bims-medica 2025-07-20 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–07–20
thirty-one papers selected by
Brett Chrest, Wake Forest University

Deletion of Skeletal Muscle Mitochondrial Glutamic-Oxaloacetic Transaminase (GOT2) Enhances Oxaloacetate Inhibition of Succinate Dehydrogenase and Alters Substrate Selectivity.
Enhanced lipid metabolism serves as a metabolic vulnerability to a polyunsaturated fatty acid (PUFA)-rich diet in glioblastoma.
Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
A primary mechanism for efficacy of the ketogenic diet may be energy repletion at the tripartite synapse.
Ketone body driven lipid remodeling supports thermogenic adaptation to fasting.
Deletion of AC8 in glioma cells elevates oxidative phosphorylation by system-wide remodeling of the mitochondrial proteome.
Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia.
Demonstration of Beat-to-Beat, On-Demand ATP Synthesis in Ventricular Myocytes Reveals Sex-Specific Mitochondrial and Cytosolic Dynamics.
The nutritional adequacy of the ketogenic diet in paediatric epilepsy: detailed nutrient analysis and dietary recommendations.
Nucleoside diphosphate kinase strongly promotes GDP and ADP metabolism in the cell and affects endogenous proton leak in mitochondria - the kinase is hampered by oxidative phosphorylation inhibitors.
Opposing effects of systemic and pancreas-specific inhibition of BCKDK on pancreatic carcinogenesis.
High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability.
Respiratory complex III 2 assembles complex I via toxic intermediate in mitochondrial disease.
Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2.
Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
Bypassing Blood-Brain Barrier and Glucose Dependency of Anti-Glioblastoma Drug Candidates Targeting Mitochondrial Respiration.
High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
Novel Devimistat Results in Complete Remissions in Heavily Pre-Treated Burkitt Lymphoma in a phase II trial.
Impact of intermittent fasting on micronutrient intake.
Cachexia in Clinical Practice: Experience from an Endocrine-Led Care Model.
Oops!…I Did it Again, I Gave You Some Carbs: Prescribing Errors in Inpatient Ketogenic Diet Management.
Ras pathways help buffer biological timekeeping against metabolic perturbations.
What's on the menu?: metabolic constraints in the pancreatic tumor microenvironment.
The acute myeloid leukemia microenvironment impairs neutrophil maturation and function through NFκB signaling.
A Platform for Mitochondrial Profiling in Enriched Kidney Segments Under Thermodynamic Control.
Digitoids: a novel computational platform for mimicking oxygen-dependent firing of neurons in vitro.
Olutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome.
BDH2 promotes GLIPR1 promoter methylation and thus increases 5-FU sensitivity in colorectal cancer.
Utility of IDH1/2 mutations as biomarkers for detection of measurable residual disease in acute myeloid leukemia.
Mitochondria dysfunction: cause or consequence of physiologic aging?
Is the vLamax for Glycolysis What the V˙O2 max is for Oxidative Phosphorylation?

FASEB J. 2025 Jul 31. 39(14): e70825

Deletion of Skeletal Muscle Mitochondrial Glutamic-Oxaloacetic Transaminase (GOT2) Enhances Oxaloacetate Inhibition of Succinate Dehydrogenase and Alters Substrate Selectivity.

Brian D Fink, Ritu Som, Liping Yu, William I Sivitz.

  Oxaloacetate (OAA) is converted to aspartate by mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) along with the conversion of glutamate to alpha-ketoglutarate (α-KG). Glutamate can also be directly converted to α-KG by glutamate dehydrogenase. In past work, we found that in skeletal muscle mitochondria energized by succinate alone, oxaloacetate accumulates and inhibits succinate dehydrogenase (complex II) in a manner dependent on inner membrane potential (ΔΨ). Here, we tested the hypothesis that deleting GOT2 would increase OAA concentrations, decrease complex II-energized respiration, and alter the selectivity of succinate versus glutamate for energy. Incubating wild-type mitochondria with succinate and glutamate revealed that increments in ADP increased OAA and caused a preferential use of glutamate for energy. Deletion of GOT2 compared to wild-type decreased complex II energized respiration, increased OAA, and decreased consumption of glutamate relative to succinate. OAA accumulation was also associated with decreased conversion of succinate to fumarate and malate. These findings are consistent with GOT2 control of metabolite flow through succinate dehydrogenase via regulation of OAA and consequent inhibition of succinate dehydrogenase. In contrast to respiration energized at complex II, when mitochondria were energized at complex I by pyruvate + malate, respiration did not differ between GOT2KO and WT mitochondria, and oxaloacetate was not detectable. In summary, GOT2 and OAA mediate complex II respiration and mitochondrial energy substrate selectivity.

Keywords:  glutamic‐oxaloacetic transaminase‐2; mitochondria; mitochondrial complex II; mitochondrial inner membrane potential; oxaloacetate; respiration; skeletal muscle; succinate dehydrogenase

DOI:  https://doi.org/10.1096/fj.202501071R
Res Sq. 2025 Jun 24. pii: rs.3.rs-6355361. [Epub ahead of print]

Enhanced lipid metabolism serves as a metabolic vulnerability to a polyunsaturated fatty acid (PUFA)-rich diet in glioblastoma.

Prakash Chinnaiyan, Shiva Kant, Yi Zhao, Pravin Kesarwani, Kumari Alka, Jacob Oyeniyi, Ghulam Mohammad, Nadia Ashrafi, Stewart Graham, C Ryan Miller.

Enhanced lipid metabolism, which involves the active import, storage, and utilization of fatty acids from the tumor microenvironment, plays a contributory role in malignant glioma transformation; thereby, serving as an important gain of function. In this work, through studies initially designed to understand and reconcile possible mechanisms underlying the anti-tumor activity of a high-fat ketogenic diet, we discovered that this phenotype of enhanced lipid metabolism observed in glioblastoma may also serve as a metabolic vulnerability to diet modification. Specifically, exogenous polyunsaturated fatty acids (PUFA) demonstrate the unique ability of short-circuiting lipid homeostasis in glioblastoma cells. This leads to lipolysis-mediated lipid droplet breakdown, an accumulation of intracellular free fatty acids, and lipid peroxidation-mediated cytotoxicity, which was potentiated when combined with radiation therapy. Leveraging this data, we formulated a PUFA-rich modified diet that does not require carbohydrate restriction, which would likely improve long-term adherence when compared to a ketogenic diet. The modified PUFA-rich diet demonstrated both anti-tumor activity and potent synergy when combined with radiation therapy in mouse glioblastoma models. Collectively, this work offers both a mechanistic understanding and novel approach of targeting this metabolic phenotype in glioblastoma through diet modification and/or nutritional supplementation that may be readily translated into clinical application.

DOI: https://doi.org/10.21203/rs.3.rs-6355361/v1
bioRxiv. 2025 May 10. pii: 2025.05.09.653205. [Epub ahead of print]

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

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

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

DOI: https://doi.org/10.1101/2025.05.09.653205
J Neural Eng. 2025 Jul 14.

A primary mechanism for efficacy of the ketogenic diet may be energy repletion at the tripartite synapse.

Shubhada N Joshi, Aditya Joshi, Narendra D Joshi.

