bims-medica 2026-05-10 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–05–10
37 papers selected by
Brett Chrest, Wake Forest University

Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
Aconitase 2 the rescue: A safeguard against excess mitochondrial citrate.
Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
Ketone ester supplementation in aged mice reduces activation of B cell subsets.
Emerging roles and regulatory mechanisms involved in glutamine metabolism.
Plasma metabolites after 10-weeks of glucose vs fructose-sweetened beverages in subjects with overweight/obesity.
HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content.
Molecular Principles of Gating Proton Transport in the Antiporter Modules of Respiratory Complex I.
Complex I protein NDUFB9 is a metabolic vulnerability in triple negative breast cancer brain metastases.
Loss of pyruvate carboxylase suppresses lethality in propionic acidemia.
Metabolic energy expenditure in human blood long-lived neutrophils reprogrammed with inflammatory cytokines.
Macronutrient Composition and Genetic Background Determine the Response to a Ketogenic Diet.
Does a low-carbohydrate diet impede endurance sports performance? No.
Lactylation landscape of mitochondrial proteins in myocardial infarction.
The Spectrum of Venetoclax-Based Treatments in Acute Myeloid Leukemia.
Transposable elements shape stemness in normal and leukemic hematopoiesis.
Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
Metabolic assessment of iPSC-derived neurons under ketone-enriched condition: Ketone sensor development and BHB-driven metabolic adaptation.
The Combination of Methionine Adenosyltransferase 2A (MAT2A) Inhibitor AG-270 and Recombinant Methioninase Is Not Cancer-selective in a Co-culture Model of Colon Cancer Cells and Normal Fibroblasts.
CPT1B promotes acute myeloid leukemia progression via fatty acid oxidation-dependent metabolic reprogramming.
Bioengineered systems to exploit tumor microenvironment metabolism.
Skeletal muscle mitochondrial bioenergetics in pregnancy: a comparison of in vivo and in vitro outcomes.
MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling.
Proteomic and Metabolomic Profiling Reveal Mitochondrial Transplantation-Mediated Reprogramming in Gastric Cancer Cells.
The role of RAS mutations in leukemia progression, differentiation, and drug resistance.
Mitochondrial Functional Capacity Is Impaired in Angiotensin II-Infused Mice and Not Recovered by Metformin.
How membranes shape up for lipid transfer.
Dual Pathways of Extracellular ATP Action in Cancer Cells: Purinergic Signaling-Driven Senescence and Macropinocytic ATP Internalization.
Lysosomes contribute to the synthesis of tricarboxylic acid-related metabolites in the hippocampus.
Age distinguishes selection from causation in cancer genomes.
Gilteritinib + chemotherapy in children with relapsed/refractory FLT3-ITD AML: results from the phase 1/2 SKIPPER trial.
Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.
Inactivation of ornithine aminotransferase by (1R,4S)-4-Amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid via a stable quinonoid intermediate.
Investigation of mitochondrial inner membrane ion conductance by planar lipid bilayer electrophysiology.
Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML.

Nat Metab. 2026 May 04.

Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.

Madeleine L Hart, David Sokolov, Serwah Danquah, Eric Zheng, Alex D Doan, Kristian Davidsen, David MacPherson, Lucas B Sullivan.

Decreased availability of the amino acid aspartate constrains cell function across diverse biological contexts, but the temporal interplay between aspartate abundance, downstream metabolic changes and functional effects remains poorly understood. Here we show that succinate dehydrogenase (SDH) inhibition suppresses pyrimidine synthesis via dual effects of cellular aspartate depletion and succinate accumulation. Using an aspartate biosensor and live-cell imaging, we monitor aspartate levels and cell proliferation across several models of aspartate limitation. While complex I inhibition or knockout of aspartate biosynthetic enzymes lead to a strict decrease in aspartate levels and impair proliferation, SDH inhibition produces a unique aspartate rebound, yet fails to restore proliferation. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis via succinate accumulation, which competitively inhibits aspartate utilization by mammalian aspartate transcarbamylase (ATCase), a key step in pyrimidine biosynthesis. This metabolic interaction occurs in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress and sensitivity to ATR kinase inhibition. Taken together, these findings define an unexpected role for succinate in modulating cellular nucleotide homeostasis and demonstrate how cascading metabolic interactions can unfold to impact cell function.

DOI: https://doi.org/10.1038/s42255-026-01524-w
Mol Cell. 2026 May 07. pii: S1097-2765(26)00244-3. [Epub ahead of print]86(9): 1595-1597

Aconitase 2 the rescue: A safeguard against excess mitochondrial citrate.

Edrees H Rashan, Sophie D'Halleweyn, Matthew G Vander Heiden.

In a recent issue of Cell, Xie et al.1 report that an important function of mitochondrial aconitase is to limit toxic citrate accumulation, suggesting a role for the canonical TCA cycle in physiology beyond ATP production and precursor biosynthesis.

DOI: https://doi.org/10.1016/j.molcel.2026.04.010
Nat Metab. 2026 May 08.

Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.

Zachary L Sebo, Ram P Chakrabarty, Rogan A Grant, Karis B D'Alessandro, Alec R Koss, Jenna L E Blum, Shawn M Davidson, Colleen R Reczek, Navdeep S Chandel.

Metformin is a versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear. Here we map these and other effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving the uptake of excess glucose and its conversion to lactate and lactoyl-phenylalanine. We also find that glucose lowering by metformin is due to repeated bolus exposure rather than a cumulative chronic response. Notably, the efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.

DOI: https://doi.org/10.1038/s42255-026-01530-y
Res Sq. 2026 Apr 23. pii: rs.3.rs-9405584. [Epub ahead of print]

AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.

Shakti P Pattanayak, Odai Darawshi, Omid Hajihassani, Jordan M Winter, Nicole Weiler, Melanie Ott, Florian Rothweiler, Jindrich Cinatl, Martin Michaelis, Daniel J Lindner, Thomas D Green, Polina Krassovskaia, Raphael T Aruleba, Kelsey H Fisher-Wellman, Jason A Mears, David Wald, Leif A Eriksson, Boaz Tirosh.

Background mTORC1 activity is oncogenic. However, in the presence of chemotherapy, suppression of mTORC1 is cytoprotective. mTOR suppression requires an intact tuberous sclerosis complex (TSC), composed of TSC1, TSC2 and TBC1D7. Small molecules that activate mTOR by blocking the TSC are lacking. Methods We applied in silico docking and medicinal chemistry to generate AcTor, a potential first-of-its-kind TSC2 inhibitor. Because inhibition of TSC2 results in increased sensitivity to proteasome inhibitors, we combined AcTor and the proteasome inhibitor ixazomib (IXZ) in various cancer cell types. Results Potentiation of cytotoxic activity of IXZ by AcTor was observed across multiple acute myeloid leukemia (AML) cell lines and primary patient samples. The combination triggered a collapse of mitochondrial respiratory capacity, loss of mitochondrial membrane potential, accumulation of ROS and apoptosis. These attributes increased in drug-resistant AML. Transcriptomic profiling revealed that AcTor alone induced anabolic and oxidative phosphorylation programs, whereas AcTor/IXZ redirected the signaling towards stress-associated and pro-apoptotic transcriptional states, including a p53 pathway signature. In vivo studies revealed reduction in AML burden, depletion of blasts and of leukemic stem cells, and retention of activity upon relapse. AcTor/IXZ was equally potent in a TP53 -mutated patient-derived xenograft model, exceeding the efficacy of standard-of-care. Conclusions As a TSC2 inhibitor, AcTor should not be used alone in cancer. When combined with proteasome inhibitors, the pharmacodynamics of AcTor shifts towards the development of a mitochondrial catastrophe in AML, which is durable, broad range, agnostic to TP53 mutations and to the acquisition of resistance to common clinical anti-AML drugs.

