bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–07–19
thirty papers selected by
Brett Chrest, Wake Forest University
  1. Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
  2. A high-fat, low-carbohydrate diet can feed intestinal tumours.
  3. Lauric acid engages an O-GlcNAc-sensitive BCKDH regulatory node to modulate branched-chain amino acid oxidation in skeletal myotubes.
  4. Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.
  5. A quantum interface with mitochondrial bioenergetics.
  6. Defining a ketone threshold for weight loss: evidence from 14 day daily β-hydroxybutyrate monitoring in 217 subjects on a ketogenic diet.
  7. Conditional dependency of oncogenic KRAS in driving ketone body catabolism and pancreatic cancer growth.
  8. Ketosis elevates plasma concentrations of D-β-hydroxybutyryl-phenylalanine (BHB-Phe) in humans.
  9. SIRT5/7 desuccinylation in cancer: linking metabolism, immunity, and drug resistance.
  10. Challenges and Solutions in Quantifying Brain β-Hydroxybutyrate (BHB) with 1 H-MRS Following Oral Keto-Ester Consumption.
  11. A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
  12. Ketogenic Diet in the Treatment of Malignant Gliomas: A Systematic Review.
  13. Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
  14. Nuclear adenosine metabolism defines a metabolic vulnerability unmasked by TP53 loss.
  15. Molecular and energetic basis of histidine switch dynamics in respiratory complex I.
  16. Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
  17. Metabolite glues as a means of purine sensing and chemotherapeutic response.
  18. Individual Amino Acid Supplementation Does Not Enhance Short-Term Proliferation of Selected Cancer Cell Lines In Vitro: Potential Implications for Nutritional Support in Cancer Cachexia.
  19. Use of Nuclear Magnetic Resonance (NMR) to Study Cancer Metabolism.
  20. Investigating the role of FOF1 ATPase in Zymomonas mobilis through deletion of its FO and F1 subcomplexes.
  21. Metabolic buffering restricts phenotype switching in melanoma.
  22. Animal models of pyruvate dehydrogenase complex deficiency: insight into mechanisms of cerebral abnormalities and tissue-specific role in metabolism.
  23. A polyadenylation enzyme rewires metabolism to fuel AML.
  24. Acetyl-CoA Metabolism in Skeletal Biology and Bone Disorders: From Mechanisms to Therapeutic Implications.
  25. Mass Spectrometry as a Tool for Metabolomics in Cancer.
  26. SLC16A6 is a tyrosine transporter for the melanosome.
  27. Mitochondrial Voltage-Dependent Anion Channel: From a Passive Pore to a Cellular Hub Through Protein Complexation.
  28. Investigation of an ALDH1A1-Specific Inhibitor, FSI-TN42, as a Treatment for Obesity in Female Mice.
  29. Standardised dual-flow cytometry workflows for quantitative assessment of mitochondrial superoxide and mitochondrial mass in live cancer cells and primary multiple myeloma cells.
  30. BACH1 meets its match: Heme licenses BACH1 destruction to tune ferroptosis.
  1. Nature. 2026 Jul 15.
    Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Shixun Han, Xiao Zhang, Johanna Ten Hoeve, Kevin J Williams, Seda Neptun, Tolga Sever, Isabela Fuentes, Sangeeta N Bhatia, Gizem Calibasi-Kocal, Matthew G Vander Heiden, Alex K Shalek, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics1. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis2. However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood3. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours4. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1038/s41586-026-10779-y
  2. Nature. 2026 Jul 15.
    A high-fat, low-carbohydrate diet can feed intestinal tumours.
    Souvik Patra, Evan C Lien.
      
    Keywords:  Cancer; Cell biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-02039-w
  3. J Biol Chem. 2026 Jul 16. pii: S0021-9258(26)02217-9. [Epub ahead of print] 113345
    Lauric acid engages an O-GlcNAc-sensitive BCKDH regulatory node to modulate branched-chain amino acid oxidation in skeletal myotubes.
    Koichiro Sumi, Miho Shioyama, Kinuyo Munakata, Satoshi Takasugi, Masashi Morifuji, Kentaro Nakamura.