   OBJECTIVE: The ketogenic diet is a well-known treatment for epilepsy. Despite decades of research, it is not yet known how the diet accomplishes its anti-seizure efficacy. One of the earliest proposed mechanisms was that the ketogenic diet is able to replenish cellular energy stores in the brain. Although several mechanisms have been suggested for how energy depletion may contribute to seizure generation and epileptogenesis, how the dynamics of energy depletion actually leads to abnormal electrical activity is not known.Approach: In this work, we investigated the behavior of the tripartite synapse using a recently developed neurochemical model, which was modified to include ketone chemistry. We ran transient, non-steady-state simulations mimicking normoglycemia and ketosis for metabolic conditions known to be clinically treated with the ketogenic diet, as well as a condition for which the ketogenic diet was not effective clinically. Main Results: We found that reduction in glucose, as well as pathological decreases in the activity of glucose transporter 1, pyruvate dehydrogenase complex, monocarboxylate transporter 1 (MCT1), and mitochondrial complex I, all led to functioning of the tripartite synapse in a rapid burst-firing mode suggestive of epileptiform activity. This was rescued by the addition of the ketone D-β-hydroxybutyrate in the glucose deficit, glucose transporter 1 deficiency, and pyruvate dehydrogenase complex deficiency, but not in MCT1 deficiency or mitochondrial complex I deficiency.Significance: We demonstrated that replenishment of cellular energy stores is a feasible mechanism for the efficacy of the ketogenic diet. Although we do not rule out other proposed mechanisms, our work suggests that cellular energy repletion may be the primary action of the ketogenic diet. Further study of the contribution of energy deficits to seizure onset and even epileptogenesis may yield novel therapies for epilepsy in the future.&#xD.

Keywords:  ATP; cell metabolism; energy metabolism; epilepsy; ketogenic diet; ketone

DOI:  https://doi.org/10.1088/1741-2552/adef7f
bioRxiv. 2025 Jun 17. pii: 2025.06.13.659540. [Epub ahead of print]

Ketone body driven lipid remodeling supports thermogenic adaptation to fasting.

Zahra Moazzami, Eric D Queathem, Jiawen Ma, Qian Chen, Rini Arianti, Ifrah Aden, Anneliese Brown, Zamzam Abdulahi, Chenxin Gu, Xuechun Chang, Yin Li, Haidong Yu, Alessandro Bartolomucci, Satchidananda Panda, Douglas G Mashek, Endre Kristof, Patrycja Puchalska, Lisa S Chow, Zhihao Jia, Peter A Crawford, Hai-Bin Ruan.

Metabolic adaptation to fasting may have conferred survival advantage to early humans and predicts weight gain caused by overnutrition in modern societies. Fasting suppresses brown adipose tissue (BAT) thermogenesis; however, it is unclear how BAT rewires cellular metabolism to balance between energy conservation and heat generation. Here, we report that BAT in mice under fasting and cold challenge consumed ketone bodies, specifically acetoacetate (AcAc). Ablating liver ketogenesis decreased, while enhancing hepatic AcAc output defended, body temperature in mice facing the dual challenge. Using stable isotope tracing in brown adipocytes in vitro combined with quantitative analysis of metabolic fluxes and lipidomics in BAT from genetic mouse models, we disentangled the two metabolic fates of AcAc - terminal oxidation in the mitochondria and lipid biosynthesis in the cytosol. Notably, AcAc-sourced carbon preferentially supported polyunsaturated fatty acid synthesis in BAT, linking to the positive impact of intermittent fasting on lipid profiles in both mice and humans. Therefore, ketone body utilization by thermogenic adipocytes contributes to metabolic resilience of mammals and can be targeted to optimize benefits of dietary regimens.

DOI: https://doi.org/10.1101/2025.06.13.659540
Biochim Biophys Acta Bioenerg. 2025 Jul 14. pii: S0005-2728(25)00033-7. [Epub ahead of print] 149567

Deletion of AC8 in glioma cells elevates oxidative phosphorylation by system-wide remodeling of the mitochondrial proteome.

Emil Jakobsen, Jacob M Bech, Jens V Andersen, Emil W Westi, Martin R Larsen, Niels H Skotte, José M A Moreira, Blanca I Aldana, Lasse K Bak.

  The Warburg effect is the reprogramming of cancer cells towards glycolytic metabolism, likely producing and releasing lactate into the tumor microenvironment. This lactate has been suggested to partly drive tumor growth by signaling through the lactate receptor, GPR81. Thus, reprogramming cancer cells away from glycolytic activity may be beneficial for cancer treatment. Here, we show that deletion of ADCY8 (coding for adenylyl cyclase 8; AC8) employing the CRISPR-Cas9 technology in U87MG glioma cells, changes the proteome of these cells through a system-wide transformation in expression of mitochondrial proteins. These changes shift the metabolic balance towards oxidative phosphorylation, as shown by an increase in oxygen consumption, an elevation in tricarboxylic acid cycle flux, and a concomitant decrease in glycolytic flux. This metabolic shift is likely driven by the absence of AC8-mediated transcriptional regulation and may suggest that inhibition of AC8 activity could hold therapeutic potential in the treatment of cancer.

Keywords:  ADCY8; Cancer; Glycolysis; Metabolism; Mitochondria; Warburg

DOI:  https://doi.org/10.1016/j.bbabio.2025.149567
bioRxiv. 2025 Jun 29. pii: 2025.06.26.661633. [Epub ahead of print]

Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia.

Stefan Bjelosevic, Rahel Fauth, Brian T Do, Gabriela Alexe, Lucy A Merickel, Thomas D Jackson, Allen T Basanthakumar, Audrey Taillon, Silvi Salhotra, Birgitta Ryback, Constanze Schneider, Giulia DiGiovanni, Ryan Elbashir, Nils Burger, Muhammad Bin Munim, Shan Lin, Pere Puigserver, David E Root, Matthew G Vander Heiden, Kimberly Stegmaier.

Riboflavin is a diet-derived vitamin in higher organisms that serves as a precursor for flavin mononucleotide and flavin adenine dinucleotide, key cofactors that participate in oxidoreductase reactions. Here, using proteomic, metabolomic and functional genomics approaches, we describe a specific riboflavin dependency in acute myeloid leukemia and demonstrate that, in addition to energy production via oxidative phosphorylation, a key biological role of riboflavin is to enable nucleotide biosynthesis and iron-sulfur cluster metabolism. Genetic perturbation of riboflavin metabolism pathways or exogenous depletion in physiological culture medium induce nucleotide imbalance and DNA damage responses, as well as impair the stability and activity of proteins which utilize [4Fe-4S] iron-sulfur clusters as cofactors. We identify a window of therapeutic opportunity upon riboflavin starvation or chemical riboflavin metabolism perturbation and demonstrate that this strongly synergizes with BCL-2 inhibition. Our work identifies riboflavin as a critical metabolic dependency in leukemia, with functions beyond energy production.

DOI: https://doi.org/10.1101/2025.06.26.661633
bioRxiv. 2025 Jul 10. pii: 2025.07.07.663572. [Epub ahead of print]

Demonstration of Beat-to-Beat, On-Demand ATP Synthesis in Ventricular Myocytes Reveals Sex-Specific Mitochondrial and Cytosolic Dynamics.

Paula Rhana, Collin Matsumoto, L Fernando Santana.