DOI: https://doi.org/10.21203/rs.3.rs-9405584/v1
bioRxiv. 2026 Apr 22. pii: 2026.04.20.718782. [Epub ahead of print]

Ketone ester supplementation in aged mice reduces activation of B cell subsets.

Ariel Adkisson-Floro, Ritesh Tiwari, Mitsunori Nomura, Rebeccah R Riley, Ryan Kwok, Durai Sellegounder, Mir M Khalid, Herbert G Kasler, John C Newman, Eric Verdin.

Aging in the immune system results in increased susceptibility to infections, exacerbated autoimmunity, and reduced responsiveness to vaccines. However, there are no current established interventions for immune aging. Ketogenic diets and fasting have been researched as interventions against other aspects of aging and age-related diseases, and they work in part by increasing circulating levels of ketone bodies, which have anti-inflammatory properties and can boost T cell function. Exogenous ketones, such as ketone esters, are currently being studied as a more accessible approach to obtain the benefits of ketone bodies through direct supplementation. Here, we investigated whether ketone ester supplementation improves immune function during aging. Aged (19-month-old) C57BL/6JN mice were given a diet supplemented with the ketone ester or a control diet for 15 weeks. We found that the ketone ester diet decreased activation of B cells, especially age-associated B cells, in the spleen. In spite of this decrease in activation, mice on the ketone ester diet showed no impairment in antibody production after nitrophenyl-ovalbumin immunization. The ketone ester diet also inhibited glucose dependence and translation of age-associated B cells, likely through inhibition of mTOR signaling via ketone bodies. Our study elucidates the effect of ketone esters on B cells in the context of aging and unveils a new immunoregulatory role of ketone bodies on B cells.

DOI: https://doi.org/10.64898/2026.04.20.718782
Trends Biochem Sci. 2026 May 07. pii: S0968-0004(26)00108-8. [Epub ahead of print]

Emerging roles and regulatory mechanisms involved in glutamine metabolism.

Keun Woo Ryu, Tak Shun Fung, Craig B Thompson.

  Glutamine is the most abundant circulating amino acid and a central nutrient supporting carbon and nitrogen metabolism. It donates nitrogen for nucleotide and amino acid biosynthesis, protein glycosylation, and provides carbon for the tricarboxylic acid cycle anaplerosis. Glutamine catabolism maintains redox homeostasis via glutathione production, as well as the synthesis of polyamines, urea cycle precursors, and neurotransmitters. Glutamine residues in proteins serve as sites for post-translational modification, while de novo glutamine synthesis is essential for ammonia detoxification. Although glutamine metabolism is regulated by mass action and product inhibition, emerging evidence reveals additional post-translational mechanisms, including regulation through higher-order structural assemblies of enzymes. In this review, we highlight the multifaceted roles of glutamine and emphasize emerging regulatory mechanisms that govern glutamine metabolism.

Keywords:  carbon metabolism; enzyme filaments; glutamine; nitrogen metabolism; post-translational regulation

DOI:  https://doi.org/10.1016/j.tibs.2026.04.008
J Endocr Soc. 2026 May;10(5): bvag097

Plasma metabolites after 10-weeks of glucose vs fructose-sweetened beverages in subjects with overweight/obesity.

Mélanie Guirette, Danielle E Haslam, Jiantao Ma, Peter J Havel, Kimber L Stanhope, Olga Ilkayeva, Christopher B Newgard, Nicola M McKeown, Mark A Herman.

  To identify metabolites as potential biomarkers of fructose vs glucose consumption and related metabolic changes, we conducted exploratory metabolomic profiling of fasting blood samples from participants in a double-blind, parallel-arm trial involving 31 male and female adults with overweight or obesity, both before and after supplementation with glucose- or fructose-sweetened beverages. Orthogonal Partial Least Square Discriminatory Analysis (OPLS-DA) was used to identify metabolites that could discriminate between the 2 intervention groups. Changes in 16 metabolites (5 of which are branched-chain amino acid catabolic pathway metabolites) and the branched chain keto acid (BCKA) composite score showed nominal (FDR adjusted P-value < .2, unadjusted P-value ≤ .08) differences in response to the 2 interventions. We observed a 2.19 µM (or 13%) and a 10.17 µM (or 25%) increase in ketomethylvaleric acid (P FDR = 0.04, P = .001) and 2-hydroxybutyrate (P FDR = 0.11, P = .008), respectively, after glucose supplementation compared to a null change after fructose supplementation. Notable trends after fructose supplementation included increased long- and median-chain acylcarnitines (ACs); decreased short-chain ACs; and increased homocysteine compared to the glucose supplementation. These data suggest that in people with overweight/obesity, consumption of beverages high in glucose vs fructose may differentially affect the metabolism of branched-chain amino acids and acylcarnitine species reflective of changes in fatty acid oxidation and de novo lipogenesis.

Keywords:  BCAA catabolic pathway; branched-chain amino acids; fructose metabolism; metabolomics; sugar-sweetened beverage

DOI:  https://doi.org/10.1210/jendso/bvag097
Elife. 2026 May 06. pii: RP104079. [Epub ahead of print]14

HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content.

Sara M Frangos, Henver S Brunetta, Dongdong Wang, Maria Joy Therese Jabile, Leslie M Jeffries, Grace Mencfeld, David W L Ma, William J Muller, Cezar M Khursigara, Kelsey H Fisher-Wellman, Jim Petrik, Gregory R Steinberg, Graham P Holloway.

  It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I-IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.

Keywords:  HER2; bioenergetics; cancer biology; cancer metabolism; cell biology; mitochondria; mouse; proteomics; transcriptomics

DOI:  https://doi.org/10.7554/eLife.104079
J Am Chem Soc. 2026 May 08.

Molecular Principles of Gating Proton Transport in the Antiporter Modules of Respiratory Complex I.

Sofia Badolato, Sarah C Rossmann, Joana Pereira, Hyunho Kim, Ville R I Kaila.

The respiratory Complex I is a highly intricate redox-driven proton pump that powers oxidative phosphorylation across all domains of life. Yet, despite major efforts, its long-range energy transduction principles remain much debated. Here, we study the molecular principles of proton transport by engineering the antiporter modules of Complex I. By combining directed mutagenesis with time-resolved spectroscopy and molecular dynamics (MD) simulations, we identify conserved residues along the proton channels that control the rate of proton transfer across proteoliposome membranes. The antiporter modules catalyze this tightly regulated proton transport by transient water wires that follow intrinsic electric fields along the proton channels. Based on MD simulations, we identify conserved gating sites, established by nonpolar residues, which modulate the hydration and electric field effects underlying the proton transport upon mutation. On a general level, our findings highlight how the modular energy-transduction machinery of Complex I employs a combination of electrostatic and conformational coupling principles to catalyze long-range proton transport, with distinct similarities to other enzymes.

DOI: https://doi.org/10.1021/jacs.6c05956
Nat Commun. 2026 May 09.

Complex I protein NDUFB9 is a metabolic vulnerability in triple negative breast cancer brain metastases.

Mingxi Lin, Zhexu Wen, Cheng Zeng, Yizi Jin, Teng Zhou, Yuxin Yan, Shenglin Huang, Xin Hu, Xiaoxiang Guan, Xichun Hu, Jian Zhang.

