basma A Yasseen, Paloma González-Sánchez, Meredith Long, Samantha Caldwell, Pritin N Soni, Suehelay Acevedo-Acevedo, Yun Huang, Elsa R Flores, Chang Jiang, Nathan P Ward, Gina M DeNicola.

The metabolic environment of a tumor is shaped by the nutrients available in its interstitial fluid, yet the redox composition of that fluid is poorly defined. Measuring sulfur metabolites in the interstitial fluid of tumors, matched healthy organs, and serum across three mouse models of cancer, we find that the tumor microenvironment (TME) is a chemically reduced compartment in which free cysteine predominates over its oxidized form, cystine. This is especially pronounced in the lung TME, where cystine is nearly absent. We further show that lung cancer cells take up cysteine and cystine with comparable efficiency and proliferate on cysteine alone, and that the abundant glutathione in the TME helps keep cysteine reduced through disulfide exchange. In a medium formulated to match the sulfur composition of the lung tumor interstitial fluid, cells become independent of cystine import through xCT. Cells cultured in this medium were resistant to glutaminase inhibitors, oxidants and ferroptosis inducers, and better maintained NADPH levels under oxidative challenge. These findings suggest that standard culture conditions overestimate the dependence of cancer cells on cystine uptake and their vulnerability to oxidative stress-targeting therapies.

DOI: https://doi.org/10.64898/2026.10.25.761647
Leuk Res Rep. 2026 ;26 100618

Therapy-related T-lymphoblastic lymphoma following acute myeloid leukemia remission with IDH2 mutation persistence.

Jonathan J Cho, Huan-You Wang, Grace Y Lin, James K Mangan.

  T-lymphoblastic lymphoma (T-LBL) is an uncommon hematological malignancy that rarely presents as a secondary cancer following chemotherapy. While IDH2 mutations are commonly identified in acute myeloid leukemia (AML), they were very rarely found in T-LBL. We present a case of an adult male diagnosed with therapy-related T-LBL with an IDH2 mutation after 3 years of complete remission following chemotherapy for AML with the same IDH2 mutation, which suggests a dedifferentiated multipotent cancer stem and progenitor cell that may give rise to both the myeloid and lymphoid malignancies.

Keywords:  Acute myeloid leukemia; Epigenetic modifiers; IDH2 mutation; Secondary T-lymphoblastic lymphoma; Thymoma

DOI:  https://doi.org/10.1016/j.lrr.2026.100618
Gastroenterology. 2026 Nov 05. pii: S0016-5085(26)07776-0. [Epub ahead of print]

Fatty acid oxidation of dietary lipids from ketogenic diets promotes intestinal tumorigenesis independently from ketone bodies.

Devon M Ivy, Gianluca Ianiro.

DOI: https://doi.org/10.1053/j.gastro.2026.11.001
Cancer Res Commun. 2026 Nov 03.

A Phase 1 Trial of Low-dose Gemcitabine Combined with ATR Inhibitor Elimusertib for Advanced Solid Tumors.

Thejus Jayakrishnan, Rebecca Porter, Alice Chen, Ningxuan Zhou, Julianne L Holleran, Massimiliano Russo, Douglas A Rubinson, Brandon M Huffman, Nabihah Tayob, Lorenzo Trippa, Kaitlyn Ramsey, Mckenzie Kelly, Leah H Biller, Panagiotis A Konstantinopoulos, Carolyn Krassner, Elizabeth K Lee, Ursula A Matulonis, Kimberly J Perez, Renata R Almeida, Srivatsan Raghavan, Alexi A Wright, Brian M Wolpin, Jonathan A Nowak, Alan D D'Andrea, Andrew J Aguirre, Steven Gore, Geoffrey I Shapiro, Jan H Beumer, James M Cleary.