The substantial energetic demands on ventricular myocytes imposed by the transport of ions and cross-bridge cycling associated with each heartbeat are well known, yet the spatiotemporal dynamics of ATP supply and demand remain poorly understood. Here, using confocal microscopy and genetically encoded fluorescent sensors targeted to mitochondria and cytosol, we visualized beat-to-beat ATP dynamics in ventricular myocytes from adult male and female mice. These probes showed fluctuations in mitochondrial ATP levels with each contraction, revealing two distinct, spatially localized waveforms-ATP "gain" and ATP "dip"-representing transient increases or decreases in matrix ATP levels, respectively. These waveforms were tightly phase-locked to intracellular Ca 2+ transients and organized into energetic microdomains. Although female myocytes exhibited larger local mitochondrial ATP transients than their male counterparts, their total mitochondrial volume was lower. Female myocytes also exhibited tighter coupling between the sarcoplasmic reticulum and mitochondria and showed a higher concentration of mitofusin 2 and ATP synthase catalytic α-subunit per unit volume, suggesting more efficient ATP production. Cytosolic ATP transients mirrored mitochondrial waveforms and domain structure in both male and female myocytes. During faster pacing, diastolic cytosolic ATP rose more rapidly in female myocytes, whereas the accompanying beat-locked ATP transients increased in both sexes but did so proportionally more in males than in females. These findings demonstrate that ATP is synthesized on demand-beat by beat-in a modular, microdomain-specific manner. We propose that male myocytes rely on greater mitochondrial mass for energetic scaling, whereas female cells employ architectural precision to optimize ATP delivery.
Key points summary: It is known that each heartbeat requires precise ATP delivery to fuel ion transport and cross-bridge cycling, but the timing and spatial organization of ATP production in heart cells has been unclear.Using advanced imaging and genetically encoded sensors, we visualized beat-to-beat ATP fluctuations in the mitochondria and cytosol of individual male and female mouse ventricular myocytes. Mitochondrial ATP levels rose or fell with each beat in spatially confined regions, forming ATP "gain" or "dip" microdomains that were synchronized with Ca 2+ transients. At higher firing rates, beat-locked, diastolic ATP transients rose more quickly in female myocytes, but were larger in male myocytes, highlighting distinct sex-specific strategies for matching energy supply to contractile demand.Ventricular myocytes "live paycheck-to-paycheck", producing just enough ATP on demand to fuel each beat. Male and female myocytes adopt distinct strategies to meet this demand: male myocytes scale output through greater mitochondrial mass, while female myocytes achieve energetic precision via enhanced sarcoplasmic reticulum-mitochondrial coupling.
Abstract Figure:

DOI: https://doi.org/10.1101/2025.07.07.663572
Clin Nutr ESPEN. 2025 Jul 14. pii: S2405-4577(25)01775-9. [Epub ahead of print]

The nutritional adequacy of the ketogenic diet in paediatric epilepsy: detailed nutrient analysis and dietary recommendations.

Erica Tsang, Richard Webster, Shekeeb Mohammad, Manoj Menezes, Kavitha Kothur, Esther Tantsis, Christopher Troedson, Sachin Gupta, Deepak Gill, Shrujna Patel, Russell C Dale.

   BACKGROUND AND AIMS: Much of the focus of ketogenic diet (KD) literature has been on the macronutrient profile, as the appropriate distribution of carbohydrate, fat and protein is essential to inducing ketosis. Few studies have evaluated the micronutrient adequacy of the KD in paediatric epilepsy, despite the importance of adequate vitamin and mineral intake in growth and development. Our study evaluated the nutritional adequacy of the Modified Atkins Diet (MAD) and Classical Ketogenic Diet (CKD) in children with epilepsy, relative to baseline diets and Nutrient Reference Values (NRVs).
METHODS: Twenty children with epilepsy on the MAD and CKD underwent dietary analysis of 28 key nutrients at baseline and 3 months on diet (+/-multivitamin). Nutrient intake was expressed as % relative to recommended daily intake (RDI), adequate intake (AI), and upper limit as per the Australian NRVs. Nonparametric statistical comparisons were performed with a significance of p<0.05.
RESULTS: Sixty percent of children were KD 'responders,' exhibiting >50% seizure reduction with median beta-hydroxybutyrate (blood ketone) level of 2.75mmol/L on MAD and 4.25mmol/L on CKD. Despite restriction of fruits, vegetables, dairy and wholegrains, children on MAD (without multivitamin) met 100% of RDI for all nutrients except potassium. Intake of fibre and polyunsaturated fat increased significantly on the MAD compared to baseline. With multivitamin supplementation, some children on MAD were close to meeting upper limits for vitamin A, zinc, and selenium. Dietary recommendations to optimise nutritional adequacy using a 'food-first' ketogenic approach are provided.
CONCLUSIONS: Although it is commonly reported that the restrictive nature of the KD induces nutritional deficiencies, our findings indicate that a well-designed MAD can induce positive dietary changes including increased fibre intake, increased mono- and polyunsaturated fat intake, and increased omega-3 essential fatty acid intake in children with epilepsy, whilst producing adequate ketosis.

Keywords:  micronutrient; neurology; nutrient reference value

DOI:  https://doi.org/10.1016/j.clnesp.2025.07.023
J Enzyme Inhib Med Chem. 2025 Dec;40(1): 2520611

Nucleoside diphosphate kinase strongly promotes GDP and ADP metabolism in the cell and affects endogenous proton leak in mitochondria - the kinase is hampered by oxidative phosphorylation inhibitors.

Andrzej M Woyda-Ploszczyca.

  Rapid GDP metabolism in mitochondria isolated from wild-type yeast is postulated. The hallmark of exogenous GDP is convergence with the effect of exogenous ADP, typically inducing oxidative phosphorylation (OXPHOS). The GDP-provoked changes in the presence of ATP, i.e. increased respiratory rate accompanied by decreased inner mitochondrial membrane electrical potential, were curtailed by OXPHOS inhibitors, such as carboxyatractyloside, which apparently merged the GDP effect with OXPHOS. However, all performed tests indicated that the response of mitochondria to GDP is indirect and involves two steps. First, GDP is transphosphorylated via nucleoside diphosphate kinase (NDPK), ATP + GDP → ADP + GTP, which is followed by ADP-induced OXPHOS. Importantly, in mitochondria isolated from mutant yeast with a deleted NDPK gene, the stimulatory effect of GDP was eliminated. Therefore, a prerequisite for GDP metabolic action is the cooperation of NDPK with the OXPHOS apparatus. This biological model can help elucidate the molecular basis of some diseases treatment, such as cancer.

Keywords:  ADP/ATP carrier; mitochondria; nucleoside-diphosphate kinase (NDPK); nucleotide metabolism; proton (H+) leak

DOI:  https://doi.org/10.1080/14756366.2025.2520611
bioRxiv. 2025 Jun 15. pii: 2025.06.10.658925. [Epub ahead of print]

Opposing effects of systemic and pancreas-specific inhibition of BCKDK on pancreatic carcinogenesis.

Michael C Noji, Christina Demetriadou, Madelyn Landis, Jennifer Pennise, Laura V Pinheiro, Alison Jaccard, Adam Chatoff, Jack Drummond, Kevin Guo, Romie Azor, Maggie R Robertson, Ryo Kawakami, Mariola M Marcinkiewicz, John W Tobias, Nathaniel W Snyder, David Feldser, Zoltan Arany, Kathryn E Wellen.