Triple-negative breast cancer (TNBC) brain metastases (BrMs) remain a therapeutic challenge. We depict the discrepancies between primary tumors and BrMs, and examine patient-matched cerebrospinal fluid and plasma to provide detailed profiles of BrMs' metabolic microenvironment. High-throughput in vivo loss of function CRISPR screens identify NDUFB9 (NADH: Ubiquinone Oxidoreductase Subunit B9) as a brain-specific metabolic vulnerability. NDUFB9-knockout selectively inhibits the BrMs outgrowth without affecting extracranial metastases. Mechanistically, TNBC cells exhibit an imbalance between aspartate upstream supply and downstream biosynthetic demand. NDUFB9-knockout disrupts mitochondrial complex I and reduces intracellular aspartate, but this alone is insufficient to inhibit TNBC proliferation. Instead, the lower asparagine concentration in the brain microenvironment induces compensatory upregulation of asparagine synthetase, which further diverts aspartate toward asparagine biosynthesis. This dual-hit mechanism exhausts the aspartate pool and restricts nucleotide biosynthesis, thereby selectively suppressing BrM outgrowth. Our findings uncover a therapeutic strategy for TNBC BrMs.

DOI: https://doi.org/10.1038/s41467-026-72927-2
Cell Rep. 2026 May 07. pii: S2211-1247(26)00435-3. [Epub ahead of print]45(5): 117357

Loss of pyruvate carboxylase suppresses lethality in propionic acidemia.

Jasmine Encarnacion, Susanna Scafidi, Michael J Wolfgang.

  Inborn errors in propionyl-CoA carboxylase cause life-threatening propionic acidemia. To understand the contribution of propionyl-CoA metabolism to cellular and systemic metabolic dysfunction, we generated inducible and tissue-specific Pcca knockout mouse models. The inducible whole-body loss of Pcca results in acute metabolic decompensation like the inborn error. The liver-specific loss of Pcca recapitulates these adverse effects, demonstrating the centrality of the liver to systemic disease. Propionate and pyruvate converge in the TCA cycle as major anaplerotic substrates. Strikingly, the lethality of Pcca knockout (KO) mice is reversed by simultaneously inhibiting pyruvate carboxylase (Pcx). Most metabolites suspected as deleterious in propionic acidemia are exacerbated in liver-specific Pcca;Pcx double KO mice with the exception of methylcitrate, suggesting a role of this metabolite in systemic toxicity. These data clarify relevant toxic biomarkers and suggest that rebalancing hepatic TCA cycle metabolism is critical to mitigate the adverse effects from alternative propionyl-CoA metabolic pathways.

Keywords:  CP: metabolism; TCA cycle; citrate; fatty acid; inborn error; knockout; liver; metabolism; propionate; propionyl-CoA; propionylation

DOI:  https://doi.org/10.1016/j.celrep.2026.117357
Free Radic Biol Med. 2026 May 05. pii: S0891-5849(26)00743-4. [Epub ahead of print]

Metabolic energy expenditure in human blood long-lived neutrophils reprogrammed with inflammatory cytokines.

Yann Breton, Jules Gignac, Tân Khoa Lam, Christopher M Fortin, Helya Mortazavi, Isabelle Allaeys, Sylvain G Bourgoin, Patrice E Poubelle, Martin Pelletier.

  The development of new analytical tools has revealed the heterogeneity of neutrophils in healthy and disease subjects. Knowledge of this heterogeneity has led to the identification, in healthy individuals, of a minor subset of blood neutrophils that express anti-protease genes characteristic of in vivo long-lived neutrophils, similar to those we previously described in vitro, which are expanded in autoimmune diseases. We can reprogram normal human blood neutrophils in vitro using GM-CSF, TNF, and IL-4, resulting in long-lived (LL) cells with enhanced glycolysis and oxygen consumption. We further report that these LL neutrophils express numerous genes associated with metabolism and mitochondria, including PLPP3 and SLC25A27. In addition, we confirmed that LL neutrophils express anti-peptidase genes, the most expressed being the PI3 gene, and secrete the peptidase inhibitor elafin and the secretory leukocyte protease inhibitor. Extracellular flux analysis revealed that PI3-expressing LL neutrophils exhibit enhanced glycolysis and respiration in response to pro-inflammatory cytokines, whereas non-reprogrammed neutrophils remain unresponsive. PI3-expressing LL neutrophils have a mitochondrial respiration partly driven by pyruvate oxidation, as demonstrated by the use of an inhibitor of mitochondrial pyruvate carrier. In contrast, oxygen consumption in control neutrophils was driven by fatty acid oxidation, as shown by the effect of inhibiting carnitine palmitoyltransferase 1. Thus, the reprogramming of neutrophils with GM-CSF, TNF, and IL-4 into cells capable of producing peptidase inhibitors is associated with an original metabolic phenotype characterized by active mitochondrial pathways.

Keywords:  arthritis; inflammation; metabolism; mitochondria; neutrophils

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.279
bioRxiv. 2026 Apr 27. pii: 2026.04.23.720368. [Epub ahead of print]

Macronutrient Composition and Genetic Background Determine the Response to a Ketogenic Diet.

Zhaoyue Zhang, Alexandre Moura-Assis, Shanshan Liu, Alon Millet, Jordan Shaked, Divya Rajan, Hanan Alwaseem, Michael Isay-Del Viscio, Henrik Molina, Kivanc Birsoy, Jeffrey Friedman.

While standard high fat diets cause hyperphagia and obesity in mice, high fat-low carbohydrate ketogenic diets (KDs) reduce food intake and body weight. Because the basis for this difference is still unclear, we systematically altered the macronutrient content of a standard KD and found that feeding C57BL/6J (B6J) mice a KD with 5% protein resulted in hypophagia, weight loss, and hypoglycemia, whereas the same diet with 10% protein led to increased adiposity and glucose intolerance. However, these effects were strain-dependent as C57BL/6NJ (B6NJ) weighed similar amounts on the two diets leading us to investigate the molecular mechanisms. When fed the KD-5% diet, B6J but not B6NJ mice showed increased levels of two anorexigenic factors, GDF15 and LCN2, and loss of function of either blunted the weight loss of B6J mice fed the diet. B6J mice harbor mutations in Nnt (Nicotinamide nucleotide transhydrogenase) and Nlrp12 (NLR family pyrin domain containing 12), both of which are wildtype in B6NJ mice. B6J mice fed the KD-5% diet showed the RNA signature of oxidative and integrated stress responses (ISR) and restoring NNT function in liver reduced the levels of GDF15. RNA-seq also revealed that B6J but not B6NJ mice had the RNA signature for hepatic inflammation and a knockout of Nlrp12 led B6NJ mice to lose weight on the KD-5% diet with increased levels of LCN2. Suppression of oxidative stress with N-acetylcysteine (NAC) reduced expression of both GDF15 and LCN2 and prevented the weight loss associated with the KD-5% protein diet in B6J mice, whereas inhibition of the integrated stress response with ISRIB only attenuated the GDF15 axis. Collectively, these findings explain why B6J mice lose weight on a ketogenic diet and reveal a critical interplay between macronutrient composition and genetic background leading to increased levels of GDF15 and LCN2 to induce hypophagia. Finally, these data suggest that the response to different diets among humans might be similarly variable based on genetic variation and macronutrient composition, suggesting the possible need for personalized dietary interventions.

DOI: https://doi.org/10.64898/2026.04.23.720368
Am J Clin Nutr. 2026 May;pii: S0002-9165(26)00078-X. [Epub ahead of print]123(5): 101269

Does a low-carbohydrate diet impede endurance sports performance? No.

Timothy D Noakes, Louise M Burke.

  Over the past decade, randomized controlled trials have established that, after eating either a low-carbohydrate, high-fat or a high-carbohydrate, low-fat diet for 4-6 wk, trained athletes performed equally well during a maximum oxygen consumption (VO2max) test; during 5 and 1.6 km laboratory treadmill time trials; during a 6 × 800 m interval repetition session; and during a prolonged cycling test to exhaustion at 70%VO2max. Indeed, during the 6 × 800 m interval repetition session, some subjects achieved the highest rates of fat oxidation (2 g/min) ever reported in humans; whereas ingestion of 10 g carbohydrate/h improved prolonged cycling test performance by 22%, equally following either diet. These data establish that muscle glycogen is not an obligatory fuel for exercise. Rather, exercise-induced hypoglycemia due to depletion of glucose in the small glucose pool in the liver and bloodstream, prevented by minimal carbohydrate ingestion during exercise, is the main metabolic contributor to premature fatigue during more prolonged submaximal exercise.

