bims-medica 2026-06-28 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–06–28
28 papers selected by
Brett Chrest, Wake Forest University

Host metabolism can produce many indoles and phenols independently of the microbiome.
Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.
A putative role for Mrx3 and Fmp10 in regulating yeast mitochondrial acyl-CoA thioesters.
Physiological media and oxygen levels modulate cancer hallmarks in cultured breast cancer cells.
High dietary fat causes muscle structural breakdown, mitochondrial dysfunction, and contractile deficits in the absence of carnitine palmitoyltransferase 2.
Ketogenic Diet in Obesity and Diabetes: A Narrative Review.
The Pyruvate Dehydrogenase Complex: A 90-Year-Old Enigma Shaping the Future of Structural Enzymology.
Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
Revealing the spatiotemporal dynamics of methionine metabolism with a genetically encoded single-fluorophore biosensor.
Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.
Molecular architecture of the human citrate synthase-malate dehydrogenase 2 metabolon.
Rosindol: A fluorogen for the quantitative measurement of reactive oxygen species in living cells.
Enzyme Assemblies in Nucleotide Metabolism: Structure, Regulation, and Disease Implications.
Adherence to the Mediterranean diet and risk of pancreatic cancer: an analysis of 2.3 million participants in the Pooling Project of Prospective Studies of Diet and Cancer (DCPP).
Glucose starvation induces fumarate hydratase succinylation and inhibits ferroptosis to maintain colon cancer cell proliferation.
Targeting metabolic dependencies to reverse chemoradiotherapy resistance in colorectal cancer.
Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics.
Small-Molecule Targeting of VDAC Disrupts Mitochondrial Bioenergetics and Suppresses Melanoma Cell Survival and Migration.
Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.
Fluxomics in precision nutrition: integrating dynamic metabolic profiling with multiomics.
A lysate of a multi-strain probiotic formulation inhibits cell growth and oxidative phosphorylation in colorectal cancer cells via a ceramide-mediated mechanism.
Assembly of the catalytic module and the rotor of human ATP synthase.
The Imipridone ONC206 Inhibits Tumor Growth and Improves Survival in Patient-Derived Xenograft Models of Uveal Melanoma.
Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma.
Discovery of SMD-6346: A Potent, Selective, and Orally Active SMARCA2 Degrader for Targeting SMARCA4-Deficient Human Cancers.
Mycobacterium tuberculosis partitions the Krebs cycle under iron starvation.
Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
Comparison of Venetoclax-Based Treatments for Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia: A Single-Center Real-World Experience.

Nat Metab. 2026 Jun 23.

Host metabolism can produce many indoles and phenols independently of the microbiome.

Jenna E AbuSalim, Kellen Olszewski, Salma Youssef, Sarah J Mitchell, Craig J Hunter, Jessica Little, Ashley Sidebottom, Jacob A Boyer, Steve D Knutson, Laith Z Samarah, Michael R MacArthur, Alessa L Henneberg, Rolf-Peter Ryseck, Christiane A Opitz, David W C MacMillan, Mohamed S Donia, Eric G Pamer, Sabrina Imam, Christopher J Lehmann, Olatoyosi Odenike, Joshua D Rabinowitz.

Indole and phenol metabolites are typically thought to be products of bacterial digestion of tryptophan (indoles) and phenylalanine or tyrosine (phenols). Interest in controlling gut microbial production of these metabolites has continually grown because they have important physiological impacts, with indoles agonizing aryl hydrocarbon receptor signalling and phenols being associated with healthy body weight. Although there is a growing body of research on which bacteria produce these metabolites, the host contribution to their circulating pools has not been characterized. Here, through stable isotope tracing in cell culture, mice and rats, we show that mammalian cells can make aryl-pyruvates, aryl-lactates, aryl-acetates and aryl-carboxylic acids independently of the microbiome. We demonstrate that circulating levels of these metabolites in mice and human patients are robust to perturbations of the microbiome. By contrast, bacterial metabolism is required to synthesize aryl-propionates and free indole, phenol and p-cresol. Overall, these results suggest that host metabolism is a major contributor to circulating indole and phenol metabolite pools.

DOI: https://doi.org/10.1038/s42255-026-01550-8
bioRxiv. 2026 Jun 10. pii: 2026.06.06.727699. [Epub ahead of print]

Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.

Kyoungmin Kim, Tanvi Shankar, Yaqi Gao, Ian K Williamson, Nathaniel Snyder, Evan P Kransdorf, Ralph DeBerardinis, Heinrich Taegtmeyer, Brandon Faubert, Anja Karlstaedt.

Background: Cardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits α-ketoglutarate dehydrogenase (α-KGDH) and is associated with reduced cardiac contractile function.
Methods: We combined stable isotope tracer studies with computational modeling to investigate the fundamental role of IDH isoforms in cardiac adaptation under oncometabolic stress.
Results: We uncovered an unexpected cardiac phenotype that expands the role of IDH1 in the heart beyond oxidative metabolism. We quantified the stable isotopomer distributions from glucose and glutamine in perfused working rat hearts and isolated adult ventricular cardiomyocytes using mass spectrometry-based metabolomics. Our analysis revealed that defective mitochondrial metabolism causes the redirection of carbon flux from oxidative towards reductive pathways. Reductive carboxylation of α-KGDH increases glutamine uptake and glutamine-derived citrate formation in working rat heart perfusions and cultured adult mouse ventricular cardiomyocytes. To identify which IDH isoform is responsible for redirecting carbon flux, we developed knockout models of IDH1, IDH2, and IDH3 in adult mouse ventricular cardiomyocytes. Loss of IDH1 expression impaired the reductive formation of citrate and caused functional defects in cardiomyocytes. Lastly, epigenetic analyses of histone marks revealed that IDH1 induces widespread alterations in histone acetylation and tri-methylation.
Conclusion: Our results highlight a novel role for IDH1 in cardiac metabolism and transcriptional control of metabolic adaptation to tumor-mediated stress and provide evidence that reductive-citrate formation may induce epigenetic modifications in the heart.

DOI: https://doi.org/10.64898/2026.06.06.727699
Biochim Biophys Acta Mol Cell Res. 2026 Jun 24. pii: S0167-4889(26)00076-5. [Epub ahead of print]1873(6): 120178

A putative role for Mrx3 and Fmp10 in regulating yeast mitochondrial acyl-CoA thioesters.