      Branched-chain amino acid (BCAA) catabolism is controlled by the phosphorylation state of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which is regulated by the opposing actions of BCKDH kinase (BDK) and the phosphatase PPM1K. Although fatty acids and amino acids both contribute to skeletal muscle energy metabolism, how fatty acid availability influences BCAA catabolic regulation remains incompletely understood. Here we examined the effects of lauric acid (C12), a medium-chain fatty acid abundant in dietary lipids, on BCAA metabolism in differentiated skeletal myotubes. Lauric acid increased phosphorylation of the BCKDH E1α subunit at Ser293 during nutrient perturbation in both mouse and human skeletal myotubes. Stable isotope tracing with U-[ˆ13C6]-leucine revealed that C12 reduced incorporation of leucine-derived carbon into downstream tricarboxylic acid (TCA) cycle-associated metabolites, indicating suppression of BCAA oxidative flux, whereas incorporation of labeled leucine into protein was not significantly altered. Mechanistically, genetic and pharmacological perturbation experiments indicated that the C12 effect requires PPM1K and is sensitive to O-GlcNAc cycling. Knockdown of O-GlcNAc transferase attenuated the C12-induced increase in BCKDH phosphorylation and reversed suppression of leucine-derived carbon flux. Dual-tracer experiments further showed that carbon derived from lauric acid and leucine converges in shared TCA cycle-associated metabolite pools, including glutamate and glutamine. Together, these findings identify a nutrient-sensitive regulatory node linking fatty acid availability, O-GlcNAc signaling, and BCKDH phosphorylation that modulates BCAA oxidation in skeletal myotubes.
    Keywords:  BCAA; Medium chain fatty acid; Myotubes; flux; lauric acid; metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2026.113345
  4. Cell Commun Signal. 2026 Jul 14.
    Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.
    Karthik Reddy Kami Reddy, Vasanta Putluri, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Aaditya Krishna Arun, Sachin B Jorvekar, Yongchao Dou, Mohammed Khurshidul Hassan, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Jun Xu, Daniel Kraushaar, Adriana Langer Gramer, Allison C Bellman, Leomar Y Ballester, Yuan Xu, Robert Taylor Ripley, Seth P Lerner, Roni J Bollag, Martha K Terris, Chong-Xian Pan, Benny Abraham Kaipparettu, Yair Lotan, Nagireddy Putluri.
       BACKGROUND: Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15-25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined.
    METHODS: To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism.
    RESULTS: PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth.
    CONCLUSION: PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3Kα inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.
    DOI:  https://doi.org/10.1186/s12964-026-03058-w
  5. bioRxiv. 2026 Jul 09. pii: 2026.07.03.736226. [Epub ahead of print]
    A quantum interface with mitochondrial bioenergetics.
    Parisa Aghaei, Sangjun Noh, Javier Noé Ramos-Silva, Minghao Jiang, Phang-Lang Chen, Yumay Chen, Fatemeh Goodarzinia, Robert Usselman, Philip Hemmer, Douglas C Wallace, Peter J Burke.
      Recent work has shown that genetically engineered proteins can serve as quantum bits in living systems. These quantum bits arise from the photochemistry of protein-bound flavins: blue-light excitation drives electron transfer to form a spin-correlated radical pair whose coherent singlet-triplet interconversion makes the protein's fluorescence sensitive to weak magnetic fields. Because this radical-pair reaction depends on the redox state of the flavin-itself a central electron carrier in cellular metabolism-the magneto-fluorescence of a biological qubit is intrinsically coupled to the biochemistry around it. This suggests a powerful application of fundamental significance in biology, until now an unsolved problem in the field of quantum sensing. Here we show a new class of quantum sensor, mtMagLOV2, that interfaces directly to a defining feature of life itself: the bioenergetic state of the cell. We genetically engineer flavin mononucleotide (FMN)-containing, magnetic-field-sensitive fluorescent proteins ("biological qubits") to be expressed and translocated into the key bioenergetic machinery of the cell: the mitochondrial matrix. Using confocal and super-resolution microscopy, mtMagLOV2 localizes to the mitochondrial cristae, home of the electron transport chain complexes I-V and ATP synthase-the site of oxidative phosphorylation (OXPHOS). By pharmacological manipulation of OXPHOS, we show that the sensor's magneto-fluorescence tracks the redox (oxidation-reduction) state of the mitochondrial flavins, providing a quantum readout of redox status. The response differs between cancer cells (which rely heavily on glycolysis) and cardiomyocytes (which rely predominantly on OXPHOS), demonstrating "quantum bioenergetic profiling". Together, these results establish biological qubits as quantum sensors capable of probing mitochondrial bioenergetics, opening a quantum window into the energetic machinery of living cells. More broadly, we anticipate that coupling quantum redox sensitivity to specific biochemical targets will extend the reach of quantum technologies across the life sciences.
    DOI:  https://doi.org/10.64898/2026.07.03.736226
  6. Nutr Diabetes. 2026 Jul 14.
    Defining a ketone threshold for weight loss: evidence from 14 day daily β-hydroxybutyrate monitoring in 217 subjects on a ketogenic diet.