Branched-chain amino acid (BCAA) metabolism is perturbed in patients with pancreatic cancer, but the contribution of systemic or pancreas-intrinsic BCAA catabolism to pancreatic carcinogenesis is unclear. We show here that pancreas-specific loss of DBT, the E2 subunit of the branched-chain keto-acid dehydrogenase (BCKDH) complex required for BCAA oxidation, strikingly exacerbates premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in KC ( p48-Cre ; Kras LSL-G12D/+ ) mice. However, deletion of upstream enzyme BCAT2 neither phenocopied nor rescued loss of DBT in KC mice, ruling out involvement of both upstream and downstream metabolites as mediators of PanIN promotion. Instead, we observed that DBT deficiency led to loss of the kinase BCKDK, a negative regulator of the BCKDH complex, and that, remarkably, pancreas-specific loss of BCKDK phenocopied DBT deficiency in accelerating PanIN formation. These data thus support a model in which pancreas BCKDK restrains tumorigenesis. In contrast, systemic treatment of KC mice with the BCKDK inhibitor BT2, which inhibits BCKDH phosphorylation across many tissues except the pancreas, reduced PanIN formation and preserved normal acinar area. Together the data reveal the promotion of BCAA catabolism systemically, but not within the pancreas, as a promising intervention strategy to suppress tumor initiation.

DOI: https://doi.org/10.1101/2025.06.10.658925
Signal Transduct Target Ther. 2025 Jul 14. 10(1): 222

High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability.

Diego A Pereira-Martins, Isabel Weinhäuser, Emmanuel Griessinger, Juan L Coelho-Silva, Douglas R Silveira, Dominique Sternadt, Ayşegül Erdem, Bruno Kosa L Duarte, Prodromos Chatzikyriakou, Lynn Quek, Antonio Bruno Alves-Silva, Fabiola Traina, Sara T Olalla Saad, Jacobien R Hilberink, Amanda Moreira-Aguiar, Maria L Salustiano-Bandeira, Marinus M Lima, Pedro L Franca-Neto, Marcos A Bezerra, Nisha K van der Meer, Emanuele Ammatuna, Eduardo M Rego, Gerwin Huls, Jan Jacob Schuringa, Antonio R Lucena-Araujo.

Metabolic reprogramming is a hallmark of cancer, with acute myeloid leukemia (AML) being no exception. Mitochondrial function, particularly its role in protecting tumor cells against chemotherapy, is of significant interest in AML chemoresistance. In this study, we identified mitochondrial DNA content (mtDNAc), measured by quantitative PCR, as a simple and precise marker to stratify the metabolic states of AML patients. We show that patients with high mtDNAc are associated with increased mitochondrial metabolism and a higher dependency on oxidative phosphorylation (OXPHOS), often correlating with chemoresistance. Clinically, patients receiving cytarabine and an anthracycline-based regimen (7 + 3 regimen) experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence. Ex vivo experiments using primary AML samples confirmed cytarabine resistance in high mtDNAc patients, which could be overcome by inhibiting mitochondrial complex I. The FDA-approved drug metformin, which targets mitochondrial metabolism, significantly enhanced apoptosis in response to chemotherapy or targeted agents, such as venetoclax, in AML models. However, metformin-treated cells adapted by increasing glycolysis and NAD+ production, a resistance mechanism that could be bypassed by targeting the nicotinamide phosphoribosyltransferase (NAMPT) enzyme. In summary, we demonstrated that mtDNAc is an effective tool for assessing the metabolic state of AML cells. This method can be easily implemented in clinical practice to identify chemoresistant patients and guide personalized treatment strategies, including novel combination therapies for those with a high reliance on mitochondrial metabolism.

DOI: https://doi.org/10.1038/s41392-025-02303-x
bioRxiv. 2025 Jun 18. pii: 2025.06.17.660237. [Epub ahead of print]

Respiratory complex III 2 assembles complex I via toxic intermediate in mitochondrial disease.

Maria G Ayala-Hernandez, Anetzy Bermudez Torales, Hannah Camille Tan, Claire B Montgomery, Abhilash Padavannil, Gino Cortopassi, James A Letts.

Mutations in mitochondrial complex I can cause severe metabolic disease. Although no treatments are available for complex I deficiencies, chronic hypoxia improves lifespan and function in a mouse model of the severe mitochondrial disease Leigh syndrome caused by mutation of complex I subunit NDUFS4. To understand the molecular mechanism of NDUFS4 mutant pathophysiology and hypoxia rescue, we investigated the structure of complex I in respiratory supercomplexes isolated from NDUFS4 mutant mice. We identified complex I assembly intermediates bound to complex III 2 , proving the cooperative assembly model. Further, an accumulated complex I intermediate is structurally consistent with pathological oxygen-dependent reverse electron transfer, revealing unanticipated pathophysiology and hypoxia rescue mechanisms. Thus, the build-up of toxic intermediates and not simply decreases in complex I levels underlie mitochondrial disease.

DOI: https://doi.org/10.1101/2025.06.17.660237
Oncogenesis. 2025 Jul 12. 14(1): 24

Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2.

Chaehyun Yum, Richard A Schaefer, Rui Wang, Ting-You Wang, Xiaotong Lu, Qi Liu, Yanan Ren, Qingshu Meng, Yongyong Yang, Xin Zhang, Yan Xiong, Xufen Yu, Xiaoyu Zhang, Jian Jin, Xuesen Dong, Yang Yi, Rendong Yang, Qi Cao.

It is well established that EZH2, a lysine methyltransferase, is upregulated in most aggressive cancers, highlighting the importance of EZH2 in cancer progression. Recent research has shown that metabolic reprogramming is pivotal in various biological processes, including cancer. Despite this, evidence of EZH2's role in regulating cancer metabolism remains limited. Our study reveals a negative correlation between EZH2 and HMGCS2, a gene belonging to the HMG-CoA synthase, in prostate and breast cancers. Interestingly, HMGCS2 is inversely related to cancer progression and prognosis in these cancers. Furthermore, HMGCS2 is epigenetically repressed by EZH2 both in vitro and in vivo. Notably, restored EZH2 reduces the elevated HMGCS2 levels observed upon EZH2 depletion. Overexpression of HMGCS2 decreases tumorigenesis in both prostate and breast cancers. Additionally, β-hydroxybutyrate (BHB), a downstream metabolite of HMGCS2, impedes prostate cancer progression by targeting EZH2 via direct protein-compound interaction-mediated protein degradation. More importantly, the ketone drink of BHB administration dramatically reduces tumor size and weight in a therapy-resistant, castration-resistant prostate cancer patient-derived xenograft model. Combining a ketone drink with FDA-approved drugs enzalutamide and Tazemetostat further suppresses tumor progression. Overall, the EZH2-HMGCS2-BHB regulatory network plays a critical role in the progression of prostate cancer, and a ketone drink is a novel therapeutic tool for patients with aggressive prostate cancer.

DOI: https://doi.org/10.1038/s41389-025-00567-0
bioRxiv. 2025 Jun 20. pii: 2025.06.16.659985. [Epub ahead of print]

Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.