Keywords:  exercise performance; exercise-induced hypoglycemia; fat oxidation; large glucose pool; low-carbohydrate diet; muscle glycogen; small glucose pool

DOI:  https://doi.org/10.1016/j.ajcnut.2026.101269
bioRxiv. 2026 Apr 28. pii: 2026.04.27.718938. [Epub ahead of print]

Lactylation landscape of mitochondrial proteins in myocardial infarction.

Ashlesha Kadam, Shiridhar Kashyap, Kunal Samantaray, Natasha Jaiswal, Shanikumar Goyani, Philip A Kramer, Pourhadi Hadi, Jingyun Lee, Cristina M Furdui, Pooja Jadiya, Dhanendra Tomar.

Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently described lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we define the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocytes-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease.
Highlights: Myocardial infarction (MI) increases mitochondrial protein lactylation, with 361 identified lactylated proteins.AZD3965-mediated MCT1 inhibition further elevates mitochondrial lactylation.Distinct alterations in mitochondrial proteins and pathways (TCA cycle, amino acid metabolism, gene expression) were observed.AZD3965 reduces cardiac fibrosis and inflammation and partly improves mitochondrial respiration post-MI, but cardiac function remains impaired.

DOI: https://doi.org/10.64898/2026.04.27.718938
Cancers (Basel). 2026 Apr 09. pii: 1201. [Epub ahead of print]18(8):

The Spectrum of Venetoclax-Based Treatments in Acute Myeloid Leukemia.

Elvira Pelosi, Germana Castelli, Ugo Testa.

  Background/Objectives: In recent years there has been a consistent development of clinical studies surrounding the incorporation of the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) into the treatment of acute myeloid leukemia (AML) Methods: A search of the literature showed a tremendous development of experimental and clinical studies evaluating the impact of VEN-based regimens in the treatment of AML patients. This review comprehensively analyzes the available scientific evidence-including prospective clinical trials, retrospective cohorts, and real-world studies-to summarize current knowledge on the efficacy and safety of venetoclax-based regimens in AML patients. Results: Recent studies have evaluated VEN-based regimens in newly diagnosed (ND) and refractory/relapsed (R/R) AML patients, showing the efficacy of these treatments. VEN with hypomethylating agents (HMAs) became the standard-of-care for elderly/unfit AML patients. Recent studies strongly support the effectiveness of VEN-based regimens in frontline treatment of adult AML patients eligible for intensive treatments. VEN-based therapies were also used in combination with targeted therapies, thus generating triplet therapeutic regimens that are under evaluation for the treatment of some AML subtypes. However, the response to VEN+HMAs is highly variable and in part depends on tumor genetics; some patients are resistant or relapse following VEN-based treatments and future studies will be required to develop therapeutic strategies able to circumvent resistance and to identify patients at high risk of relapse. Prospective randomized trials are required to establish the real efficacy of VEN in various clinical settings and to refine maintenance and discontinuation strategies, aiming to improve long-term outcomes and to make more safe treatments based on VEN.

Keywords:  acute myeloid leukemia; clinical studies; genomic profiling; hypomethylating agents; targeted therapy; venetoclax

DOI:  https://doi.org/10.3390/cancers18081201
Nat Genet. 2026 May 04.

Transposable elements shape stemness in normal and leukemic hematopoiesis.

Giacomo Grillo, Bettina Nadorp, Aditi Qamra, Bryce Drylie, Amanda Mitchell, Christopher Arlidge, Ankita Nand, Naoya Takayama, Alex Murison, Seyed Ali Madani Tonekaboni, Komaldeep Kaur Kang, Andrea Arruda, Jean C Y Wang, Mark D Minden, Özgen Deniz, Héléna Boutzen, John E Dick, Mathieu Lupien.

Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds relapse within 5 years. AML follows a cellular hierarchy sustained by leukemia stem cells (LSCs), which drive tumor progression and relapse. Little is known about the genetic determinants driving LSCs stemness properties. By identifying chromatin variants from accessibility measurements across LSCs, hematopoietic stem cells and downstream progeny, we identified transposable elements (TEs) as genetic determinants of primitive versus mature populations. Accessibility at 121 TE subfamilies distinguished LSCs from mature leukemic cells and stratified AML patients by stemness and survival. Functional assays revealed that these TE subfamilies serve as docking sites for genome topology regulators or lineage-specific transcription factors, including LYL1 in LSCs. Chromatin editing established the necessity of accessibility at LTR12C elements to maintain LSC stemness. Thus, TEs regulate primitive versus mature cell states, with distinct subfamilies underlying stemness in normal versus leukemic stem cells.

DOI: https://doi.org/10.1038/s41588-026-02585-z
Sci Transl Med. 2026 May 06. 18(848): eads2673

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.

David R Ziehr, Fei Li, K Mark Parnell, Nathan M Krah, Kevin J Leahy, Christelle Guillermier, Ce Gao, Sean A Prell, Niv Vigder, Sergio Poli, Jack Varon, Rebecca M Baron, Bradley A Maron, Nancy J Philp, Lida P Hariri, Edy Y Kim, Kevin S Wei, Matthew L Steinhauser, Rachel S Knipe, Jared Rutter, William M Oldham.

Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. Although glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how monocarboxylate transporters (MCTs) 1 and 4, key pulmonary lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings revealed that inhibiting MCT1 or MCT4 using RNA interference or small molecules reduced transforming growth factor-β1 (TGFβ)-stimulated myofibroblast differentiation in lung fibroblasts from healthy donors and patients with idiopathic pulmonary fibrosis. Small-molecule MCT inhibitors also decreased bleomycin-induced pulmonary fibrosis in C57Bl6/N mice aged 10 to 12 weeks. Through bioenergetic analyses, stable isotope tracing, metabolomics, and imaging mass spectrometry in both human cells and mice, we demonstrate that inhibiting lactate transport enhanced oxidative phosphorylation, reduced reactive oxygen species production, and diminished glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, an MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors as a therapy for patients with limited treatment options.

DOI: https://doi.org/10.1126/scitranslmed.ads2673
Nat Metab. 2026 May 08.

Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.

DOI: https://doi.org/10.1038/s42255-026-01532-w
iScience. 2026 May 15. 29(5): 115702

Metabolic assessment of iPSC-derived neurons under ketone-enriched condition: Ketone sensor development and BHB-driven metabolic adaptation.

Rohollah Nasiri, Farzaneh Fayazbakhsh, Reyhaneh Sanei, Tingting Wu, Nayere Taebnia, Rouhollah Habibey, Omid Fotouhi, John Cognetti, Volker M Lauschke, Aman Russom, Anna Herland.

  Neurons depend on glucose to sustain their high energetic demands; yet, ketone bodies can serve as alternative substrates during ketogenic states. Here, we examined how β-hydroxybutyrate reshapes metabolism and function in human iPSC-derived neurons. Neurons generated from neuroepithelial stem cells were cultured in glucose-rich media or low-glucose media supplemented with β-hydroxybutyrate. We developed an electrochemical biosensor for ketone detection and validated its performance by cyclic voltammetry and amperometry, achieving linear sensitivity in the 0.01 to 0.1 mM range. Metabolic changes for neurons were assessed through glucose consumption and lactate production, and transcriptional profiling revealed reduced expression of selected metabolic and ketone-associated genes under ketone supplementation. Calcium imaging further showed lower firing rates in ketone exposed neurons compared with glucose conditions. Together, these results demonstrate how alternative energy substrates modulate neuronal metabolism and excitability, providing a framework to evaluate metabolic interventions for neurological disorders.