    Antonio Paoli, Giuseppe Cerullo, Samuele Paoli, Davide Charrier, Jacopo Givralli, Antonino Bianco, Giovanna Boccuzzo, Pietro Belloni, Lorenzo Cenci, Tatiana Moro.
       BACKGROUND: The ketogenic diet (KD) is a widely used nutritional intervention for weight loss. The beneficial effects of the KD are intrinsically linked to the state of physiological ketosis, where ketone bodies (KBs) raise, even though minimal effective threshold of blood ketone concentration that correlates with significant weight loss remains unclear. Therefore, the main purpose of this study was to identify the optimal β-hydroxybutyrate (βHB) threshold associated with weight loss in individuals with overweight or obesity undergoing a KD.
    METHODS: This secondary analysis included 217 participants (111 males and 106 females) with overweight or obesity, who followed a KD for 14 days. Time to Ketosis (TtK)-defined as the number of days needed to reach and maintain a given ketone concentration-was calculated for each threshold.
    RESULTS: Regression analysis showed that a βHB concentration of ≥0.5 mmol/L was the most associated with significant weight loss. Moreover, body weight and gender significantly influenced TtK, suggesting interindividual variability in achieving effective ketosis.
    CONCLUSIONS: Achieving and maintaining a ketonemia of at least 0.5 mmol/L may represent a clinically meaningful threshold to optimize weight loss in individuals undergoing a KD. Monitoring βHB levels and reducing TtK may improve individual responsiveness to KD-based interventions.
    DOI:  https://doi.org/10.1038/s41387-026-00454-6
  7. J Biol Chem. 2026 Jul 14. pii: S0021-9258(26)02204-0. [Epub ahead of print] 113332
    Conditional dependency of oncogenic KRAS in driving ketone body catabolism and pancreatic cancer growth.
    Runze Wang, Xue Li, Tongxin Zhang, Yinuo Chen, Juanjuan Liu, Yuanjing Wang, Xuanzhe Wang, Lianjing Cao, Zhimin Lu, Leina Ma.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy driven predominantly by oncogenic KRAS mutations, which enforce extensive metabolic reprogramming to support tumor progression. Although ketone body catabolism has emerged as a critical metabolic adaptation in PDAC, the signaling mechanisms that link mutant KRAS to the ketolytic machinery remain largely unexplored. Here, we identify a previously unrecognized, context-dependent role of oncogenic KRAS in driving ketone body utilization. We show that KRAS mutation alone is insufficient to fully activate ketolysis; instead, it primes the ketolytic pathway in a manner that requires cooperative input from additional tumor microenvironment signals. Mechanistically, oncogenic KRAS engages a downstream signaling cascade that leads to specific post-translational modifications of key mitochondrial enzymes. These modifications enhance the flux of ketone body catabolism, thereby increasing acetyl-CoA and ATP production and promoting pancreatic cancer cell proliferation and xenograft tumor growth. In a clinical PDAC cohort, activation of this KRAS-dependent ketolytic axis was elevated in KRAS-mutant tumors compared with KRAS wild-type cases, albeit with a trend that requires further validation. Collectively, our findings define a conditional dependency of mutant KRAS on cooperative signals to drive ketone body catabolism, linking oncogenic signaling to mitochondrial ketone metabolism in PDAC. This study expands our understanding of KRAS-driven metabolic reprogramming and highlights the ketolytic pathway as a context-dependent vulnerability for therapeutic intervention in pancreatic cancer.
    Keywords:  Ketolysis; Metabolic reprogramming; Oncogenic KRAS; PDAC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jbc.2026.113332
  8. Nutr Metab (Lond). 2026 Jul 15.
    Ketosis elevates plasma concentrations of D-β-hydroxybutyryl-phenylalanine (BHB-Phe) in humans.
    Mette Glavind Bülow Pedersen, Emaan Ghias, Maj Bangshaab, Thien Vinh Loung, Mads Bisgaard Bengtsen, Mads Vandsted Svart, Esben Søndergaard, Lars Christian Gormsen, Niels Møller, Mogens Johannsen, Nikolaj Rittig.
       INTRODUCTION: β-hydroxybutyrate (BHB), produced during ketosis, can conjugate with amino acids forming BHB-amino acids. D-BHB-phenylalanine (D-BHB-Phe) is the most abundant BHB-amino acid and has been shown to reduce appetite and induce weight loss in mice, but its function and regulation in humans remain unclear. The objective of this study was to determine whether D-BHB-Phe concentrations vary across different degrees and forms of ketosis in humans.