Joy Omini, Inga Krassovskaya, Taiwo Dele-Osibanjo, Connor Pedersen, Toshihiro Obata.

The tricarboxylic acid (TCA) cycle enzymes, malate dehydrogenase (MDH1) and citrate synthase (CIT1), form a multienzyme complex called 'metabolon' that channels intermediate, oxaloacetate, between the reaction centers of the enzymes. Since the MDH1-CIT1 metabolon enhances the pathway reactions in vitro, it is postulated to regulate the TCA cycle flux through dynamic assembly in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the pathway flux was enhanced by acetate. Pharmacological TCA cycle inhibitions dissociated the complex, while electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1-CIT1 complex affinity in vitro. Especially the buffer pH significantly changed the MDH1-CIT1 affinity within the pH range between 6.0 and 7.0, which is observed in the mitochondrial matrix under physiological conditions. These results show a dynamic association and dissociation of a metabolon in the mitochondria and its relationship with pathway flux, supporting the metabolon's role in metabolic regulation. Multiple factors, including pH and metabolite availabilities, possibly regulate MDH1-CIT1 interaction.

DOI: https://doi.org/10.1101/2025.06.16.659985
J Cell Physiol. 2025 Jul;240(7): e70062

Bypassing Blood-Brain Barrier and Glucose Dependency of Anti-Glioblastoma Drug Candidates Targeting Mitochondrial Respiration.

Charles H Ingraham, Diana Polania Villanueva, Annamarie Macaluso, Annelise Tramuta, Cecilia Vittori, Jean-Jacques Hunter, Monika Rak, Pier Paolo Claudio, Mohamed A Ibrahim, Luis Del Valle, Francesca Peruzzi, Branko S Jursic, Krzysztof Reiss.

  We attempt to address two key therapeutic obstacles affecting glioblastoma patients: low ability of anticancer drugs to penetrate the blood-brain barrier (BBB), and temozolomide (TMZ) resistance, by targeting mitochondrial respiration of glioblastoma cells. We designed and tested over 100 new compounds based on the chemical structure of fenofibrate (FF), which in its prodrug form is cytotoxic to cancer cells by causing severe impairment of mitochondrial respiration. The compounds were designed using two key predictive tools: central nervous system-multiparameter optimization (CNS-MPO) and BBB_SCORE. These algorithms assess how effectively compounds can penetrate the BBB. We initially selected PP1 as a lead compound by testing its BBB penetration, metabolic performance, and antitumoral efficacy. PP1 accumulated in brain tumors and triggered glioblastoma cell death. However, PP1-induced inhibition of mitochondrial respiration was followed by an immediate glycolytic response, which attenuated PP1 toxicity in a glucose-dependent manner. To bypass this limitation, we tested two strategies: (1) the use of PP1 in combination with glycolysis inhibitors; and (2) introduction of a new compound, PP211, which inhibited mitochondrial respiration in the absence of a concomitant increase of glycolysis. Although the combination of PP1 with glycolysis inhibitors was very effective in vitro, this drug combination demonstrated elevated toxicity in mice. PP211, instead, attenuated TMZ-resistant tumor growth and prolonged mouse survival with only minimal general animal toxicity. In summary, we developed and tested a novel mitochondria-targeting drug candidate, PP211, which effectively crosses the BBB, overcomes TMZ resistance, and induces tumor cell death independently of glucose levels-while exhibiting minimal systemic toxicity in preclinical models. These findings support further development of PP211 for glioblastoma therapy.

Keywords:  blood‐brain barrier; drug development; glioblastoma; mitochondrial respiration

DOI:  https://doi.org/10.1002/jcp.70062
bioRxiv. 2025 Jun 15. pii: 2025.06.15.659774. [Epub ahead of print]

High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.

Luke W Koblan, Kathryn E Yost, Pu Zheng, William N Colgan, Matthew G Jones, Dian Yang, Arhan Kumar, Jaspreet Sandhu, Alexandra Schnell, Dawei Sun, Can Ergen, Reuben A Saunders, Xiaowei Zhuang, William E Allen, Nir Yosef, Jonathan S Weissman.

Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here we present the design, development, and extensive validation of PEtracer, a prime editing-based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstruct the growth of individually-seeded tumors in vivo and uncover distinct modules of cell-intrinsic and cell-extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically-relevant temporal and spatial scales.

DOI: https://doi.org/10.1101/2025.06.15.659774
Blood Adv. 2025 Jul 17. pii: bloodadvances.2025016168. [Epub ahead of print]

Novel Devimistat Results in Complete Remissions in Heavily Pre-Treated Burkitt Lymphoma in a phase II trial.

Raphael E Steiner, Liana Nikolaenko, Ranjit Nair, Venkatraman E Seshan, Swetha Thiruvengadam, Niloufer Khan, Jeremy S Abramson, Steven M Horwitz, Matthew J Matasar, Colette N Owens, Ildefonso Ismael Rodriguez-Rivera, David Strauss, Timothy S Pardee, Sanjeev Luther, Sabrina Saboukoulou, Win Su Thet, Shreya Vemuri, Ariela Noy.

Patients with primary refractory or relapsed (RR) MYC-driven aggressive B-cell lymphomas, such as Burkitt lymphoma (BL), plasmablastic lymphoma (PBL), and double/triple hit lymphoma (DHL), have a dismal prognosis with few survivors. The deregulated MYC protein drives proliferation with dependence on tricarboxylic acid cycle intermediates as biosynthetic precursors. Devimistat disrupts mitochondrial production of ATP and biosynthetic intermediates. We conducted a Phase II trial to explore the efficacy of devimistat in RR-BL, RR-PBL, and RR-DHL, administered daily for 5 days every 14 days for 2 cycles, followed by maintenance for 5 days every 21 days until progression, toxicity, or transplant. No responses were seen in the enrolled 2 RR-PBL and 9 RR-DHL/THL patients. Among the 13 RR-BL patients, 2 had a complete response (CR), resulting in a CR rate (CRR) of 15%, while the others experienced rapid disease progression. The median follow-up time for RR-BL patients was 1 month (range, 0-47 months). Among the 2 RR-BL CR patients, the response duration was 8 months in one and ongoing at the time of data cutoff, 17 months post-study entry. Three patients had grade 3 events at least possibly related to the study drug: neutropenia, thrombocytopenia, headache, non-cardiac chest pain, and increase of troponin. Considering the dismal prognosis of RR MYC-driven aggressive B-cell lymphomas with the current standard of care and low CRR with devimistat, efforts should be made to improve the outcome of these malignancies with their first line of therapy and explore novel therapies in the RR setting. NCT03793140.

DOI: https://doi.org/10.1182/bloodadvances.2025016168
Curr Opin Clin Nutr Metab Care. 2025 Jul 14.

Impact of intermittent fasting on micronutrient intake.

Sabina Wallerer, Lukas Schwingshackl.