Keywords:  Analytical chemistry; Bioengineering; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2026.115702
Cancer Diagn Progn. 2026 May-Jun;6(3):6(3): 586-595

The Combination of Methionine Adenosyltransferase 2A (MAT2A) Inhibitor AG-270 and Recombinant Methioninase Is Not Cancer-selective in a Co-culture Model of Colon Cancer Cells and Normal Fibroblasts.

Jinsoo Kim, Qinghong Han, Shukuan Li, Byung Mo Kang, Kohei Mizuta, Yohei Asano, Yuta Miyashi, Michael Bouvet, Robert M Hoffman.

   Background/Aim: Methionine addiction is a fundamental and general hallmark of cancer cells. Recombinant methioninase (rMETase) degrades extracellular methionine. rMETase, or other means of restricting methionine, in combination with numerous types of chemotherapy have shown synergistic cancer-selective efficacy. AG-270, a methionine adenosyltransferase 2A (MAT2A) inhibitor, blocks intracellular conversion of methionine to S-adenosylmethionine (SAM), the central reaction of the methionine cycle. The present study aimed to evaluate the synergistic and cancer-selective efficacy of the combination of AG-270 and rMETase in a co-culture model of cancer and normal cells.
Materials and Methods: HCT116 human colon-cancer cells expressing green fluorescent protein (GFP) and human Hs-27 normal fibroblasts were co-cultured in Dulbecco's Modified Eagle's Medium (DMEM) with 10% fetal bovine serum in 12-well plates. Co-cultures were treated with AG-270 (6 μM and 10 µM) and rMETase (0.3 U/ml and 0.5 U/ml) alone or in combination. Cell growth and viability were assessed by phase-contrast microscopy and fluorescence imaging over 6 days.
Results: Treatment with AG-270 or rMETase alone inhibited HCT116 colon-cancer cell viability in a dose-dependent manner, whereas Hs-27 normal fibroblasts remained viable on day 6 in co-culture. In contrast, the combination of AG-270 and rMETase produced a strong, synergistic reduction of the viability of both HCT116 and Hs-27 cells, accompanied by extensive morphological damage, in co-culture. GFP-expressing HCT116 colon-cancer cells were nearly eradicated by the combination treatment, as visualized by fluorescence imaging on day 6 in co-culture with Hs-27 fibroblasts.
Conclusion: Dual inhibition of methionine metabolism by AG-270 and rMETase was toxic to both cancer cells and normal fibroblasts in a co-culture model which is internally controlled. In contrast, rMETase combined with numerous first-line chemotherapeutic drugs acted selectively and synergistically against cancer cells while sparing normal cells, including co-culture models. The present results suggest that AG-270 may have limited potential as an anticancer agent.

Keywords:  AG-270; HCT116 colon cancer cells; Hoffman effect; Hs-27 normal fibroblasts; MAT2A inhibitor; Methionine addiction; co-culture; combination treatment; recombinant methioninase

DOI:  https://doi.org/10.21873/cdp.10559
Transl Oncol. 2026 May 07. pii: S1936-5233(26)00140-3. [Epub ahead of print]69 102803

CPT1B promotes acute myeloid leukemia progression via fatty acid oxidation-dependent metabolic reprogramming.

Rui Cao, Ling-Ling Zhou, Qi Liu, Guo-E Liu, Ling Xu, Han He.

   BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with limited treatment options, especially in cases of relapse or refractory disease. Metabolic reprogramming, particularly fatty acid oxidation (FAO), has emerged as a critical mechanism in AML progression. Carnitine palmitoyltransferase 1B (CPT1B), a rate-limiting enzyme in mitochondrial FAO, is highly expressed in metabolically active tissues, yet its role in AML remains poorly defined.
METHODS: CPT1B expression was analyzed using TCGA datasets, patient samples, and AML cell lines. Functional studies employed CPT1B knockdown (shRNA) and overexpression (lentiviral) models in AML cell lines (THP-1, KG-1, HL-60, HEL). In vitro and in vivo effects were assessed via CCK-8, flow cytometry, western blot, ELISA, and xenograft models in immunodeficient mice. The FAO inhibitor Etomoxir was used to evaluate metabolic dependency.
RESULTS: CPT1B was significantly overexpressed in AML tissues and cell lines compared to normal controls and correlated with poorer overall survival. CPT1B knockdown reduced proliferation, induced G0/G1 cell cycle arrest, and promoted apoptosis in AML cells. CPT1B silencing inhibited tumor growth and dissemination in vivo. Conversely, CPT1B overexpression enhanced FAO activity, increased lipid droplet accumulation, and upregulated PPARA, CPT1A, and ACOX1 expression. Treatment with Etomoxir reversed these effects, restoring apoptosis and inhibiting CPT1B-driven proliferation both in vitro and in mouse models.
CONCLUSIONS: CPT1B acts as a key metabolic driver of AML progression through FAO-dependent lipid metabolic reprogramming. Its inhibition suppresses leukemic growth and improves survival outcomes, identifying the CPT1B-FAO axis as a promising therapeutic target and prognostic biomarker in AML.

Keywords:  Acute myeloid leukemia; Apoptosis; CPT1B; Etomoxir; Fatty acid oxidation; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.tranon.2026.102803
Trends Cancer. 2026 May 07. pii: S2405-8033(26)00078-6. [Epub ahead of print]

Bioengineered systems to exploit tumor microenvironment metabolism.

Christine Sanganoo, Ilaria Caturegli, Zachary Mattes, Jordan Ryan, Wilson W Wong, Mark W Grinstaff.

  Our understanding of cancer metabolism has afforded the opportunity to develop therapies specific to tumor metabolic dysregulation. While molecular therapeutics targeting cancer metabolism have found success in the clinic, bioengineering approaches are nascent. Here, we describe key metabolic pathways and their genetic dysregulations in the tumor microenvironment (TME) that are ripe for intervention. We examine bioengineered biomaterial and cellular systems that harness the metabolic and immune landscape of the TME to target metabolic dependencies of tumor growth. These therapeutic strategies include, for example, preventing the uptake of essential metabolites, delivering metabolic inhibitors, and restoring an immunostimulating environment. With a focus toward clinical applications and tolerability, we identify key limitations and conclude with future directions.

Keywords:  antimetabolite delivery; biomaterials; cancer metabolism; immunosuppressive metabolite modulation; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2026.04.003
J Endocr Soc. 2026 May;10(5): bvag093

Skeletal muscle mitochondrial bioenergetics in pregnancy: a comparison of in vivo and in vitro outcomes.

Ericka M Biagioni, Polina M Krassovskaia, Gillian Tiralla, Kelsey H Fisher-Wellman, Chien-Te Lin, Abby D Altazan, R Caitlin Hebert, Sripallavi Yendamuri, Maninder Singh, Owen T Carmichael, P Darrell Neufer, Kristen E Boyle, Leanne M Redman, Nicholas T Broskey.