    METHODS: Plasma D-BHB-Phe was measured in samples from four clinical cross-over trials (i) after 21 days on a ketogenic diet (n = 10), (ii) after oral consumption of 30 g ketone salt (KS) and 30 g ketone ester (KE) (n = 14), (iii) after oral KE at doses of 10, 20 and 40 g (n = 10) and (iv) after oral versus intravenous KS administration (n = 8).
    RESULTS: After 21 days of ketogenic dieting, plasma D-BHB-Phe became detectable (median 2.1 nmol/L; range 0.9-19.9), compared with near-undetectable concentrations during the standard diet (median 0; range 0-0.9; p = 0.005). Oral KS and KE increased D-BHB-Phe compared with placebo (intervention x time, p < 0.001). D-BHB-Phe rose dose-dependently after 10 g, 20 g, and 40 g of KE (intervention x time, p < 0.001). Oral KS induced higher peak concentrations of D-BHB-Phe (15.6 ± 6.4 nmol/L) compared with iso-ketotic intravenous KS infusion, which elicited only a modest peak (1.5 ± 0.3 nmol/L; intervention x time, p < 0.001). A positive association between the D-BHB and D-BHB-Phe concentration was observed in pooled analyses but was not consistent across cohorts.
    CONCLUSION: D-BHB-Phe is inducible by ketosis in humans. Our findings suggest involvement of the splanchnic bed in its production and support further exploration of D-BHB-Phe's role in appetite regulation and metabolic health.
    CLINICAL TRIAL REGISTRATIONS: NCT05012748, NCT03935841, NCT05263401, NCT05581043.
    Keywords:  Amino acid conjugates; Appetite regulation; Beta-Hydroxybutyrate; D-β-hydroxybutyryl-phenylalanine; Ketogenic diet; Ketone supplementation
    DOI:  https://doi.org/10.1186/s12986-026-01172-7
  9. Biochem Pharmacol. 2026 Jul 15. pii: S0006-2952(26)00597-6. [Epub ahead of print] 118258
    SIRT5/7 desuccinylation in cancer: linking metabolism, immunity, and drug resistance.
    Ping Luo, Xinghua Long.
      The sirtuin family proteins SIRT5 and SIRT7, as NAD⁺-dependent lysine desuccinylases, exert critical yet context-dependent roles in cancer progression. Mitochondrial SIRT5 functions as a metabolic rheostat, desuccinylating key enzymes in the TCA cycle, glutaminolysis, and fatty acid oxidation to maintain redox balance and bioenergetic output. Conversely, nuclear SIRT7 acts as an epigenetic modulator, regulating chromatin architecture and DNA damage repair via histone and non-histone desuccinylation. These compartmentalized activities converge to coordinate a metabolic-epigenetic axis that drives tumor adaptation to metabolic stress, evasion of immune surveillance, and therapeutic resistance. Given this functional duality, biomarker-guided therapeutic strategies are imperative. This review synthesizes the emerging roles of SIRT5/7-mediated desuccinylation in cancer metabolism, immunity, and drug resistance, highlighting their potential as targets for synergistic metabolic-immunotherapy interventions.
    Keywords:  Cancer metabolism; Desuccinylation; Drug resistance; Immune evasion; Metabolic reprogramming; SIRT5; SIRT7; Therapeutic targeting
    DOI:  https://doi.org/10.1016/j.bcp.2026.118258
  10. bioRxiv. 2026 Jul 09. pii: 2026.07.04.736442. [Epub ahead of print]
    Challenges and Solutions in Quantifying Brain β-Hydroxybutyrate (BHB) with 1 H-MRS Following Oral Keto-Ester Consumption.
    Mansimran Virk, Kennedy T Connors, Razi Kitaneh, Marcella M Mignosa, Scott McIntyre, Terence W Nixon, Kelly DeMartini, Stephanie O'Malley, John H Krystal, Henk M De Feyter, Gustavo A Angarita, Graeme F Mason, Robin A de Graaf, Chathura Kumaragamage.
       Purpose: β-hydroxybutyrate (BHB), a ketone body and alternative cerebral energy substrate, can be measured in vivo using J-difference edited proton magnetic resonance spectroscopy ( 1 H-MRS). Oral ketone supplementation with substrates such as the ketone monoester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate (KME) and 1,3-butanediol (BD) have gained attention as a mechanism to elevate circulating BHB and induce ketosis without dietary restrictions. Elevated brain ketone availability is of growing therapeutic interest as a strategy to support neuronal energetics in conditions such as epilepsy, neurodegenerative disease, and alcohol use disorder (AUD). However, both pathways introduce BD into the bloodstream, which crosses the blood-brain barrier. Critically, BD exhibits a spectral signature that closely resembles the prominent BHB peak in JDE-MR spectroscopic imaging (MRSI), identified in a pilot AUD study.