   PURPOSE OF REVIEW: This narrative review aims to evaluate the current evidence on how intermittent fasting regimens - including alternate-day fasting (ADF) and time-restricted eating (TRE) - affect micronutrient intake in adults.
RECENT FINDINGS: Several randomized controlled trials have reported reductions in the intake of key micronutrients such as calcium, magnesium, potassium, folate, vitamin C, and various B vitamins during ADF and TRE. These deficiencies are largely driven by lower total energy intake and reduced consumption of nutrient-dense foods on fasting days. While some studies found no significant differences in micronutrient adequacy between ADF/TRE and continuous energy restriction, others observed higher prevalence of inadequate micronutrient intake with intermittent fasting regimens. Dietary supplement use varied across studies and may help mitigate deficiency risks. Variations in study design, dietary adherence, dietary patterns, baseline nutritional status and nutritional advice appear to influence outcomes substantially.
SUMMARY: Although intermittent fasting is an effective and flexible approach to weight management, it may compromise micronutrient intake if dietary quality is not prioritized. Emphasis should be placed on nutrient-dense food choices during eating windows. Dietary supplements may be necessary in restrictive or prolonged fasting regimens to prevent deficiencies and support overall metabolic health.

Keywords:  intermittent fasting; micronutrients; time-restricted eating

DOI:  https://doi.org/10.1097/MCO.0000000000001148
medRxiv. 2025 Jul 10. pii: 2025.07.09.25331020. [Epub ahead of print]

Cachexia in Clinical Practice: Experience from an Endocrine-Led Care Model.

Anirudh Murthy, Morgan Simons, Anne Jablonski, Maurice Hurd, Alpana Shukla, Marcus D Goncalves.

Background: Cachexia is a multifactorial syndrome of involuntary weight loss, skeletal muscle wasting, and metabolic dysregulation, commonly seen in advanced cancer and other chronic diseases. Despite its prevalence and prognostic significance, effective treatment strategies remain limited, and there is no standardized model of outpatient care in the US.
Objective: To describe the structure, patient characteristics, and outcomes of a multidisciplinary cancer cachexia clinic embedded within an academic endocrinology practice.
Methods: We conducted a retrospective analysis of 103 patients referred to a single-center cachexia clinic over five years. Patients underwent comprehensive assessments including weight trajectory, nutritional status, physical performance (5x sit-to-stand test, handgrip strength), and received individualized interventions involving nutrition counseling, resistance training, and pharmacologic management.
Results: The median patient age was 69.7 years, with 64.1% having a cancer diagnosis (61.0% with metastases). Median monthly weight loss decreased from -0.5 kg/month in the 6 months pre-enrollment to 0.0 kg/month after 3 months post enrollment (p < 0.0001), indicating significant stabilization. The 5x sit-to-stand test improved (p = 0.022), though handgrip strength remained unchanged. Patients prescribed an exercise video program trended toward greater weight gain (β = +1.988, p = 0.079), while those prescribed protein powder tended to experience more weight loss (β = -2.102, p = 0.113), although this difference was not statistically significant.
Conclusion: A multimodal cachexia clinic can stabilize weight loss and improve physical function in medically complex patients. These findings support the integration of interdisciplinary approaches to cachexia management and provide a framework for evaluating future interventions in routine clinical settings.

DOI: https://doi.org/10.1101/2025.07.09.25331020
Epilepsy Curr. 2025 Jul 13. 15357597251358412

Oops!…I Did it Again, I Gave You Some Carbs: Prescribing Errors in Inpatient Ketogenic Diet Management.

Mackenzie C Cervenka.

DOI: https://doi.org/10.1177/15357597251358412
FEBS J. 2025 Jul 13.

Ras pathways help buffer biological timekeeping against metabolic perturbations.

Patricia Lakin-Thomas.

  Circadian clocks need to be buffered against changes in conditions that could affect their rate and disrupt their timekeeping function. The circadian period of the fungus Neurospora is compensated across a range of nutritional conditions. Several gene products are implicated in the mechanism, but a complete picture is lacking. Sárkány et al. report that a Ras pathway linked to cAMP is required to maintain a constant period under low glucose conditions. They extend this work to a human cell line showing similar effects of the homologous Ras pathway, pointing toward potential conservation of compensation pathways across eukaryotes.

Keywords:  Neurospora; Ras; circadian; compensation; osteosarcoma

DOI:  https://doi.org/10.1111/febs.70188
J Clin Invest. 2025 Jul 15. pii: e191940. [Epub ahead of print]135(14):

What's on the menu?: metabolic constraints in the pancreatic tumor microenvironment.

Colin Sheehan, Alexander Muir.

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is composed of a dense stromal compartment and is poorly vascularized, resulting in limited nutrient delivery. As a result, PDAC cells must adapt to cope with the metabolic stresses brought on by TME nutrient limitation. In this article, we first review recent studies that have provided quantitative measurements of nutrient levels in the PDAC TME. These studies have provided a new understanding of the nutrient limitations and metabolic stresses that occur in PDAC. We next discuss the adaptive strategies employed by PDAC in response to TME nutrient limitation. We propose that PDAC adaptations to metabolic stress can be generalized into four categories: (a) cutting down on metabolic costs by recycling metabolites and suppressing nonessential processes, (b) upregulating biosynthetic pathways to meet TME metabolic demands, (c) supporting essential metabolic processes with alternative fuel sources, and (d) dampening antiproliferative and cell death responses that nutrient limitation normally triggers. Improving our understanding of the nutrient limitations within the TME, and the adaptations cells employ to cope with these stresses, provides a more complete picture of PDAC biology and reveals new opportunities for therapeutic targeting of this disease.

DOI: https://doi.org/10.1172/JCI191940
Blood. 2025 Jul 15. pii: blood.2024028199. [Epub ahead of print]

The acute myeloid leukemia microenvironment impairs neutrophil maturation and function through NFκB signaling.

Paran Goel, Sajesan Aryal, Alana M Franceski, Valeriya Kuznetsova, Amanda Fernandes De Oliveira Costa, Francesca Luca, Ashley N Connelly, Daniel W Phillips, Caroline C Ennis, Brittany M Curtiss, Sourajeet Karfa, Brittany L Crown, Christina R Larson, Estelle Carminita, Virginia Camacho, Doug Welsch, Changde Cheng, Asumi Yokota, Isidoro Cobo, Hideyo Hirai, Rui Lu, Ravi Bhatia, Pran K Datta, Paul Brent Ferrell, Robert S Welner.

Acute myeloid leukemia (AML), an aggressive hematological malignancy, is driven by oncogenic mutations in stem and progenitor cells that give rise to AML blasts. While these mutations are well-characterized, their impact on healthy hematopoiesis-those blood cells exposed to AML but not mutated-has not been well-characterized. As the marrow is the major site for granulopoiesis, neutrophils are heavily influenced by AML pathobiology. Indeed, most AML patients report neutropenia, rendering them susceptible to infections. However, since AML studies use peripheral blood mononuclear cells devoid of neutrophils, the characterization of neutrophil dysfunction remains poorly understood. To investigate AML-exposed neutrophils, a pre-clinical AML mouse model was used where primary leukemic cells were transplanted into non-irradiated neutrophil reporter (Ly6G-tdTomato; Catchup) hosts. Neutrophils could not completely mature, suggesting impaired granulopoiesis. Single-cell transcriptomics of AML-exposed neutrophils revealed higher inflammation signatures and expression of CD14, an inflammatory marker. To address the factors contributing to this biology, an ex vivo cytokine screen was performed on marrow neutrophils and identified that NFκB signaling drove CD14 expression. AML-exposed neutrophils displayed widespread chromatin remodeling, and de novo motif discovery predicted increased binding sites for CCAAT-enhancer-binding proteins (C/EBPs) and Interferon regulatory factors (IRFs). Moreover, AML-exposed neutrophils inhibited T-cell proliferation, highlighting their immune-suppressive capability. Finally, similar biology of immature, inflammatory neutrophils was found in AML patients, again indicating dysregulated granulopoiesis. Collectively, these data show that AML-associated inflammation alters neutrophil granulopoiesis, impairs neutrophil function, and drives immunosuppression, thus contributing to patient susceptibility to infection.