Marcelo Mesa Costa-Lima, Fernando Gomes, Thaynara Roberta Damaceno, Mário H Barros.

  The hotdog-fold acyl-CoA thioesterases (ACOTs) are enzymes typically related to lipid metabolism and are widely spread across the tree of life, but many members of this group are poorly characterized. In this work, through in silico analyzes we identified the MICOS-associated mitochondrial proteins of unknown function Mrx3 and Fmp10 as two putative ACOTs in Saccharomyces cerevisiae with structural homology to the mammalian thioesterases Them4 and Them5, which possess a conserved motif that is catalytic toward thioester hydrolysis. Lipidomics analyses revealed that the mrx3Δ and fmp10Δ mutants have lower free fatty acid (FFA) levels with concomitant accumulation of storage lipids, besides a decreased pool of cardiolipin species. During our functional investigation, we observed that the absence of either protein partially restores respiratory capacity in the leu5Δ strain, whose mutation has been previously linked to very slow respiratory growth due to severe Coenzyme A (CoA) depletion in the mitochondrial matrix. We verified that the respiratory defect of the leu5Δ mutant is also related to a defect in the respiratory chain given the low NADH-dependent oxygen consumption rate and is specifically linked to defective Complex IV activity. The strain's growth defect was exacerbated by deletion of the glycine transporter HEM25 and was ameliorated by either δ-aminolevulinic acid (ALA, a heme precursor) or iron supplementation. These results may indicate that the leu5Δ strain has a subtle heme deficiency. We propose a model in which Mrx3 and Fmp10 control the mitochondrial acyl-CoA/CoA ratio through a thioesterase activity, which finely modulates the mitochondrial membrane lipidome, with a concomitant effect in heme biosynthesis. In the leu5Δ mutant, there is a disturbed metabolic homeostasis. Deleting these hotdog-fold proteins cause increased acyl-CoA levels and partially restores metabolic balance, potentially by repartitioning carbon flux through the tricarboxylic acid (TCA) cycle to replenish succinyl-CoA using the limited available CoA pool, which may be sufficient to restore heme biosynthesis. This mechanism highlights the critical role of CoA compartmentalization and the underlying connection of distinct metabolic pathways.

Keywords:  Coenzyme A (CoA) transport; Heme biosynthesis; Mitochondrial lipid metabolism; Saccharomyces cerevisiae

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120178
FEBS J. 2026 Jun 21.

Physiological media and oxygen levels modulate cancer hallmarks in cultured breast cancer cells.

Jacob E Wiebe, Ricardo Alva, Fereshteh Moradi, Sarah Alderman, Ping Liang, Jeffrey A Stuart.

  The concepts of physioxia and physiological media for mammalian cell culture have gained attention over the past several years. Although the effects of oxygen tension or nutrient composition have been examined individually, their combined, large-scale impacts on cancer cell biology remain poorly understood. Here, we integrated transcriptomic, proteomic, and functional analyses to assess how oxygen levels (18% vs. 5% O2) and medium composition (DMEM vs. Plasmax) influence human breast cancer (MCF7) cells. We found that culturing MCF7 cells in physioxia (5% O2) and Plasmax medium induces a transcriptional profile that more closely resembles breast tumors in vivo. Moreover, changes in transcript and protein abundance were significantly associated with cellular growth, motility, and metabolism. At the functional level, oxygen level and culture medium affected proliferation, migration, glucose consumption, and metabolic activity in MCF7 cells. We conclude that both oxygen levels and medium composition in culture modulate hallmark cancer phenotypes, underscoring the importance of mimicking physiological microenvironments when studying biological mechanisms and therapeutic approaches in cancer.

Keywords:  cancer cells; cell culture; culture media; oxygen; physiological cell culture; proteomics; transcriptomics

DOI:  https://doi.org/10.1111/febs.70629
Mol Genet Metab. 2026 Jun 22. pii: S1096-7192(26)00480-4. [Epub ahead of print]148(4): 110197

High dietary fat causes muscle structural breakdown, mitochondrial dysfunction, and contractile deficits in the absence of carnitine palmitoyltransferase 2.

Andrea S Pereyra, Filip Jevtovic, Adam J Amorese, Chien-Te Lin, P Darrell Neufer, Espen E Spangenburg, Jessica M Ellis.

  Carnitine palmitoyltransferase 2 (CPT2) deficiency is an inherited autosomal recessive disorder of fatty acid oxidation, which commonly manifests in adolescences and adulthood as muscle weakness and recurrent rhabdomyolysis, limiting physical activity and compromising quality of life. Despite the recognition and avoidance of known triggers such as exercise, fasting, and stress, many patients suffer unexplained periodic episodes of muscle breakdown. While avoidance of fatty meals is recommended, the impact of high-fat consumption alone on muscle biology of CPT-deficient patients is not well defined. Mice with muscle specific CPT2-deletion (Cpt2Sk-/-) and control littermates, were placed on control or high-fat diet (HFD) (60% kcal) for up to 8 weeks. Muscle contractility, transcriptional and protein signatures, mitochondrial metabolic capacity, and histopathology were determined. After 8 weeks on the diet, Cpt2Sk-/- ex vivo muscle force production was significantly reduced by high-fat feeding in the glycolytic EDL and oxidative soleus muscles. In response to HFD, Cpt2Sk-/- muscle mitochondrial respiratory capacity was significantly reduced, despite increased mitochondrial biogenesis, across various muscles. Importantly, HFD further deteriorated the structural integrity of oxidative soleus muscle in CPT2-deficient mice, characterized by reduced fiber size and the presence of ragged red fibers. Together, these data indicate that chronic high dietary fat intake exacerbates the underlying mitochondrial and myopathic dysfunction caused by CPT2 deficiency. This diet-induced worsening of muscle pathology may provide a mechanistic explanation for the symptom exacerbation experienced by individuals with CPT2 deficiency following fatty food consumption.