    Methods: Two separate JDE-MRSI acquisitions tailored for BHB and BD editing were implemented, exploiting frequency separation between the BHB (4.14ppm) and BD (3.95ppm) coupling partners of the observed 1.2ppm resonance to independently quantify each metabolite.
    Results: Brain BD concentrations (0.25-0.58mM) were comparable to or exceeded corresponding BHB concentrations (0.20-0.27mM) in all volunteers after consumption of a single dose of the KME, indicating that BD constitutes a major fraction of the signal conventionally attributed to BHB. Combined BHB+BD concentrations (∼0.45-0.85mM) were consistent with brain BHB values reported in prior studies employing similar doses of the KME, indicating that those measurements likely reflect a combined BHB+BD signal.
    Conclusions: Separate quantification of the two metabolites is important for interpreting brain ketone studies and for understanding the full pharmacology of KME supplementation.
    DOI:  https://doi.org/10.64898/2026.07.04.736442
  11. Science. 2026 Jul 16. 393(6808): eadx8675
    A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
    Alex C Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, Xin Zhao, Jeffrey I Traylor, Lei Guo, Ji Hyung Jun, Morgan Fleishman, Tracey Shipman, Vinesh T Puliyappadamba, Pranita Kaphle, Qing Ouyang, Michael Schmidt, Diana D Shi, Milan R Savani, Alexander C-Y Tsai, Joyce H Lee, Ruth Gordillo, Javier Garcia-Bermudez, Yoon Jung Kim, Shih-Chia Tso, Chad A Brautigam, Lauren G Zacharias, Thomas P Mathews, Lin Xu, John G Doench, Vidyasagar Koduri, Kalil G Abdullah, Michalis Agathocleous, Laura A Banaszynski, Ralph J DeBerardinis, Eric M Morrow, Samuel K McBrayer.
      The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.
    DOI:  https://doi.org/10.1126/science.adx8675
  12. Nutrients. 2026 Jul 03. pii: 2166. [Epub ahead of print]18(13):
    Ketogenic Diet in the Treatment of Malignant Gliomas: A Systematic Review.
    Michela Persiani, Laura Dallolio, Alice Masini, Yari Longobucco, Simona Bertoli, Emilia Guberti, Marta Pellizzari, Maria Letizia Petroni, Federica Valeriani, Francesca Gallè, Rossella Sacchetti.
      Background: The Ketogenic Diet (KD) has been proposed as an adjunct to standard therapy for gliomas by targeting tumor glycolysis. We systematically reviewed evidence on KD interventions in patients with glioma across multiple outcomes. Methods: Following Cochrane guidelines, we searched MEDLINE, Embase, and Cochrane Library (until 1 February 2025) for studies on humans with glioma treated with any KD versus usual care or other diets. Outcomes included overall survival (OS) and progression-free survival (PFS), quality of life (QoL), biochemical markers (glucose, ketones, glucose-ketone index GKI), anthropometric measures, safety, and tolerability. All study designs were eligible. The quality of the studies was assessed with JBI tools. Data were narratively synthesized due to heterogeneity. The PROSPERO registration is CRD42024547388. Results: Twenty-three studies (306 patients) were included: two RCTs, 11 quasi-experimental studies, six case series, and four case reports. Dietary interventions included classic KD, modified KD, medium-chain triglyceride KD, and Modified Atkins Diet, sometimes combined with fasting. The overall dropout was 20.3%, mainly due to dietary restrictiveness, disease progression, adverse effects, or QoL concerns. Survival results were inconsistent: RCTs showed no significant OS/PFS differences versus controls, although exploratory analyses suggested better outcomes with lower glucose levels. Ketosis was commonly achieved; glucose reductions were variable, and GKI was rarely reported, with target values seldom reached outside fasting periods. Weight/BMI generally decreased modestly or remained stable; adverse events were mostly mild and tolerability was acceptable. Conclusions: Evidence for KDs in glioma patients is heterogeneous and limited. Although ketosis and safety are achievable, survival or QoL benefits remain unproven. Given the methodological challenges, the clinical complexity, and the promising potential of the Ketogenic Diet, further well-designed studies are needed to clarify its clinical utility in glioma treatment.
    Keywords:  glioma; ketogenic diet; overall survival; quality of life; safety; tolerability
    DOI:  https://doi.org/10.3390/nu18132166
  13. Mol Metab. 2026 Jul 17. pii: S2212-8778(26)00106-7. [Epub ahead of print] 102422
    Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
    Emma Frank, Kaspar W Persson, Pauline Morigny, Zakarias Kefil Jensen Ogueboule, Tang Cam Phung Pham, Jonas R Knudsen, Maria Rohm, Lykke Sylow, Steffen H Raun.