DOI: https://doi.org/10.1182/blood.2024028199
bioRxiv. 2025 May 09. pii: 2025.05.05.652276. [Epub ahead of print]

A Platform for Mitochondrial Profiling in Enriched Kidney Segments Under Thermodynamic Control.

Stephen T Decker, Precious C Opurum, Ran Hee Choi, Venisia L Paula, Anu S Kurian, Deborah Stuart, Linda S Nikolova, Alejandro Sanchez, Laith Al-Rabadi, Nirupama Ramkumar, Kelsey H Fisher-Wellman, Katsuhiko Funai.

Mitochondrial function varies widely across kidney nephron segments, yet conventional approaches lack the resolution and control needed to assess cell-type-specific bioenergetics in situ. We present a methodological platform that enables segment-resolved profiling of mitochondrial respiration, conductance, and membrane potential in freshly isolated mouse nephron segments. Combining mechanical sieving and adhesion-based enrichment with permeabilized high-resolution respirometry, we adapted the creatine kinase clamp to quantify oxygen flux and mitochondrial membrane potential across defined free energies. Using this approach, we found that proximal tubules exhibit high respiratory conductance and dynamic mitochondrial polarization, while distal tubules and glomeruli maintain static membrane potential and low conductance. In a model of adenine-induced nephropathy, only proximal tubule mitochondria showed marked reductions in respiration and ATP production. This segment-specific dysfunction was not detectable in bulk mitochondrial isolates. Our approach provides thermodynamically anchored, segment-resolved insight into mitochondrial adaptation under physiological and pathological conditions. It is broadly applicable to other tissues with metabolic heterogeneity and compatible with disease models, genetic tools, and pharmacological interventions. This platform bridges a critical gap between conventional respirometry and functional mitochondrial phenotyping in native tissue structures.

DOI: https://doi.org/10.1101/2025.05.05.652276
Front Neuroinform. 2025 ;19 1549916

Digitoids: a novel computational platform for mimicking oxygen-dependent firing of neurons in vitro.

Rachele Fabbri, Ermes Botte, Arti Ahluwalia, Chiara Magliaro.

   Introduction: Computational models are valuable tools for understanding and studying a wide range of characteristics and mechanisms of the brain. Furthermore, they can also be exploited to explore biological neural networks from neuronal cultures. However, few of the current in silico approaches consider the energetic demand of neurons to sustain their electrophysiological functions, specifically their well-known oxygen-dependent firing.
Methods: In this work, we introduce Digitoids, a computational platform which integrates a Hodgkin-Huxley-like model to describe the time-dependent oscillations of the neuronal membrane potential with oxygen dynamics in the culture environment. In Digitoids, neurons are connected to each other according to Small-World topologies observed in cell cultures, and oxygen consumption by cells is modeled as limited by diffusion through the culture medium. The oxygen consumed is used to fuel their basal metabolism and the activity of Na+-K+-ATP membrane pumps, thus it modulates neuronal firing.
Results: Our simulations show that the characteristics of neuronal firing predicted throughout the network are related to oxygen availability. In addition, the average firing rate predicted by Digitoids is statistically similar to that measured in neuronal networks in vitro, further proving the relevance of this platform.
Dicussion: Digitoids paves the way for a new generation of in silico models of neuronal networks, establishing the oxygen dependence of electrophysiological dynamics as a fundamental requirement to improve their physiological relevance.

Keywords:  digitalized neuronal network; in silico modeling; in vitro neuronal network; neuron firing; oxygen metabolism

DOI:  https://doi.org/10.3389/fninf.2025.1549916
Blood Adv. 2025 Jul 16. pii: bloodadvances.2025016718. [Epub ahead of print]

Olutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome.

Jorge E Cortes, Jay Yang, Gail J Roboz, Shira Naomi Dinner, Eunice S Wang, Andrew H Wei, Hua Tian, Francois di Trapani, Maria R Baer, William B Donnellan, Justin M Watts.

Olutasidenib, a potent, selective, oral small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is FDA-approved for mIDH1 relapsed/refractory (R/R) acute myeloid leukemia based on results from the pivotal AML cohort of a multi-arm phase 1/2 trial that also enrolled patients with MDS (NCT02719574). We report pooled data evaluating olutasidenib as monotherapy or combined with azacitidine in R/R and treatment-naïve (TN) higher-risk MDS harboring mIDH1. Endpoints included safety, overall response rate (ORR), complete remission (CR) rate, time-to-response (TTR), duration of response (DOR), overall survival (OS), and transfusion-independence. Twenty-two patients (median age 74 years, 59% male) with IPSS-R intermediate- to very high-risk MDS (n=6 monotherapy [4 R/R, 2 TN]; n=16 combination [11 R/R, 5 TN]) were analyzed. The most frequent AEs were fatigue and cytopenias. Differentiation syndrome occurred in 3 patients (14%); 1(5%) grade 3 severity. QT prolongation occurred in 1 patient receiving combination therapy. ORR was 59% (CR: 27%, 6/22; marrow CR: 32%, 7/22) in intent-to-treat (n=22, ITT) and 68% (CR: 32%, 6/19; marrow CR: 37%, 7/19) in response-evaluable (n=19) patients. ORR (ITT population) was 33% (2/6) for monotherapy (3/6 patients received £half the recommended dose) and 69% (11/16) for combination therapy. Median TTR was 2 months (range 1-13), median DOR 14.6 months (95% CI, 5.8-32.8), and median OS 27.2 months (95% CI, 6.9-37). 62% and 67% of patients who were transfusion-dependent at baseline achieved 56-day RBC and platelet transfusion independence, respectively. Olutasidenib with or without azacitidine demonstrated encouraging clinical activity and tolerability in patients with higher-risk mIDH1 MDS. NCT02719574.

DOI: https://doi.org/10.1182/bloodadvances.2025016718
Biochem Pharmacol. 2025 Jul 12. pii: S0006-2952(25)00418-6. [Epub ahead of print] 117153

BDH2 promotes GLIPR1 promoter methylation and thus increases 5-FU sensitivity in colorectal cancer.

Dapeng Lu, Lin Ma, Qingyue Zhang, Chengzhong Xing, Yanke Li.