PURPOSE: Preclinical data suggest that the anti-cancer efficacy of ATR inhibitors can be synergistically enhanced by low-dose gemcitabine. To test the clinical feasibility of this regimen, we conducted a phase 1 trial of low-dose gemcitabine combined with the ATR inhibitor elimusertib (BAY1895344).
PATIENTS AND METHODS: This phase 1 study evaluated the combination of gemcitabine and elimusertib in patients with previously treated, incurable solid tumors. The primary objective was to assess the safety and tolerability of this regimen and to determine the maximum tolerated dose (MTD). Secondary objectives included assessment of objective response rate (ORR) per RECIST v.1.1 and characterization of the pharmacokinetic (PK) profile.
RESULTS: Fourteen patients were enrolled; most patients had pancreatic cancer (n=6) or ovarian cancer (n=6). The median age was 63.5 years of age, and the median number of prior therapies was 2. The regimen caused significant toxicity, and four patients (28%) discontinued the trial due to treatment-related adverse events. The trial was stopped prior to establishing an MTD due to the pharmaceutical company's decision to halt development of the agent. A confirmed partial response was observed in one patient with platinum-refractory ovarian cancer harboring a gain in CCNE1. Another patient with pancreatic adenocarcinoma harboring biallelic ATM loss remained on trial for 9.5 months with stable disease, with an 85% decrease in CA19-9.
CONCLUSIONS: The combination of low-dose gemcitabine combined with elimusertib was not tolerable. Although evidence of anti-tumor activity was observed, significant improvements in tolerability are required for future ATR inhibitor combinations to be clinically feasible.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0505
Biochimie. 2026 Nov 02. pii: S0300-9084(26)00280-4. [Epub ahead of print]

Regulation of ketone body metabolism: biochemical mechanisms controlling ketogenesis and ketolysis.

Souad Nasser, Aneta Balcerczyk, Luciano Pirola.

  Traditionally considered as alternative energy substrates, ketone bodies (KBs), notably β-hydroxybutyrate (β-OHB) and acetoacetate, are now recognized as key metabolic intermediates whose circulating levels must be tightly controlled to ensure energy homeostasis. KBs are mostly hepatically produced, via ketogenesis, and catabolized by extrahepatic tissues during fasting or carbohydrate restriction. The regulation of KBs metabolism relies on a coordinated network of hormonal, enzymatic and transcriptional mechanisms that control KBs synthesis and degradation. KBs anabolic and catabolic rates are controlled by the rate-limiting enzymes 3-hydroxy-3-methylglutaryl-CoA-synthase 2 (HMGCS2), governing ketogenesis, and succinyl-CoA:3-ketoacid-CoA transferase (SCOT), driving ketolysis. Their activity and expression are finely orchestrated, especially by the insulin/glucagon ratio, to adapt to the organism's fluctuating energy demands. Transcriptionally, ketogenesis is regulated through peroxisome-proliferator-activated-receptor-alpha (PPARα) and the transcription factor forkhead-box-A2 (FOXA2), which respond to nutrient availability and hormonal cues. In parallel, ketolysis is tightly controlled through the regulation of SCOT expression, notably via PPARα-dependent mechanisms, as well as through post-translational modifications (PTMs) affecting enzyme activity. Together, these regulatory mechanisms ensure a precise balance between KBs production and utilization. Emerging evidence also suggests that additional modulators, such as the gut microbiota, indirectly influence KBs metabolism by affecting substrate availability and metabolic signaling pathways, although its quantitative contribution remains to be established. Here, we provide a mechanistic overview of the pathways governing KBs metabolism, with focus on the regulation of ketogenesis and ketolysis. We discuss how these processes are integrated at multiple levels to maintain systemic energy homeostasis and consider their implications for metabolic disease.

Keywords:  Enzymatic regulation; HMGCS2; Histone β-hydroxybutyrylation; Ketone bodies; SCOT

DOI:  https://doi.org/10.1016/j.biochi.2026.10.034
Biol Open. 2026 Nov 06. pii: bio.062686. [Epub ahead of print]

Continuous measurement of oxygen consumption rate in hypoxic conditions with adherent cells using an oxygen-sensitive optode.

Nick Taber, Ricardo Alva, Jacob E Wiebe, Dorcas Adewumi, Jeffrey A Stuart.