Keywords:  Carnitine palmitoylcarnitine transferase 2; Contraction; Fatty acid oxidation disorders; High-fat diet; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1016/j.ymgme.2026.110197
Nutrients. 2026 Jun 20. pii: 2004. [Epub ahead of print]18(12):

Ketogenic Diet in Obesity and Diabetes: A Narrative Review.

Yousun An, Nicholas Norris, Donglai Li, Jenny E Gunton.

  A ketogenic diet (KD) is a low-carbohydrate, high-fat dietary approach. Beyond treating neurologic disorders, KDs have attracted significant media attention for their potential to improve obesity and diabetes. The diet induces a metabolic shift from glucose toward fatty acid oxidation and ketone body production. This shift leads to ketosis, which may reduce hunger, partly through the anorexigenic effects of ketone bodies, thereby contributing to weight loss and improved metabolic parameters, including glycaemic control and insulin sensitivity. In particular, the positive effects of KDs lower insulin demand and may thereby improve β-cell function. However, the long-term efficacy, safety, and sustainability of KDs, especially for diabetes, remain debated. This review offers current insights into the effects of ketogenesis and ketosis, as well as the potential mechanisms underlying them. We explore the metabolic effects of KDs in obesity and diabetes, drawing on preclinical and clinical studies, and suggest that combining KDs with antidiabetic agents may provide synergistic benefits. However, combining KDs with these pharmacotherapies, particularly SGLT-2 inhibitors, requires careful clinical supervision because of potential risks, including euglycaemic diabetic ketoacidosis. We explore how a KD alters the composition of the gut microbiota, thereby affecting host health. We conclude by highlighting challenges and future directions for optimising KD-based therapies and by outlining the limitations of the current review.

Keywords:  KD; diabetes; glycaemic control; gut health; immune response; obesity; weight loss; β-cells

DOI:  https://doi.org/10.3390/nu18122004
Adv Exp Med Biol. 2026 ;1514 207-253

The Pyruvate Dehydrogenase Complex: A 90-Year-Old Enigma Shaping the Future of Structural Enzymology.

Toni K Träger, Fotis L Kyrilis, Greg Kafetzopoulos, Christian Tüting, Panagiotis L Kastritis.

  The ancient pyruvate dehydrogenase complex (PDHc) performs the "link reaction" of cellular respiration-a discovery from the 1930s that was central in the award of the 1953 Nobel Prize in Physiology and Medicine to Krebs and Lipmann. Fast forward to 2024, PDHc emerges with roles in Alzheimer's, cancer, and neurodegeneration, as well as in obesity and aging processes. Due to these recent reports, structural analysis of PDHc, a 10-megadalton enzymatic complex, comes into focus-only now this analysis begins to unveil an enormous and challenging molecular complexity. Cutting-edge techniques and methods, such as cryo-electron microscopy (cryo-EM), cross-linking (XL) and mass spectrometry (MS), advanced molecular and biochemical analysis, and computational structural biology, powered by artificial intelligence (AI), converge to systematically probe the mechanistic details governing PDHc function. This chapter collects and updates the knowledge in PDHc structure and function and pinpoints unresolved questions, with the hope of not waiting another 90 years for their answer.

Keywords:  Acetyl-CoA; Citric acid cycle; Enzyme regulation; Glycolysis; Histone acetylation; Keto acid dehydrogenase complex family; Krebs cycle; Metabolic diseases; Metabolon; Mitochondria; Mitochondrial pyruvate carrier; Nuclear function; Pyruvate oxidation regulation; Respirasome; Structural biology; TCA cycle

DOI:  https://doi.org/10.1007/978-3-032-26629-3_9
Nat Commun. 2026 Jun 23. pii: 5563. [Epub ahead of print]17(1):

Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.

Laura Pérez Pañeda, Jelena Misic, Tereza Kadavá, Nils-Göran Larsson, Albert J R Heck.

Mitochondrial oxidative phosphorylation (OXPHOS) comprises multi-subunit protein complexes that operate in coordination with the tricarboxylic acid (TCA) cycle to generate ATP. Although these systems are metabolically interconnected, complex II is generally regarded as the only direct structural link between OXPHOS and TCA cycle. Here, we combine in-solution crosslinking mass-spectrometry (XL-MS), quantitative proteomics, complexome profiling and blue native PAGE (BN-PAGE) to explore how ATP synthase (complex V) is positioned within the mitochondrial metabolic network under physiological and pathological conditions. We demonstrate that in murine wild-type hearts, the F₁ catalytic head of ATP synthase forms extensive contacts with TCA cycle enzymes, establishing a previously unanticipated spatial link between OXPHOS and central carbon metabolism. We further report that loss of the mitochondrial RNA-stabilizing protein LRPPRC, which disrupts mtDNA gene expression in the mouse heart, results in ATP synthase destabilization and enhanced F1-TCA cycle interactions. Moreover, ATP synthase dysfunction promotes binding of the ATPase inhibitory factor 1 (ATIF1) to the F₁ head via its N-terminal inhibitory region, shifting the ATP synthase toward an energy-preserving state. Together, our findings show that impaired mitochondrial gene expression leads to secondary ATP synthase remodeling and reshaping of its interaction landscape, revealing how mitochondria may adapt to bioenergetic stress.

DOI: https://doi.org/10.1038/s41467-026-74730-5
bioRxiv. 2026 Jun 09. pii: 2026.06.05.730515. [Epub ahead of print]

Revealing the spatiotemporal dynamics of methionine metabolism with a genetically encoded single-fluorophore biosensor.

Katarina A Cohen, Arnav Jhawar, Gilberto Garcia, Naiara Goni, Megan Chen, Athena Alcala, Ryo Higuchi-Sanabria, Danielle L Schmitt.

Methionine is an essential amino acid, used for protein synthesis, redox homeostasis, and methylation reactions throughout the cell. However, the compartmentalized dynamics of methionine have remained elusive, due to a lack of available tools to measure methionine with high spatial and temporal resolution. To address this limitation, we have developed a single fluorescent protein-based methionine optical reporter (Meteor) which reports subcellular changes in methionine with high dynamic range. Using Meteor, we demonstrate the subcellular uptake of methionine in multiple cell lines into several locations, including the mitochondrial matrix. Furthermore, we use Meteor to illuminate the dynamics of the methionine cycle in the cytoplasm and nucleus, finding cancer cells can rapidly increase methionine from metabolic precursors in both locations. Finally, demonstrated that Meteor can be used to visualize methionine dynamics in vivo using Caenorhabditis elegans . Thus, we have developed a new tool to measure methionine dynamics across scales with high dynamic range and spatiotemporal resolution.