       PURPOSE: Cancer cachexia is a life-threatening complication of advanced malignancies, driven by profound systemic metabolic reprogramming and anorexia. Insulin action is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between weight loss, food intake, and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies.
    METHODS: We assessed metabolic rewiring by temporal evaluation of glucose tolerance and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as healthy mice undergoing food restriction.
    RESULTS: Cachectic C26- and KPC-tumor mice showed increased glucose tolerance compared to non-tumor-bearing control mice, and non-cachectic tumor-bearing mice. Increased glucose tolerance appeared prior to overt muscle loss, independent of tumor size and changes in food intake. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice with anorexia compared to weight stable C26-cancer mice and control mice. This increase was associated with enhanced AKT signaling. Food restriction in healthy mice increased glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling.
    CONCLUSIONS: Our findings suggest that glucose hypermetabolism appears prior to overt weight loss in pre-clinical cachexia, whereas late-stage cachexia with anorexia increased skeletal muscle insulin responsiveness. This highlights AKT signaling as a key node connecting nutrient status with muscle metabolism in cancer cachexia.
    Keywords:  Cancer cachexia; food restriction; glucose metabolism; insulin sensitivity; muscle
    DOI:  https://doi.org/10.1016/j.molmet.2026.102422
  14. bioRxiv. 2026 Jul 07. pii: 2026.07.06.736733. [Epub ahead of print]
    Nuclear adenosine metabolism defines a metabolic vulnerability unmasked by TP53 loss.
    Julia Urgel-Solas, Anna Benito-Ferrer, Laura Ortet, Savvas Kourtis, Etna Abad, Albert Coll Manzano, Anna Shevzov-Zebrun, Camilla Reiter Elbæk, Carlos M Martínez, Matthew G Vander Heiden, Sara Sdelci, Ana Janic.
      Metabolic adaptation is essential for cells experiencing chronic genomic stress, yet how such adaptations are organized at the nuclear level remains poorly understood. Loss of TP53 is associated with elevated genomic instability, DNA damage and altered metabolic requirements, creating context specific dependencies. Here, we identify a requirement for de novo purine biosynthesis in TP53-deficient cells, with a pronounced dependence on adenosine related metabolism. Perturbation of purine synthesis increases DNA damage and reduces nuclear ATP availability, particularly in TP53-deficient cells, and is accompanied by a rapid increase in histone methylation. This chromatin response is also induced by acute DNA damage and occurs with fast kinetics, indicating that histone methylation is an early, intrinsic feature of the nuclear stress response rather than a secondary epigenetic remodeling. Interfering with histone methylation is associated with reduced nuclear ATP levels and impaired DNA damage resolution, linking chromatin state to nuclear energy homeostasis. Genetic disruption of the purine biosynthesis enzyme PFAS selectively impairs the growth of TP53-deficient tumours in vivo , establishing the physiological relevance of this metabolic dependency. Together, these findings reveal nuclear adenosine metabolism as a compartmentalised adaptive response to genotoxic stress and highlight chromatin associated methylation as a key feature of nuclear metabolic regulation unmasked by TP53 loss.
    DOI:  https://doi.org/10.64898/2026.07.06.736733
  15. Protein Sci. 2026 Aug;35(8): e70720
    Molecular and energetic basis of histidine switch dynamics in respiratory complex I.
    Erik Endres, Mahdi Torabi, Mai Jousmäki, Kim Vy Huynh, Cristina Pecorilla, Oleksii Zdorevskyi, Volker Zickermann, Vivek Sharma.
      The respiratory complex I in mitochondria and bacteria drives the two-electron reduction of quinone to pump protons across the membrane. The molecular basis of this catalytic reaction remains enigmatic despite significant progress in structural characterization of the complex. A highly conserved histidine residue in the distal antiporter-like subunit of its membrane domain has been shown to undergo conformational changes in molecular simulations and cryo-EM structures. However, the function of histidine switch dynamics and the energetics of its conformational transitions remain unclear. Here, by applying enhanced sampling classical molecular dynamics simulations, we evaluate the energetics of the histidine switch dynamics and demonstrate that it is coupled to the tautomeric state of histidine and to the charge state of lysine residues ca. 10 Å apart, which cause hydrogen bond restructuring and stabilize the histidine residue in specific conformations. Hybrid QM/MM metadynamics-based free energy simulations show that the histidine switch participates in gated proton transfer and may function as a proton confurcation device in complex I and related proteins.