  Cellular oxygen consumption rate (OCR) is a widely used readout of mitochondrial respiration and oxidative metabolism. However, many OCR assay workflows are limited by short assay durations, expensive specialized instrumentation, and reduced flexibility under controlled low-oxygen conditions. Here, we describe an in-incubator method for continuous, non-disruptive OCR measurement in adherent cell cultures using the PreSens OxoDish optical oxygen-sensing system. OCR is estimated by applying the steady-state solution of Fick's law to pericellular oxygen measurements acquired at well bottoms. This approach enables OCR monitoring over several hours to 24 hours without removing plates from a standard cell-culture incubator. Using MCF-7 breast cancer cells cultured in DMEM, we calculated basal OCR values of 20.07-32.79 amol cell-1s-1, similar to published values obtained using other methods. We also demonstrate a respiration profiling approach analogous to SeahorseXF Mito Stress Tests by quantifying OCR in parallel wells exposed to oligomycin, FCCP, or antimycin A/rotenone. Importantly, we demonstrate that the method remains functional under hypoxia (1.5% O2) without modification. Benchmarking the PreSens system against the SeahorseXF yielded values within the expected reported range. The approach we describe provides an accessible option for continuous OCR measurements in adherent cell cultures under a range of oxygen levels.

Keywords:  Adherent cell culture; Hypoxia; Mito stress test; Mitochondrial respiration; Oxygen consumption rate; Oxygen sensitive optode; Pericellular Oxygen

DOI:  https://doi.org/10.1242/bio.062686
Physiol Rep. 2026 Nov;pii: e71167. [Epub ahead of print]14(21):

Whole-body glucose tolerance is impaired in male and female congenic mice lacking nicotinamide nucleotide transhydrogenase (NNT).

Jinmeng Yang, Jingyi Song, Jo-Lene de Deugd, Marcel Jaklofsky, Georgios Nikolopoulos, Melissa Bekkenkamp-Grovenstein, Claudia Carmone, Jaap Keijer, Heather L Petrick, Sander Grefte.

  Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial redox protein. Previous reports of NNT deficiency impairing glucose tolerance in young male mice were potentially confounded by background strain differences. This study investigated whether an NNT deletion specifically in a congenic mouse model induces glucose intolerance across sexes and ages. Indirect calorimetry, oral glucose tolerance tests, and tissue analyses were performed in adult (6-month-old) and old (24-month-old) male and female congenic mice with (NntWT) and without (NntΔ) NNT (n = 8-15). While older mice exhibited increased body weight and higher fasted insulin levels (p < 0.0001), NNT deficiency did not affect these parameters, energy expenditure, or substrate utilization in either sex. Following glucose ingestion, glucose tolerance worsened in NntΔ mice of both sexes. Glucose-stimulated serum insulin was unaffected in adult females, but was lower in 24-month NntΔ females (p = 0.009) and 6-month NntΔ males (p = 0.0303). However, there were no effects of genotype on glucose-stimulated signaling pathways (including PI3K, STAT3, phosphorylated-AKT, sarcolemmal GLUT4 localization) in skeletal muscle (p > 0.295) collected 30 min following glucose administration. Similarly, glucose-stimulated AKT phosphorylation ratio did not differ between genotypes within liver or mesenteric white adipose tissue (mWAT). Combined, congenic NNT deficiency induces whole-body glucose intolerance in both male and female adult and old mice.

Keywords:  adipose tissue; aging; glucose homeostasis; insulin resistance; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.71167
Nat Metab. 2026 Nov 03.

Balancing de novo and salvage pathways in cellular nucleotide synthesis.

Tina Becirovic, Tuan-Anh Nguyen, Stefan Kubicek.

Nucleotides are essential for DNA replication, repair and transcription and are supplied through two principal pathways, salvage and de novo synthesis. While the core enzymes underlying these pathways have long been characterized, recent work has uncovered mechanisms that regulate pathway choice across cell states. This Review summarizes our current understanding of how cells govern the balance between salvage and de novo synthesis of nucleotides. We examine context-dependent pathway utilization across organisms, tissues and physiological contexts, and discuss the molecular determinants of pathway choice, including precursor availability, cellular demand, transcriptional programmes, mitochondrial and one-carbon metabolism, post-translational regulation and multienzyme organization. We further explore how disruption of this balance shapes human disease and consider the translational potential of nucleotide metabolic plasticity. Finally, we highlight emerging technologies for resolving tissue-specific and cell-type-specific pathway utilization and outline outstanding questions in pathway regulation and therapeutic targeting. Collectively, this Review summarizes current knowledge of how cells dynamically balance de novo synthesis and salvage and highlights opportunities to therapeutically target nucleotide metabolic dependencies.

DOI: https://doi.org/10.1038/s42255-026-01628-3