DOI: https://doi.org/10.64898/2026.06.05.730515
Cell Death Dis. 2026 Jun 25.

Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.

Lauren Brakefield-Laird, Amit Budhraja, Peter M Hall, Dixie Brewington, Jamila Moore, Josi Lott, Yonghui Ni, Dennis Voronin, Oliver Grant-Chapman, Tresor O Mukiza, Tristen Wright, Yong-Dong Wang, Sandi Radko-Juettner, Shondra M Pruett-Miller, Stanley Pounds, Peter Vogel, Joseph T Opferman.

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

DOI: https://doi.org/10.1038/s41419-026-09037-w
Acta Crystallogr D Struct Biol. 2026 Jul 01.

Molecular architecture of the human citrate synthase-malate dehydrogenase 2 metabolon.

Angela J Kayll, Umanga Rupakheti, Renee St John, Gabriel Rementeria, Joseph J Provost, Christopher E Berndsen.

  Metabolons are transient biomolecular complexes that enhance the efficiency of metabolic pathways through substrate channeling. These complexes are difficult to study because of their transient nature, thus limiting our understanding of how they are formed and regulated. The citric acid cycle is proposed to contain many such complexes, although few have been characterized structurally. Here, we provide direct structural evidence for the complex of human citrate synthase (hCS) and human mitochondrial malate dehydrogenase 2 (hMDH2), which is part of the larger proposed citric acid cycle metabolon. Our structural model supports previous cross-linking studies and suggests that hMDH2 can interact with each subunit of the hCS dimer, forming up to a hexameric complex. However, this complex appears to be transient, as titration of hMDH2 into hCS in activity assays does not saturate. We further show that the interaction site with hCS is nonspecific, as hCS could also stimulate oxaloacetate formation by cytosolic and plant MDH enzymes. This structural model will provide a basis for understanding the structure and regulation of the broader citric acid cycle metabolon.

Keywords:  SAXS; citrate synthase; malate dehydrogenase; metabolons

DOI:  https://doi.org/10.1107/S2059798326005802
bioRxiv. 2026 Jun 09. pii: 2026.06.04.730197. [Epub ahead of print]

Rosindol: A fluorogen for the quantitative measurement of reactive oxygen species in living cells.

Andrew Monnone, Molly Nicknish, Juan Jaramillo Montezco, Christine Sanganoo, Nalin Aggarwal, Arista Luong, Scott Schaus, Mark Grinstaff.

Reactive oxygen species (ROS) are key mediators of disease, yet accurate characterization in living systems remains challenging because current probes lack oxidation specificity and produce nonlinear, pH-dependent signals. Here we introduce Rosindol, a novel thioacetal-based fluorogenic probe that overcomes these limitations. Rosindol undergoes an umpolung oxidation in the presence of ROS to generate fluorescence, displaying dose-linear responses to H 2 O 2 , O 2 •⁻, OH•, and HOCl with minimal background signal. Unlike conventional probes, Rosindol is pH-independent, photostable, water soluble, and agnostic to glucose concentration, esterase expression, and ambient oxygen. Validation in human cells-including PMA-stimulated neutrophils and SOD knockout models-confirms accurate detection of cytosolic and mitochondrial ROS. In pancreatic cancer cells, Rosindol reveals a fourfold increase in mitochondrial O 2 •⁻ generation capacity via Complex I of the electron transport chain. Glucose stimulation induces twofold higher ROS generation in malignant cells, highlighting a connection between Warburg metabolism and the etiology of oxidative stress in pancreatic cancer. These studies illustrate the utility of Rosindol to provide valuable insight to oxidative stress processes in complex biological environments.

DOI: https://doi.org/10.64898/2026.06.04.730197
Adv Exp Med Biol. 2026 ;1514 255-298

Enzyme Assemblies in Nucleotide Metabolism: Structure, Regulation, and Disease Implications.

Jack P Boylan, Timothy D Iles, Alexis Nguyen, Anthony M Pedley.

  Nucleotide biosynthesis is essential for cell growth and relies on the coordination of both salvage and de novo pathways to satisfy intracellular needs. While traditionally, the regulation of these pathways has been attributed to factors like substrate availability, genetic rewiring, and metabolite-driven feedback inhibition, recent findings have unveiled a new, more complex layer of regulation. Enzymes within these pathways assemble into dynamic supramolecular protein assemblies, such as metabolons and filaments, which findings suggest might influence enzymatic activity and regulate nucleotide flux. Advances in fluorescence microscopy and cryo-electron microscopy have enhanced our ability to characterize the spatial and temporal dynamics, as well as the biophysical properties, of these assemblies. In this chapter, we explore the diverse higher-order purine and pyrimidine metabolic enzyme assemblies, highlight how state-of-the-art microscopy has transformed our understanding of their structures and regulatory roles in nucleotide biosynthesis, and discuss their implications in human disease.

Keywords:  Biomolecular condensates; Filaments; Metabolism; Metabolon; Nucleotide; Protein complexes; Purine; Pyrimidine; Regulation

DOI:  https://doi.org/10.1007/978-3-032-26629-3_10
Eur J Epidemiol. 2026 Jun 25.

Adherence to the Mediterranean diet and risk of pancreatic cancer: an analysis of 2.3 million participants in the Pooling Project of Prospective Studies of Diet and Cancer (DCPP).