   Purpose: Exercise-mediated adaptations to mitochondria are well established in nongravid populations; however, the extent to which these adaptations occur during pregnancy remains unclear. Therefore, the objective of this study was to compare skeletal muscle mitochondrial bioenergetics in physically active (n = 10) vs sedentary (n = 9) pregnant women.
Methods: Groups were matched for age, race, and pregravid body mass index and were studied in the second (T2; weeks 21-25) and third trimester (T3; weeks 31-35). Free-living physical activity was assessed by accelerometry and aerobic fitness by peak oxygen uptake (VO2peak) testing. In vivo mitochondrial capacity was assessed by 31P-magnetic resonance spectroscopy. Primary skeletal muscle myotubes were obtained via muscle biopsy between late T2 and early T3. Mitochondrial in vitro respiration was assessed by high-resolution respirometry, and mitochondrial content was measured by Western blot and enzyme activity.
Results: Despite a decline in physical activity across gestation, active women maintained a higher VO2peak at T2 (P < .05) and T3 (P < .01) compared with sedentary. There were no differences in phosphocreatine recovery time between groups or timepoints. Myotube mitochondrial respiratory capacity was similar between groups; however, compared with sedentary mothers, active mothers demonstrated increased expression of mitochondrial complexes I, II, and IV proteins (all P < .05). Additionally, myotube mitochondrial efficiency (adenosine triphosphate-to-oxygen consumption ratio) measures were positively correlated with maternal VO2peak at T3 (r = 0.49, P < .05), suggesting a link between fitness and mitochondrial efficiency.
Conclusion: These findings suggest that late pregnancy may blunt mitochondrial adaptations to aerobic exercise despite a preservation of cardiovascular fitness. Future studies are needed to determine whether increasing activity throughout gestation can enhance mitochondrial respiration.

Keywords:  exercise; metabolism; mitochondria; myotube; pregnancy

DOI:  https://doi.org/10.1210/jendso/bvag093
bioRxiv. 2026 Apr 20. pii: 2026.04.20.719537. [Epub ahead of print]

MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling.

Anastasia Rumyantseva, Alissa Wilhalm, William Carter, Trevor S Tippetts, Marco Moedas, Florian A Rosenberger, David Moore, Ákos Végvári, Yvonne Hinze, Linden Muellner-Wong, David Alsina, Rolf Wibom, Rainah Winston, Thomas P Mathews, Lars H Lund, Daniel C Andersson, Gianluigi Pironti, Anna Wedell, Ralph J DeBerardinis, Christoph Freyer, Anna Wredenberg.

The neonatal heart undergoes a rapid metabolic transition from fetal glycolysis to oxidative phosphorylation, requiring coordinated metabolic remodeling. Mechanisms driving this transition remain unclear. Here, we demonstrate that sufficient mitochondrial S-adenosylmethionine (mitoSAM), imported via the solute carrier Slc25a26 , is essential for this shift by sustaining the lipoylation of 2-oxoacid dehydrogenases, critical for TCA cycle activation. Proteomic and metabolomic profiling revealed that reduced mitoSAM availability impaired lipoylation, blocking TCA cycle function and restricting nucleotide synthesis, while mitochondrial gene expression and respiratory capacity remained largely intact. In vivo EdU labeling showed persistent cardiomyocyte proliferation imposing further strain on nucleotide pools. Supplementation with medium-chain triglycerides during the suckling-to-weaning transition restored metabolic function and normalized cardiac growth and morphology. Our data reveal a critical developmental window in which mitoSAM-dependent lipoylation ensures heart maturation.

DOI: https://doi.org/10.64898/2026.04.20.719537
Kaohsiung J Med Sci. 2026 May 07. e70232

Proteomic and Metabolomic Profiling Reveal Mitochondrial Transplantation-Mediated Reprogramming in Gastric Cancer Cells.

Ping-Chen Chen, Chen-Kai Liu, Ching-Chung Tsai, Erna Sulistyowati, Fu-An Li, Chung-Jung Liu, Deng-Chyang Wu, Shih-Hsuan Chou, Fu-Chen Kuo, Bin Huang.

  Mitochondria provide multiple functions for cellular physiology. Transplantation of mitochondria isolated from gastric epithelial cells GES-1 reducing the malignancy of gastric cancer cells AGS was previously reported. To elucidate the underlying mechanisms, TMT-based proteomic analysis coupling ingenuity pathway software prediction revealed that 257 upregulated and 34 downregulated proteins were implicated in 14 signaling pathways, including mitochondrial cell dysfunction (data became available from ProteomeXchange with identifier PXD061705). The upregulation of p53, Bax, p-AktS473, p-mTORS2448 and the downregulation of Sirt 3, p-NRF2S40, and HO-1 were further verified by western blotting. In the metabolomic analysis, 3 upregulated and 8 downregulated metabolites involved in glycolysis, TCA cycle, pentose phosphate pathway (PPP) and ATP production were identified. Aligning the catalytic step of these metabolites in glycolysis and TCA cycle, the lower fructose 1,6-bisphosphate, 2-phosphoglyceric acid and phosphoenolpyruvate was coupled with higher isocitrate while the reduced α-ketoglutarate, malate, ATP and NADH all implied an accumulation of pyruvate in the cytosol. Western blotting, along with pyruvate and lactate assays, showed decreased extracellular lactate due to upregulated MCT1 (lactate importer) and downregulated MCT4 (lactate exporter). The higher pyruvate was caused by increased LDHB (lactate-to-pyruvate conversion) and a decrease in mitochondrial pyruvate carrier (MPC). With the finding that transplanted GES-1 mitochondria led to an accumulation of pyruvate, the inhibitory effect of elevated pyruvate on migrated AGS cells was observed. In conclusion, combining proteomic and metabolomic analysis revealed the underlying mechanisms for understanding how transplanted GES-1 mitochondria attenuate AGS gastric cancer malignancy.

Keywords:  gastric cancer; metabolomics; mitochondrial transplantation; proteomics; pyruvate

DOI:  https://doi.org/10.1002/kjm2.70232
Leuk Res Rep. 2026 ;25 100589

The role of RAS mutations in leukemia progression, differentiation, and drug resistance.

Congfa Jiang, Hangxuan Wang, Jiaxin Zhao, Yuwei Xu, Shiwei Duan.

  Mutations in the RAS gene family (NRAS, KRAS) are critical drivers of late-stage acute myeloid leukemia (AML) progression. They are frequently detected in relapsed/refractory AML and AML transformed from myelodysplastic syndrome (MDS). Occurring as late-stage genetic events, RAS mutations synergize with early drivers to promote leukemogenesis. While mutually exclusive with FLT3-ITD mutations, they coexist with KIT, RUNX1, CEBPA mutations and MLL rearrangements. Granulocyte-monocyte progenitors (GMPs) serve as the cellular origin for RAS-mutant leukemia stem cells (LSCs). Ultimately, RAS mutations drive monocytic differentiation of LSCs and venetoclax (VEN) resistance through BCL-2 family rewiring. Beyond AML, they are hallmark genetic lesions in juvenile myelomonocytic leukemia (JMML) and present in 15%-20% of pediatric acute lymphoblastic leukemia (ALL) cases. Here, we propose a comprehensive pathogenic model and targeted therapeutic framework focusing on RAS, MCL-1, BCL2L1 to overcome drug resistance and improve patient outcomes.

Keywords:  ALL; AML; JMML; RAS mutations; Venetoclax resistance

DOI:  https://doi.org/10.1016/j.lrr.2026.100589
Biomedicines. 2026 Mar 26. pii: 759. [Epub ahead of print]14(4):

Mitochondrial Functional Capacity Is Impaired in Angiotensin II-Infused Mice and Not Recovered by Metformin.

Amanda Balboa Ramilo, Kevin Mani, Anders Wanhainen, Malou Friederich-Persson, Dick Wågsäter.

  Background: The pathophysiological mechanisms of Abdominal Aortic Aneurysm (AAA) are not elucidated. Alterations in mitochondrial function, such as a reduction in oxidative phosphorylation (OXPHOS), have been observed at genome level and functionally in vascular smooth muscle cells. Metformin reduces AAA development and growth in diabetic patients, but the precise mechanisms are not known. In this paper we aim to demonstrate the feasibility of measuring mitochondrial functional capacity ex vivo in intact murine aneurysmal tissue and confirm a decrease in OXPHOS, and to determine if the protective effect of metformin on AAA is mediated by mitochondrial function. Methods: AAA was induced in ApoE KO mice by administration of angII (1000 ng/kg/min) through osmotic minipumps. Metformin was administered in drinking water at a dose of 100 mg/kg/day. The abdominal aorta was isolated in situ and mitochondrial functional capacity was analyzed ex vivo in whole permeabilized tissue by high-resolution respirometry. Results: Mitochondrial respiration was successfully measured ex vivo in whole aneurysmal tissue. Mitochondrial function was impaired in angII-treated mice, with decreased fold change in Complex I and Complex I+II oxygen consumption, relative to basal levels. Complex II oxygen consumption was also decreased in angII-treated mice. Rescue treatment of mice with metformin did not affect or restore mitochondrial function. Conclusions: Mitochondrial function can be evaluated in murine whole aneurysmal tissue, providing a method for a physiological approach to the study of mitochondrial function in AAA. Mitochondrial function is impaired in AAA. However, rescue treatment with metformin is not sufficient to recover mitochondrial function and seems not to be the mechanism behind prevention of aneurysm.