    Keywords:  bioenergetics; enhanced sampling simulations; hybrid QM/MM; mitochondrial respiration; proton pumping
    DOI:  https://doi.org/10.1002/pro.70720
  16. Nat Metab. 2026 Jul 14.
    Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
    Jiayin Tang, Gerard Pernes, Brenda Nakagaki, Nhien Tran, Laura Bokor, Fran Prenen, Mingyang Yi, Avery E Robertson, Rachel Cronin, Mohamad Sarmini, Jacob Pierscianowski, Victoria Roberts, Birgitta A Ryback, Carl D Novina, Karine Auclair, Haopeng Xiao, Evanna L Mills.
      Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3-14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance.
    DOI:  https://doi.org/10.1038/s42255-026-01572-2
  17. Nature. 2026 Jul 15.
    Metabolite glues as a means of purine sensing and chemotherapeutic response.
    Samuel R Witus, Megan M Kober, Heegwang Roh, Zhi Yang, Fouad Choueiry, Avani S Ghate, Denis V Titov, Michael Rapé.
      Molecular glues stabilize weak interactions to impart new functionalities to complexes1-3. Although molecular glues have been described in plant signalling and as human therapeutics4,5, it is unclear whether this modality provides endogenous regulation in human cells. Here we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme in purine biosynthesis-phosphoribosyl pyrophosphate amidotransferase (PPAT)-to its inhibitor NUDT5. This mechanism allows cells to sense the levels of purines and to establish essential feedback control of their synthesis. We refer to such molecules as metabolite glues. Thiopurine chemotherapeutics6, which have been in clinical use since the 1950s, glue the same complex but adopt distinct orientations for enhanced function. Unlike most known glues, the PPAT-NUDT5 metabolite-glue pocket can adjust its conformation to notable compound alterations, enabling increased glue potency and improved on-target activity. We therefore identify endogenous metabolite glues as a mode of nutrient sensing that can be exploited for therapeutic benefit.
    DOI:  https://doi.org/10.1038/s41586-026-10790-3
  18. Nutrients. 2026 Jul 01. pii: 2125. [Epub ahead of print]18(13):
    Individual Amino Acid Supplementation Does Not Enhance Short-Term Proliferation of Selected Cancer Cell Lines In Vitro: Potential Implications for Nutritional Support in Cancer Cachexia.
    Walburga Dieterich, Rashmita Pradhan, Abdulhadi Suwandi, Rabia Ülkü Korkmaz, Markus F Neurath, Yurdagül Zopf.
      Background: Cancer-related cachexia is primarily characterized by systemic inflammation and progressive muscle wasting, which is why a high-protein diet (from 1.2 to 1.5 g/kg/day) is commonly recommended. However, concerns remain that an excessive supply of amino acids could promote tumor growth due to the metabolic flexibility of cancer cells, thereby favoring proliferation and survival. Systematic evidence addressing these concerns under controlled conditions for various types of cancer cells remains limited and inconclusive. Methods: We investigated the short-term effects of all 20 amino acids at both moderate (2×) and high (10×) concentrations to evaluate three key oncological endpoints in four human cancer cell lines: MDA-MB-231 (breast), HT29 (colorectal), PC3 (prostate), and PANC-1 (pancreatic). Cell proliferation was assessed by BrdU incorporation, metabolic activity by WST-1 assay, and apoptosis signaling by caspase-3/7 activity measurement. Results: Amino acid supplementation was not associated with a significant change in proliferation at either concentration across all four cell lines studied. Metabolic activity showed only minor variations throughout, with PC3 cells exhibiting slightly greater variability, although this did not reach statistical significance. Caspase-3/7 activity remained largely unchanged under all conditions; however, high-concentration lysine induced an approximately 2.5-fold increase in PANC1 cells, which was not statistically significant. Conclusions: These findings suggest that short-term exposure to individual amino acids, even at supraphysiological conditions, does not acutely enhance proliferative activity in the cancer cell lines studied, supporting the rationale for adequate protein and amino acid intake in patients with cancer cachexia.
    Keywords:  amino acid supplementation; apoptosis; cancer cachexia; cell metabolism; nutritional support; sarcopenia; tumor cell proliferation
    DOI:  https://doi.org/10.3390/nu18132125
  19. Adv Exp Med Biol. 2026 ;1501 505-523
    Use of Nuclear Magnetic Resonance (NMR) to Study Cancer Metabolism.
    Catarina Freitas-Dias, Luís Gafeira Gonçalves.