Qinting Shen, Claire Mobley, Molin Wang, Pietro Ferrari, Hans-Olov Adami, Nina Afshar, Ana Babic, Piet A van den Brandt, En Cheng, A Heather Eliassen, Teresa T Fung, Edward L Giovannucci, Mayo Hirabayashi, Tao Hou, Brian Z Huang, Wen-Yi Huang, Corinne E Joshu, Rieko Kanehara, Verena Katzke, James V Lacey, Matthew J Landry, Susanna C Larsson, Linda M Liao, Maria Elena Martinez, Marjorie L McCullough, Anthony B Miller, Roger L Milne, Steven C Moore, Lorelei A Mucci, Sabine Naudin, Anna Prizment, Song-Yi Park, Thomas E Rohan, Elio Riboli, Kim Robien, Sven Sandin, Norie Sawada, Marissa M Shams-White, Rashmi Sinha, Karl Smith-Byrne, Meir J Stampfer, Rachael Z Stolzenberg-Solomon, Caroline Y Um, Kala Visvanathan, Sophia S Wang, Elisabete Weiderpass, Emily White, Walter C Willett, Alicja Wolk, Brian M Wolpin, Chen Yuan, Stephanie A Smith-Warner, Jeanine M Genkinger.

  Pancreatic cancer incidence is rising, yet few modifiable risk factors have been identified. The Mediterranean diet, which lowers inflammation and improves healthy weight maintenance and insulin control, may lower pancreatic cancer risk, yet the evidence for this association is inconsistent. To investigate the association, we conducted a pooled analysis of 2,315,406 individuals from 23 prospective cohorts in the Pooling Project of Prospective Studies of Diet and Cancer (DCPP), of whom 10,748 developed incident pancreatic cancer over a mean follow-up duration ranging from 8.1 to 23.3 years across studies. Adherence to the Mediterranean diet was assessed using the alternative Mediterranean diet score (aMED) and a modified score excluding alcohol (maMED). Study- and sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models and then pooled using random effect models. No statistically significant association was found between aMED or maMED and pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) risk. For aMED, the pooled pancreatic cancer HR was 0.96 (95% CI: 0.90-1.02) comparing the fourth to the first quartile, 0.94 (0.88-1.00) comparing high (6-9) versus low (0-3) scores, and 0.98 (0.96-1.00) per 2-unit increment in the score. Overall, there was no evidence of heterogeneity in these associations by sex, attained age, race, BMI, physical activity, or follow-up time; a positive association between maMED and pancreatic cancer risk was observed in past smokers (HR = 1.04, 95% CI 1.00-1.09) but not in never or current smokers (Pinteraction=0.04). In conclusion, there was little evidence of an association between a Mediterranean diet score and pancreatic cancer risk in this large international pooled analysis.

Keywords:  Dietary patterns ; Mediterranean diet; Pancreas; Pancreatic cancer; Pooled analysis; Pooling project

DOI:  https://doi.org/10.1007/s10654-026-01418-x
Cell Death Dis. 2026 Jun 22.

Glucose starvation induces fumarate hydratase succinylation and inhibits ferroptosis to maintain colon cancer cell proliferation.

L T Sun, X H Qin, Y D Zheng, Z Y Zhang, Q Wang.

Cancer cells frequently reside in a glucose-deprived microenvironment due to rapid tumor proliferation and insufficient angiogenesis. However, the mechanisms by which colorectal cancer cells (CRC) adapt to glucose starvation to sustain proliferation remain unclear. Succinylation, a novel post-translational modification, has been implicated in regulating tumor cell proliferation and survival under nutrient stress. Our study reveals that fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, is downregulated in CRC and acts as a tumor suppressor. Under glucose starvation mimicked in vitro, FH protein expression is reduced, leading to abnormal accumulation of its upstream metabolites fumarate and succinate, which correlates with advanced clinical stage and poor prognosis in CRC patients. Mechanistically, accumulated fumarate specifically binds to and stabilizes the NRF2 protein, upregulating the expression of GPX4 and FTH1 to inhibit ferroptosis, thereby sustaining CRC cell proliferation. Meanwhile, glucose starvation induces CPT1A-mediated succinylation of FH at residues K66/K80, reducing FH protein stability and promoting its degradation via the autophagy-lysosome pathway. Our findings reveal the critical role of FH and its succinylation in CRC cell adaptation to glucose starvation, inhibiting ferroptosis, and maintaining cancer cell proliferation, providing novel potential targets and a theoretical basis for the clinical treatment of CRC.

DOI: https://doi.org/10.1038/s41419-026-08975-9
J Exp Clin Cancer Res. 2026 Jun 23. pii: 143. [Epub ahead of print]45(1):

Targeting metabolic dependencies to reverse chemoradiotherapy resistance in colorectal cancer.

Maximilian Hellkamp, Simon Gertken, Jonas Buchloh, Julius-Leonard Hellwig, Lukas Ben Kowitzke, Ningjun Duan, Ilaria Gaspardo, Stefan Küffer, Michael Linnebacher, Philipp Ströbel, Matthias Wirth, Volker Ellenrieder, Stefan Rieken, Jochen Gaedcke, Michael Ghadimi, Jürgen Wienands, Günter Schneider, Melanie Spitzner, Marian Grade.

  Neoadjuvant chemoradiotherapy (CRT) constitutes a standard treatment for locally advanced rectal cancer (RC), frequently followed by radical surgical resection. Yet, therapeutic responses vary widely, and intrinsic radioresistance remains a major barrier to cure. To uncover actionable determinants of CRT response, we established a panel of patient-derived colorectal cancer cell lines (PDCLs) followed by integrated phenotypic and functional characterization. We identified metabolic reprogramming as a hallmark of radioresistance and, through orthogonal validation experiments, confirmed elevated glycolytic and mitochondrial ATP production in (chemo)irradiation-resistant PDCLs. The causative relationship of this association and its potential for therapeutic intervention was shown by subsequent drug screening, showing resistance to most of the applied drugs and revealing a critical dependency on the monocarboxylate transporter (MCT1) and the glucose transporter 1 (GLUT1). Metabolism-targeting compounds re-sensitized resistant PDCLs to irradiation; especially inhibition of GLUT1 exhibits a robust radiosensitizing activity across models. Concordantly, GLUT1 expression correlated with poor response to neoadjuvant CRT in our own RC patient cohort and various publicly available patient datasets. Collectively, our study defines metabolic dependency as a key driver of CRT resistance in RC, and reveals glycolysis- and lactate-transport-associated pathway activities as targetable vulnerabilities. These findings provide a mechanistic basis for patient stratification and support the development of metabolism-directed strategies to overcome (chemo)radioresistance in RC.