Keywords:  abdominal aortic aneurysm; high-resolution respirometry; mitochondria

DOI:  https://doi.org/10.3390/biomedicines14040759
Elife. 2026 May 07. pii: e111373. [Epub ahead of print]15

How membranes shape up for lipid transfer.

Takashi Hirashima, Toshiya Endo.

  The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.

Keywords:  biochemistry; cardiolipin; chemical biology; lipid transport; mitochondria; none; phosphatidic acid

DOI:  https://doi.org/10.7554/eLife.111373
bioRxiv. 2026 Apr 23. pii: 2026.04.23.720363. [Epub ahead of print]

Dual Pathways of Extracellular ATP Action in Cancer Cells: Purinergic Signaling-Driven Senescence and Macropinocytic ATP Internalization.

Nicole Stone, Ryan Ward, Lindsey Bachmann, Subhodip Adhicary, Corinne M Nielsen, Nikunj Mehta, Yunsheng Li, Haiyun Zhang, Jingwen Song, Sam Prinz, Stephen Chang, Dennis Roberts, Stephen Bergmeier, Pratik Shriwas, Xiaozhuo Chen.

Background: Opportunistic nutrient uptake is a hallmark of cancer metabolism. Cancer cells upregulate macropinocytosis to acquire extracellular nutrients to support growth and stress adaptation. We previously showed that extracellular ATP (eATP) is internalized by macropinocytosis and promotes multiple cancer phenotypes. Here, we tested whether eATP uptake is prevalent across cancers and whether eATP also induces senescence through purinergic receptor (PR) signaling.
Methods: Intracellular ATP (iATP) levels were measured following eATP exposure across multiple cancer cell lines. eATP internalization was visualized in vitro and in vivo using a non-hydrolyzable fluorescent ATP analog together with high-molecular-weight dextran as a macropinocytosis marker. Senescence was quantified using three SA-β-galactosidase assays and flow cytometry. Pharmacologic inhibitors of macropinocytosis and purinergic receptors were used to define pathway dependence. Combination treatments with the glucose transporter inhibitor DRB18 and the senolytic navitoclax were evaluated for antiproliferative effects.
Results: eATP produced dose- and time-dependent increases in iATP across diverse cancer cell types. Imaging demonstrated widespread macropinocytic internalization of ATP in vitro and in tumor xenografts. eATP induced senescence in NSCLC cells, confirmed by multiple β-gal assays and flow cytometry. PR inhibition significantly reduced senescence, whereas macropinocytosis inhibition had minimal effect on senescence induction.
Conclusions: eATP acts through dual pathways in cancer cells: macropinocytic internalization that elevates iATP and PR signaling that drives senescence. Targeting metabolic uptake together with senolytic therapy may offer a novel anticancer strategy.

DOI: https://doi.org/10.64898/2026.04.23.720363
Life Metab. 2026 Jun;5(3): loag005

Lysosomes contribute to the synthesis of tricarboxylic acid-related metabolites in the hippocampus.

Liangliang Kong, Hongying Tan, Xiaoting Zhu, Yiqing Wen, Yang Li.

  The central nervous system is highly sensitive to energy supply, and the hippocampus operates under sustained metabolic load due to continuous synaptic activity and information processing. Lysosomes couple nutrient status to cellular energetics through the mechanistic target of rapamycin complex 1 (mTORC1) and the autophagy-lysosome pathway, yet their -subcellular contribution to neuronal metabolic profiles remains unclear. To address this, we established an in vivo AAV-LysoTag/Lyso-IP workflow combined with metabolomics to quantify metabolites within mouse hippocampal lysosomes. An in vitro Lyso-IP platform and immunofluorescence provided cell-based validation. Under every-other-day fasting, hippocampal lysosomes exhibited reprogramming: small-molecule substrates derived from amino acids and fatty acids accumulated; bis(monoacylglycero)phosphate was upregulated, indicating enhanced intraluminal vesicle formation and lipid degradation/sorting; -sphingolipids and cardiolipin increased, consistent with selective mitophagy. Notably, high basal lysosomal levels of malic acid and α-ketoglutarate (α-KG) suggested additional sources beyond the mitochondria. Immunofluorescence further showed lysosomal localization of isocitrate dehydrogenase and fumarate hydratase, suggesting partial residency of these enzymes. The oxoglutarate carrier (SLC25A11) signals were observed in LAMP1+ compartments, suggesting potential transmembrane exchange of α-KG and malic acid. Together, our data indicate that lysosomal tricarboxylic acid -related metabolites are maintained by three parallel routes: mitochondrial delivery to lysosomes, local production by resident enzymes, and transporter-mediated exchange. These metabolites supplement and reshape neuronal carbon flux and metabolic resilience at the subcellular level. Our findings elevate lysosomes from degradative endpoints to mobilizable metabolic hubs in the brain and provide both methodological and conceptual frameworks for neurometabolic adaptation under energy scarcity.

Keywords:  Lyso-IP; TCA cycle; lysosome; metabolomics; mouse hippocampus

DOI:  https://doi.org/10.1093/lifemeta/loag005
Nat Genet. 2026 May 05.

Age distinguishes selection from causation in cancer genomes.

David Cheek, Martin Blohmer, Martin A Nowak, Tibor Antal, Kamila Naxerova.

Cancer-causing mutations have been identified primarily from positive selection signals in cancer genomes. However, positive selection is also a ubiquitous feature of normal tissue aging. Here we develop a statistical framework to disentangle selection in normal tissue and causation of carcinogenesis. By comparing cancer and normal tissue genomes, we estimate the effects of mutations on cancer risk in the blood, esophagus and colon. We determine that stronger cancer-causing mutations are enriched at younger patient ages. This enables cancer-causing mutations to be identified from patient age distributions, even without normal tissue data. Moreover, we show for acute myeloid leukemia that the age-dependence of purported causal mutations can be explained largely by normal blood evolution, challenging the long-standing notion that childhood cancers require distinct mutations. Broadly, our framework delineates carcinogenesis from normal tissue aging, improving the assessment of cancer risk conferred by mutations.

DOI: https://doi.org/10.1038/s41588-026-02593-z
Blood Adv. 2026 May 08. pii: bloodadvances.2026020144. [Epub ahead of print]

Gilteritinib + chemotherapy in children with relapsed/refractory FLT3-ITD AML: results from the phase 1/2 SKIPPER trial.

Philip Connor, Raul C Ribeiro, Albert Catala, Alice Norton, Michael M Schündeln, Nahla Hasabou, David Delgado, Alexandra Natalie Heinloth, Jason E Hill, Stanley C Gill, Theophile Bigirumurame, Sarah K Tasian, Franco Locatelli.

Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) occurs in ~15% of pediatric patients with acute myeloid leukemia (AML) and is associated with high relapse risk with conventional chemotherapy. Gilteritinib is a selective, next-generation FLT3 inhibitor (FLT3i) approved for adults with relapsed/refractory FLT3‑mutated AML, but pediatric-specific data remain limited. The multi-national phase 1/2 SKIPPER study evaluated gilteritinib combined with fludarabine and cytarabine chemotherapy and granulocyte colony‑stimulating factor (FLAG) in children and adolescents/young adults with relapsed/refractory FLT3‑ITD AML. Nine patients, aged 8-15 years, were enrolled in phase 1 of the study between 2020 and 2023. Recruitment challenges, including disease rarity, off‑label FLT3i availability, and competing trials, led to study termination after phase 1. The composite complete remission rate in the study population was 66.7% (95% confidence interval: 29.9%-92.5%). Two‑year event‑free and overall survival probability was 41.7% and 55.6%, respectively. Treatment‑emergent adverse events, most commonly reversible hepatic enzyme elevations and cytopenias, were consistent with known toxicity profiles of gilteritinib and FLAG. Pharmacokinetic parameters were comparable to those of adults, and pharmacodynamic plasma inhibitory activity assays confirmed sustained FLT3 inhibition. No dose‑limiting toxicities were observed, and the recommended phase 2 dose of gilteritinib was established at 2 mg/kg/day for patients ≥2 years old. The gilteritinib and FLAG regimen had manageable safety, induced high remission rates, and enabled allogeneic hematopoietic stem cell transplant for several patients. Although limited by a small sample size, these findings support further evaluation of gilteritinib in pediatric patients with FLT3-mutated AML, particularly in frontline settings (ClinicalTrials.gov Identifier: NCT04240002).

DOI: https://doi.org/10.1182/bloodadvances.2026020144
Elife. 2026 May 05. pii: RP106587. [Epub ahead of print]14

Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.

David Papadopoli, Ranveer Palia, Predrag Jovanovic, Sébastien Tabariès, Emma Ciccolini, Valerie Sabourin, Sebastian Igelmann, Shannon McLaughlan, Lesley Zhan, HaEun Kim, Nabila Chekkal, Krzysztof J Szkop, Thierry Bertomeu, Jibin Zeng, Julia Vassalakis, Farzaneh Afzali, Slim Mzoughi, Ernesto Guccione, Mike Tyers, Daina Avizonis, Ola Larsson, Lynne-Marie Postovit, Sergej Djuranovic, Josie Ursini-Siegel, Peter M Siegel, Michael Pollak, Ivan Topisirovic.

  Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.

Keywords:  cancer biology; cell biology; human; mRNA translation; metabolism; mouse; signal transduction

DOI:  https://doi.org/10.7554/eLife.106587
Med Chem Res. 2026 ;35(4): 792-803

Inactivation of ornithine aminotransferase by (1R,4S)-4-Amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid via a stable quinonoid intermediate.

Koon Mook Kang, Abigail L Vargas, Wei Zhu, Inna Sokolenko, Dali Liu, Richard B Silverman.

  Ornithine aminotransferase (OAT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme, is a key contributor to glutamine supply in cancer cells, suggesting its therapeutic potential for hepatocellular carcinoma (HCC), the most common form of liver cancer. To identify an initial set of OAT inactivators, we have tested inactivators of γ-aminobutyric acid aminotransferase (GABA-AT), a homologous PLP-dependent enzyme, with human OAT (hOAT) and identified several co-inactivators. Among the active molecules, (1R,4S)-4-amino-3-(trifluoromethyl)cyclopent-2-ene-1-carboxylic acid (2) has not been thoroughly investigated for its time-dependent kinetics and mechanistic pathways with OAT. In this study, we evaluated the time-dependent inactivation of hOAT by 2 and investigated the underlying mechanism, primarily based on X-ray crystallography. The results demonstrated that 2 acts as a time-dependent OAT inactivator with an inactivation efficiency (k inact/K I = 5.1 min-1mM-1) approximately 30-fold higher than that for GABA-AT (k inact/K I = 0.17 min-1mM-1) and, notably, revealed an inactivation pathway that proceeds via a stable quinonoid intermediate, as evidenced by the UV-Vis spectroscopy.

Keywords:  Hepatocellular carcinoma; Mechanism-based inactivator; Ornithine aminotransferase; Pyridoxal 5’-phosphate-dependent enzyme; Stable quinonoid intermediate; X-ray crystallography

DOI:  https://doi.org/10.1007/s00044-026-03538-1
Front Physiol. 2026 ;17 1782998

Investigation of mitochondrial inner membrane ion conductance by planar lipid bilayer electrophysiology.

Amrendra Kumar, Eleanora Margulis, Nelli Mnatsakanyan.

  Mitochondrial ion channels are proteins of the inner and outer mitochondrial membranes that regulate ion flux and control various cellular processes, including calcium signaling, bioenergetic and metabolic functions, and cell death. Their precise regulation is essential to maintaining normal mitochondrial function and preventing pathological processes. Patch-clamp and planar lipid bilayer electrophysiology techniques have been used to measure ion flow directly across the membrane, thereby revealing the gating kinetics and pharmacological profile of ion channels in real time. Here, we describe a planar lipid bilayer electrophysiology approach for assessing mitochondrial ion channel conductance using mitochondrial inner membrane vesicles (IMVs). The comparative electrophysiology analysis between IMVs and purified mitochondrial proteins, ATP synthase, and the adenine nucleotide translocator (ANT), demonstrates that planar lipid bilayer electrophysiology is a robust tool for biophysical characterization of mitochondrial ion channels using IMVs. This approach is particularly valuable for investigating ion channel properties under controlled yet physiologically relevant conditions and for evaluating the direct modulatory effects of different pharmacological agents.

Keywords:  ATP synthase leak channel; adenine nucleotide translocator (ANT); mitochondria; patch-clamp; planar lipid bilayer electrophysiology

DOI:  https://doi.org/10.3389/fphys.2026.1782998
Cell Stem Cell. 2026 May 07. pii: S1934-5909(26)00152-9. [Epub ahead of print]

Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML.

Alexander Waclawiczek, Aino-Maija Leppä, Simon Renders, Ines Bergerweiss, Karolin Stumpf, Barbara Betz, Susanna Gabrowski, Frank Y Huang, Maria-Eleni Lalioti, Bendix Hempel, Markus Sohn, Heikki Kuusanmäki, Vera Thiel, Julia M Unglaub, Rabia Shahswar, Sarah Richter, Maike Janssen, Darja Karpova, Elisa Donato, Halvard Bonig, Christoph Röllig, Simon Raffel, Michael Heuser, Michael Hundemer, Mika Kontro, Ann-Kathrin Eisfeld, Tim Sauer, Nina Cabezas-Wallscheid, Carsten Müller-Tidow, Andreas Trumpp.

  The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling of LSCs from >150 patients, we identify four LSC subtypes. These mirror distinct hematopoietic lineage stages, which determine the expression ratio between the venetoclax target BCL-2 and resistance-inducing proteins MCL-1 and BCL-xL (MAC-score). Longitudinal analyses reveal that venetoclax resistance mostly arises in LSCs through plasticity toward a megakaryocytic/erythroid-progenitor (MEP)-LSC state that switches survival dependency from BCL-2 to BCL-xL. In rare cases, mature monocytic/dendritic (MoDe)-LSCs, found within LAMP5+ monocytic AMLs, drive venetoclax resistance. LSC subtyping improves genetic risk stratification and provides subtype-specific therapies: venetoclax-resistant MEP-LSCs respond to BCL-xL inhibitors, whereas MoDe-LSCs are sensitive to MEK1/2 inhibition. Our findings reveal four distinct LSC types with unique vulnerabilities and propose biomarker-guided treatment strategies that complement genetic profiling to overcome venetoclax resistance.

Keywords:  BCL-2; MAC-score; acute myeloid leukemia; azacitidine; chemotherapy; leukemic stem cells; personalized medicine; plasticity; therapy resistance; venetoclax

DOI:  https://doi.org/10.1016/j.stem.2026.04.012