  5-Fluorouracil (5-FU) is an effective drug in the treatment of colorectal cancer (CRC); however, the development of acquired resistance to 5-FU poses a great challenge in clinical practice. Through the analysis of public datasets, we found that reduced 3-Hydroxybutyrate Dehydrogenase 2 (BDH2) expression in CRC tissues predicted poor survival in CRC patients. Low expression of BDH2 in clinical CRC tissue samples predicted a higher degree of malignancy. In addition, public dataset analysis showed that GLI Pathogenesis Related 1 (GLIPR1) expression was elevated in CRC patients following 5-FU treatment, contrasting with the expression pattern of BDH2. We reported that in 5-FU-resistant CRC cell lines (LOVO/5-FU and HCT15/5-FU), BDH2 was downregulated, while the expression of GLIPR1 was increased. To explore the regulatory relationship between BDH2 and GLIPR1 in 5-FU resistance, BDH2 and GLIPR1 overexpression plasmid vectors were constructed to transfect 5-FU resistant CRC cell lines. BDH2 led to enhanced 5-FU sensitivity in 5-FU-resistant CRC cell lines and inhibited the malignant behavior of CRC-resistant cells in vitro. In nude mice with subcutaneous tumors and intraperitoneal injections of 5-FU, tumor tissues formed by BDH2-overexpressing cells exhibited slower growth and increased apoptosis. Mechanistically, the upregulation of BDH2 increases GLIPR1 promoter methylation, mediated by DNA methyltransferases, thereby inhibiting GLIPR1 expression. High expression of GLIPR1 reduces 5-FU sensitivity in 5-FU-resistant CRC cell lines, which abolished the impact of BDH2 expression. These results suggest that BDH2 inhibits GLIPR1 expression by increasing GLIPR1 promoter methylation, thereby enhancing 5-FU sensitivity of 5-FU-resistant CRC cell lines and inhibiting CRC progression.

Keywords:  3-Hydroxybutyrate dehydrogenase 2 (BDH2); 5-Fluorouracil sensitivity; Colorectal cancer (CRC); GLI pathogenesis related 1 (GLIPR1)

DOI:  https://doi.org/10.1016/j.bcp.2025.117153
Blood Adv. 2025 Jul 17. pii: bloodadvances.2025016726. [Epub ahead of print]

Utility of IDH1/2 mutations as biomarkers for detection of measurable residual disease in acute myeloid leukemia.

Emma L Boertjes, Christian M Vonk, François G Kavelaars, Marie Engvall, Sofia Nordin, Lisanne Beugelink, Melissa Rijken, Jolinda Konijnenburg, Jurjen Versluis, Bob Löwenberg, Peter J M Valk.

Molecular measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) patients has been established for only a few specific markers, i.e. mutant NPM1 and FLT3-ITD. Mutations in IDH1/2 are present in approximately 20% of AML patients. However, validation of mutant IDH1/2 MRD has been hampered by cohort size as well as the availability of highly sensitive and specific MRD detection assays. Here, we comprehensively investigate the impact of persisting IDH1/2 mutations in complete remission (CR) after intensive chemotherapy in a cohort of 163 newly diagnosed IDH-mutant AML patients enrolled in HOVON-SAKK clinical trials using a next-generation sequencing (NGS)-based approach, targeting all hotspot mutations in IDH1 (R132) and IDH2 (R140, R172). The high sensitivity (10-4) as well as the levels of persisting IDH1/2 mutations detected by the NGS-based approach were confirmed by an independent rolling circle amplification (superRCA) assay. We demonstrate that relapse risk was significantly increased in AML patients with measurable persisting IDH2 mutations (p=0.027, SHR:2.34), but not in patients with persisting mutant IDH1 (p=0.591, SHR:0.80). Moreover, the association of persistence of mutant IDH2 and increased risk of relapse was most pronounced in mutant IDH2 AML patients without concomitant NPM1 mutations or FLT3-ITD (p=0.011, SHR:5.29). Thus, mutant IDH2 appears a potentially useful novel molecular MRD marker with prognostic significance in AML.

DOI: https://doi.org/10.1182/bloodadvances.2025016726
Genes Dev. 2025 Jul 11.

Mitochondria dysfunction: cause or consequence of physiologic aging?

G R Scott Budinger, Navdeep S Chandel.

  Mitochondria are no longer viewed solely as ATP- or metabolite-generating organelles but as key regulators of cellular signaling that shape physiologic aging. Contrary to earlier theories linking aging to mitochondrial DNA mutations and oxidative damage, current evidence shows that these factors do not causally limit physiologic aging. Instead, an evolving literature links age-related loss of mitochondrial signaling and function to important physiologic changes of aging. Moreover, mild inhibition of mitochondrial respiratory function with drugs like metformin promote health span. These findings open new paths for pharmacologically reprogramming mitochondrial signaling to extend healthy aging.

Keywords:  aging; mitochondria; senescence

DOI:  https://doi.org/10.1101/gad.353106.125
Sports Med. 2025 Jul 17.

Is the vLamax for Glycolysis What the V˙O2 max is for Oxidative Phosphorylation?

Henning Wackerhage, Athanasios Kabasakalis, Stephen Seiler, Hermann Heck.

Oxidative phosphorylation and glycolysis are the two truly major energy metabolism pathways in humans. While maximal oxygen uptake ( V˙O2 max) has been used for a century as a whole-body measure of maximal oxidative phosphorylation, there is no universally accepted, comparable measure of maximal glycolysis. However, already in 1984, Alois Mader introduced the maximal rate of lactate accumulation in mmol/kg/s related to active muscle weight (vLamaxmuscle) for his mathematical model of human exercise metabolism. In 1994, on the basis of a critical analysis of glycolytic tests at the time, Mader proposed a practical test of the maximal rate of lactate accumulation in mmol per litre of earlobe or fingertip blood per second, corrected for alactic time (talac), that is measured during an ~ 10-15-s all-out exercise test (vLamaxblood). The variant vLamaxblood differs from the original vLamaxmuscle, as it is normalized to 1 L of blood volume and is today measured as the maximal rate of blood lactate accumulation in mmol/L/s. To measure it, participants typically perform a 10-15-s all-out test followed by quantification of the rise of the blood lactate concentration from pre-test to the maximum after exercise. Some few seconds of a 10-15-s all-out test are "alactic" and should be subtracted from the work time to more accurately estimate the vLamaxblood. However, (1) glycolytic flux is unlikely to be truly maximal during an all-out exercise test, (2) peak glycolytic flux occurs only briefly, (3) there is no criterion for reaching the vLamaxblood, (4) there is no correction for lactate clearance in the time from exercise cessation to blood sampling, (5) there is no correction for ATP resynthesis by oxidative phosphorylation and (6) the talac correction is error-prone. Therefore, we propose the peak rate of lactate accumulation in mmol/L/s in arterialized earlobe or fingertip blood during an all-out exercise test lasting 10-15 s (vLapeak) as a simplified estimate of peak glycolytic rate analogous to the V˙O2 peak. In contrast to the vLamaxblood, the vLapeak is not corrected for talac. Modelling using Alois Mader's model of human exercise metabolism suggests that (with everything else being the same) a higher vLamaxmuscle will (a) improve performance in events where a large part of the hydrolysed ATP is resynthesized by glycolysis, (b) cause a leftward shift of the lactate curve and (c) increase carbohydrate usage and accelerate glycogen depletion at a given exercise intensity. There is large potential for research on the validation and improvement of vLapeak tests for athletes, healthy sedentary individuals and patients. This research should improve estimation of vLamaxmuscle from vLapeak and experimentally test the modelling predictions of the effects of changes in vLamaxmuscle on exercise performance and fatigue.

DOI: https://doi.org/10.1007/s40279-025-02259-6