Keywords:  GLUT1; MCT1; chemoradiotherapy; glycolysis; metabolism; rectal cancer; therapy resistance

DOI:  https://doi.org/10.1186/s13046-026-03755-x
Nat Cancer. 2026 Jun;7(6): 944-963

Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics.

Xin He, Lei Zhang, Yang Li, Song-Bai Liu, Zheng Li, Haojie Dong, Genevieve E Baker, Le Xuan Truong Nguyen, Wei Chen, Jinhui Wang, Zhilian Jia, Xiyuan Lu, Yi-Chun Lin, Zunsong Hu, Umesh Prasad Yadav, Meng Liu, Lianjun Zhang, Zhenhua Chen, Xiwei Wu, Jianjun Chen, Chun-Wei Chen, Stefano Tiziani, Weidong Hu, Ya-Huei Kuo, Sheng-Li Xue, Yong Zhang, Min Li, Yaoqiu Zhu, Guido Marcucci, Zhaohui Gu, J Jefferson P Perry, Yun Lyna Luo, Ling Li.

De novo purine synthesis is required to maintain tumor growth; however, its impact on therapy resistance remains unclear. Here, through a dynamic BH3-priming-based CRISPR screen, we found that deletion of ADSS2, which encodes the adenylosuccinate synthase 2 enzyme essential for adenosine monophosphate (AMP) synthesis, re-sensitizes drug-resistant acute myeloid leukemia cells to venetoclax and a myeloid cell leukemia-1 (MCL1) inhibitor. Single-cell sequencing analysis of patient-derived xenograft samples revealed a positive association of high ADSS2 activity in TP53-mutant cells with poor responsiveness to venetoclax. We developed an ADSS2 antagonist, which synergized with BH3 mimetics to promote apoptosis in preclinical models. Mechanistically, sensitization mediated by ADSS2 targeting correlated with downregulated AMP-activated protein kinase activity, which in resistant cells promotes mitophagy to eliminate damaged mitochondria after BH3 mimetic treatment. These data show that AMP synthesis promotes BH3 mimetic resistance and that combining ADSS2 targeting with BH3 mimetics represents a promising anti-cancer approach.

DOI: https://doi.org/10.1038/s43018-026-01184-5
Cells. 2026 Jun 11. pii: 1066. [Epub ahead of print]15(12):

Small-Molecule Targeting of VDAC Disrupts Mitochondrial Bioenergetics and Suppresses Melanoma Cell Survival and Migration.

Zhi-Wei Ye, Leilei Zhang, Xuhong Zhang, John Culpepper, Eduardo N Maldonado, Kenneth D Tew, Jie Zhang, Danyelle M Townsend.

  Melanoma is a highly aggressive and metabolically adaptable cancer that often resists conventional therapies. Targeting core bioenergetic pathways may, therefore, represent an effective strategy to improve therapeutic responses, particularly in tumors dependent on mitochondrial function. SC18 is an imidazolidine-2,4-dione compound that binds the NADH-binding pocket of voltage-dependent anion channels (VDACs), inducing mitochondrial dysfunction. VDAC expression is increased in melanoma and strongly associated with advanced disease stage and poor prognosis. In this study, we evaluated the effects of SC18 in melanoma cell lines with distinct pigmentation states, including melanin-rich melanotic human MNT-1 and mouse B16-F1, as well as low/amelanotic human SKMel28 and mouse YUMM cells. VDAC1, VDAC2 and VDAC3 were highly expressed across these melanoma lines, all of which relied on both glycolysis and mitochondrial oxidative phosphorylation for ATP production. SC18 reduced mitochondrial membrane potential and oxygen consumption rates, accompanied by declines in intracellular ATP levels and TCA cycle substrate utilization. SC18 also increased reactive oxygen species, mitochondrial superoxide, and lipid peroxidation, indicating enhanced oxidative stress. These metabolic and redox disturbances were associated with reduced cell viability and significantly impaired migration in multiple melanoma cell lines, supporting a potential anti-metastatic effect. In addition, SC18 showed synergistic cytotoxicity when combined with other chemotherapeutic agents. Overall, SC18 disrupted mitochondrial metabolism, induced oxidative stress, and impaired survival and motility pathways, with more pronounced effects in low/amelanotic than in melanotic melanoma cells. Together, these findings support the further development of SC18 as a mitochondrial metabolic disruptor that targets redox vulnerabilities in melanoma.

Keywords:  SC18; VDAC; amelanotic melanoma; melanoma; mitochondrial bioenergetics; oxidative stress; reactive oxygen species; redox vulnerability

DOI:  https://doi.org/10.3390/cells15121066
Nature. 2026 Jul;655(8121): 45-46

Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.

Amaia Zabala-Letona, Arkaitz Carracedo.



Keywords:  Biochemistry; Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-026-01802-3
Nutrition. 2026 May 27. pii: S0899-9007(26)00209-1. [Epub ahead of print]150 113301

Fluxomics in precision nutrition: integrating dynamic metabolic profiling with multiomics.

Fabian Lanuza, Sharon Viscardi, David S Wishart, Cristina Andrés-Lacueva.

  Precision nutrition requires tools that move beyond static dietary biomarkers toward approaches that capture the dynamic nature of human metabolism. Fluxomics, the study of metabolic fluxes, offers valuable opportunities to enrich nutritional research by revealing temporal patterns of dietary responses and clarifying mechanisms that underlie inter-individual variability. In this review, we examine how fluxomics, when combined with metabolomics and broader multiomics approaches, can help identify responder and nonresponder phenotypes, refine metabotype-based dietary recommendations, and strengthen causal inference in nutrition studies. We outline the methodological foundations of fluxomics, including stable isotope tracer administration, high-resolution MS and NMR, and computational frameworks that translate isotopomer data into quantitative flux maps. We further examine recent advances in postprandial profiling, isotopic tracing, and longitudinal repeated-measure designs that are expanding the translational potential of fluxomics in nutrition research. Artificial intelligence is positioned as a supportive analytical layer that facilitates the integration, scalability and interpretation of complex datasets in fluxomics-informed precision nutrition. Finally, we discuss current challenges related to standardization, reproducibility, scalability, and ethical governance. Addressing these barriers through well-designed longitudinal interventions in diverse populations will be essential to advance fluxomics from experimental settings toward more targeted and equitable precision nutrition strategies.

Keywords:  Artificial intelligence; Biomarkers; Fluxomics; Metabolomics; Multiomics; Nutrition precision

DOI:  https://doi.org/10.1016/j.nut.2026.113301
Benef Microbes. 2026 Jun 23. 1-13

A lysate of a multi-strain probiotic formulation inhibits cell growth and oxidative phosphorylation in colorectal cancer cells via a ceramide-mediated mechanism.

D Gnocchi, F Lombardi, B Cinque, R R Paparella, P Palumbo, A Mazzocca.

The multi-strain probiotic formulation (MPF - Oxxyslab™) regulates several biological processes, including oxygenation in human and mouse models of neurodegenerative diseases. Its effect on oxidative metabolism of tumour cells has not yet been investigated. Employing a polarographic approach, we examined the effect of a lysate of MPF and its constituent strains on oxidative phosphorylation (OXPHOS) in colorectal cancer cells. Results indicate that MPF lysate selectively inhibits OXPHOS in undifferentiated but not in differentiated Caco-2 cells. Ceramides, produced through bacterial sphingomyelinase activity, mediate the inhibitory effects of MPF lysate, and the efficacy of the lysate of individual MPF strains in blocking cellular respiration varies due to strain-specific differences in ceramide production. Our results demonstrate that MPF lysate exhibits anti-OXPHOS activity in human colorectal carcinoma cells, selectively targeting undifferentiated Caco-2 cells but not differentiated ones. The reliance of colorectal cancer cells on OXPHOS provides a scientific basis for exploring MPF probiotic formulation as a complementary approach to conventional pharmacology.

DOI: https://doi.org/10.1163/18762891-bja00124
EMBO J. 2026 Jun 26.

Assembly of the catalytic module and the rotor of human ATP synthase.

Jiuya He, Joe Carroll, Shujing Ding, Jiao Li, Ian M Fearnley, John E Walker.

Human ATP synthase is a molecular rotary machine bound in inner mitochondrial membranes, built from twenty-eight subunits of seventeen kinds, two encoded in mitochondrial DNA, the remainder in nuclear genes. The machine consists of a rotor and an interacting stator. Turning of the rotor driven by a transmembrane proton motive force effects a cycle of structural changes in the catalytic part of the stator, producing three ATP molecules per rotation. Here, to establish how the stator and rotor are assembled, we deleted subunits and known assembly factors from human cells, purified and accumulated assembly intermediate complexes, and characterized them by gel analysis and mass spectrometry, allowing us to propose pathways of assembly of the rotor and the catalytic F1-module of the stator. These observations provide opportunities for further development by structural analysis of the accumulated intermediates. The compositions of the various assembly intermediates support the view that ATP synthase arose via independent evolution of its three constituent structural components, the catalytic F1-module, the peripheral stalk module, and the membrane-associated Fo-module.

DOI: https://doi.org/10.1038/s44318-026-00842-9
Cancers (Basel). 2026 Jun 10. pii: 1895. [Epub ahead of print]18(12):

The Imipridone ONC206 Inhibits Tumor Growth and Improves Survival in Patient-Derived Xenograft Models of Uveal Melanoma.

Mir Mustafa Ali, Md Alauddin, Iqbal Mahmud, Aron Joon, Aalim B Momin, Jacob R Cortez, Huiqin Chen, Lin Tan, Waikin Chan, Rachel William Anantha, Danielle L Stolley, Diana Shamsutdinova, Kurt Evans, Funda Merric-Bernstam, Meenhard Herlyn, Monzy Thomas, Yeqing Chen, Michael A Davies, Chandrani Chattopadhyay.

  Background/Objectives: Uveal melanoma is the most common primary ocular cancer in adults. Patients with metastatic uveal melanoma (mUM) have limited treatment options and poor prognosis. mUM is characterized by high oxidative phosphorylation (OXPHOS), which may be a therapeutic vulnerability for this disease. ONC206 is an imipridone compound that can inhibit OXPHOS indirectly and is currently being evaluated in clinical trials. Thus, we tested the effects of ONC206 on human uveal melanoma cell lines and patient-derived xenografts (PDXs) in vitro and in vivo. Methods: The effects of ONC206 on cell survival, apoptosis, autophagy, oncogenic signaling pathways, and metabolic networks were assessed in vitro using human melanoma cell lines. ONC206 was then tested for safety and anti-tumor activity in vivo using two mUM PDX models. Results: ONC206 treatment produced dose-dependent inhibition of mUM cell growth in vitro, with induction of varying levels of apoptosis and autophagy. ONC206 treatment also downregulated OXPHOS effector proteins and metabolites, thereby impairing mitochondrial OXPHOS. Treatment with ONC206 significantly reduced tumor burden and improved survival in two UM PDX mouse models in vivo. Conclusions: Our findings position ONC206 as a mechanistically distinct agent to target mitochondrial metabolism and to inhibit mUM. As ONC206 is currently being evaluated in multiple clinical studies, our data support further evaluation as a potential new therapeutic strategy for mUM.

Keywords:  PDX; autophagy; imipridones; lipidomics; liver metastasis; oxidative phosphorylation; uveal melanoma (UM)

DOI:  https://doi.org/10.3390/cancers18121895
Cell Death Dis. 2026 Jun 25.

Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma.

Yeting Xu, Hongjiang Guo, Shengxi Li, Yucheng Wang, Yinghao Cao, Lin Wang, Qiuxia Chen, Ziyi Qin, Jiaxing Qiu, Yuhan Liu, Yunfan Li, Jiaming Zou, Yingying Wang, Kaihan Zhang, Rui Ju, Lei Guo.

Pancreatic ductal adenocarcinoma (PDAC) exhibits hyperactive mitochondrial metabolism, yet how this rewiring spatially restricts the availability of metabolites for oncogenic signaling and drives systemic metabolic dysregulation in PDAC remains unknown. Here, we identify enhanced mitochondrial α-ketoglutarate (α-KG) sequestration as a key metabolic vulnerability in PDAC. Using multi-omics, preclinical models, and clinical correlation analyses, we identified elevated mitochondrial metabolic gene expression in PDAC. Moreover, higher expression of dihydrolipoamide succinyltransferase (DLST) correlates with poorer PDAC prognosis, suggesting the role of mitochondrial α-KG sequestration in PDAC progression. Targeting mitochondrial respiration with the complex I inhibitor carboxyamidotriazole orotate (CTO) redirected α-KG flux from mitochondrial sequestration, and increased α-KG-dependent m6A demethylation of MYC mRNA and HIF-1α hydroxylation. Combining CTO or α-KG dehydrogenase complex inhibitor devimistat with an α-KG analog (dimethyl α-KG) amplified c-Myc/HIF-1α suppression. Consequently, prolonged CTO exposure downregulated multiple metabolic pathways (glycolysis, pentose phosphate pathway, fatty acid synthesis) regulated by c-Myc/HIF-1α, and significantly delayed PDAC progression in vitro and in vivo. Our work first identify a novel mechanism whereby mitochondrial metabolism drives systemic metabolic dysregulation in PDAC through the sequestration of α-KG, and establishes "redirecting α-KG flux from mitochondrial sequestration" as a strategy to disable PDAC's metabolic adaptability. The orotate salt form of carboxyamidotriazole effectively disrupts mitochondrial α-KG sequestration to suppresses PDAC growth at a dose equivalent to the clinically tested level.

DOI: https://doi.org/10.1038/s41419-026-09016-1
J Med Chem. 2026 Jun 23.

Discovery of SMD-6346: A Potent, Selective, and Orally Active SMARCA2 Degrader for Targeting SMARCA4-Deficient Human Cancers.

Lingying Leng, Liyue Huang, Wenbin Tu, Wei Jiang, Rohan Kalyan Rej, Srinivasa Rao Allu, Yu Wang, Mi Wang, Jelena Tošović, Meilin Wang, Bo Wen, Duxin Sun, Shaomeng Wang.

Selective targeting SMARCA2 by degradation represents a promising new therapeutic strategy for human cancers harboring deficient SMARCA4. Herein we report the discovery of highly potent, selective and oral available SMARCA2 PROTAC degraders, as exemplified by SMD-6346. SMD-6346 achieves DC50 = 3.3 nM and Dmax > 90% against SMARCA2 and only modest activity against SMARCA4 (DC50 > 1000 nM, Dmax = 46%). SMD-6346 potently and effectively inhibits cell growth in SMARCA4-deficient cancer cell lines and displays minimal cell growth inhibition activity in SMARCA2/4 wild-type cancer cell lines. SMD-6346 attains an excellent pharmacokinetic profile and 61% oral bioavailability in mice. Daily oral administration of SMD-6346 induces robust SMARCA2 depletion in tumor tissues in mice and significantly inhibits tumor growth in the H838 SMARCA4-deficient xenograft model in mice. SMD-6346 is a promising, orally bioavailable SMARCA2 degrader for further optimization for the development of a new therapy for SMARCA4-deficient human cancers.

DOI: https://doi.org/10.1021/acs.jmedchem.6c01093
Elife. 2026 Jun 25. pii: RP107596. [Epub ahead of print]14

Mycobacterium tuberculosis partitions the Krebs cycle under iron starvation.

Agnese Serafini, Acely Garza-Garcia, Davide Sorze, Luiz Pedro Sorio de Carvalho, Riccardo Manganelli.

  In this study, we investigated how iron limitation alters central metabolism in Mycobacterium tuberculosis using metabolomics and stable isotope tracing. Our findings reveal a well-orchestrated metabolic programme to enable Krebs cycle activity despite the inefficient action of its iron-dependent enzymes. Under such conditions, carbon flux through the oxidative branch of the Krebs cycle is stalled, resulting in the accumulation of metabolites that are partially secreted. As a result, carbon flux from glycolysis is partially diverted to the reductive branch of the Krebs cycle to support the production of oxaloacetate and malate through the activity of phosphoenolpyruvate carboxykinase and pyruvate carboxylase. Both branches terminate with the synthesis of malate, which is secreted. This unprecedented split of the Krebs cycle and malate secretion in a bacterial pathogen facilitates the continuous flow of carbon through the core of carbon metabolism, overcoming the metabolic stalling triggered by iron starvation.

Keywords:  Mycobacterium tuberculosis; central carbon metabolism; infectious disease; iron starvation; isotope tracing; microbiology; nutritional immunity

DOI:  https://doi.org/10.7554/eLife.107596
bioRxiv. 2026 Jun 10. pii: 2026.06.09.730804. [Epub ahead of print]

Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.

Michel Thiebaut de Schotten, Cynthia C Liu, Catherine Kelly, Ke Bo, Tor D Wager, Eugene V Mosharov, Martin Picard.

Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.

DOI: https://doi.org/10.64898/2026.06.09.730804
EJHaem. 2026 Jun;7(3): e70280

Comparison of Venetoclax-Based Treatments for Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia: A Single-Center Real-World Experience.

Benjamin Heyman, Michael Choi, Thomas J Kipps.

   Introduction: The optimal venetoclax-based treatment for patients with relapsed/refractory (R/R) CLL is still unknown, especially for high-risk patients.
Methods: We performed a retrospective analysis of 98 patients with R/R CLL treated with venetoclax-based regimens. Patients received venetoclax alone or in combination with rituximab (VenR), obinutuzumab (VenO), or a BTKi (primarily ibrutinib).
Results: Combination groups achieved higher complete remission (CR) and uMRD rates: VenO (CR 68%, uMRD 86%), VenR (CR 63%, uMRD 82%), Ven + BTKi (CR 43%, uMRD 70%), versus monotherapy (CR 51%, uMRD 67%). At a median 52-month follow-up, median PFS was superior in combination arms (76.6 months) compared to monotherapy (58.9 months, p = 0.04).
Conclusion: This analysis validates, in a real-world academic cohort, that venetoclax-based combination therapy, particularly with obinutuzumab or BTKi, yields higher rates of deep remission and superior PFS compared to monotherapy for R/R CLL.

Keywords:  BTKi; chronic lymphocytic leukemia; minimal residual disease; obinutuzumab; relapsed/refractory; rituximab; venetoclax

DOI:  https://doi.org/10.1002/jha2.70280