      Nuclear magnetic resonance (NMR) spectroscopy has emerged as an important tool in cancer metabolism research, providing noninvasive, quantitative, and revealing insights into tumor biochemistry. This chapter discusses a wide range of NMR applications in oncology, including biofluid metabolomics for early diagnosis and prognosis, high-resolution magic angle spinning (HR-MAS) NMR for intact tissue profiling, and stable isotope-resolved metabolomics (SIRM) for mapping metabolic fluxes. Furthermore, the use of NMR in cancer cell culture models and the transformative influence of dynamic nuclear polarization (DNP)-enhanced NMR for real-time metabolic imaging are addressed. Collectively, these techniques allow for thorough analysis of metabolic reprogramming in cancer, biomarker development, and tailored therapy strategies.
    Keywords:  Cancer metabolism; Dynamic nuclear polarization (DNP)-enhanced NMR; High-resolution magic angle spinning (HR-MAS); Metabolomics; Nuclear magnetic resonance (NMR); Stable isotope-resolved metabolomics (SIRM)
    DOI:  https://doi.org/10.1007/978-3-032-12166-0_18
  20. Microb Cell Fact. 2026 Jul 13. pii: 161. [Epub ahead of print]25(1):
    Investigating the role of FOF1 ATPase in Zymomonas mobilis through deletion of its FO and F1 subcomplexes.
    Gerrich Behrendt, Reinis Rutkis, Uldis Kalnenieks, Katja Bettenbrock.
      Zymomonas mobilis has a typical FOF1 ATPase, yet does not exhibit oxidative phosphorylation. In order to investigate the function of the ATPase we sought to delete the FO and the F1 subcomplexes, respectively. Clean mutants could be obtained after selection under aerobic conditions. Growth analysis of the mutants showed that they strictly require oxygen for growth and that the oxygen supply is a factor determining maximal growth rate. This is contrary to the wild type, which grows fastest under anaerobic conditions. In the mutant strains, ethanol remains the main catabolic product; however glucose consumption rates are reduced, and the mutants show a higher sensitivity to low medium pH. Compared to the wild type, the mutants show an increased biomass yield. Our data support the previously proposed regulatory role of the FOF1 ATPase in controlling glycolytic flux, and indicate that the FOF1 ATPase plays an important role in expelling protons from the cytoplasm. In the mutants, this function is taken over by the electron transport chain in the presence of oxygen.
    Keywords:   Zymomonas mobilis ; FoF1 ATPase; Respiration; Uncoupled growth
    DOI:  https://doi.org/10.1186/s12934-026-03059-x
  21. EMBO J. 2026 Jul 15.
    Metabolic buffering restricts phenotype switching in melanoma.
    Ana Ramírez-Sánchez, Miguel Jociles-Ortega, José Manuel García-Martínez, Irene Torrens-Martínez, Javier Martínez-Useros, Pakavarin Louphrasitthiphol, Mollie I Sweeney, Ana Morente-Carrasco, Sergio Ruiz-Reyes, Nerea Redondo-Díaz, Teresa Olmos-De Blas, María Jesús Fernández-Aceñero, José N Rodriguez-López, Tomoyoshi Soga, Richard M White, Colin R Goding, Luis Sanchez-Del-Campo, Custodia García-Jiménez, Ana Chocarro-Calvo.
      The impact of the metabolic microenvironment on epigenetically plastic cancer cells underpins phenotypic heterogeneity, a major cause of metastasis and therapy resistance. Nutrient limitation is a key microenvironmental stress, and can cause cells to transition from proliferative to invasive phenotypes, however, whether cancer cells have the capacity to delay phenotype switching remains unknown. Here, using melanoma as a model, we reveal that the ability to buffer glucose availability by accumulating and mobilizing glycogen can determine cancer cell phenotypic transitions. While proliferating cells contain high levels of glycogen, invasive cells are marked by depleted glycogen stores. Accordingly, the inability to store and metabolize glycogen leads to phenotype instability and a switch from proliferation to invasion. The amount of stored glycogen inversely correlates with tissue invasion depth in primary melanomas, and reduced expression of the glycogen phosphorylases PYGB/L and phosphoglucomutase 1 (PGM1) is associated with worse patient survival. Together, we identify metabolic glucose buffering as a determinant of invasive phenotype transitions in skin cancer, suggesting similar paradigms in other cancer types.
    DOI:  https://doi.org/10.1038/s44318-026-00857-2
  22. Front Med (Lausanne). 2026 ;13 1861016
    Animal models of pyruvate dehydrogenase complex deficiency: insight into mechanisms of cerebral abnormalities and tissue-specific role in metabolism.
    Mulchand S Patel, Todd C Rideout.
      Primary pyruvate dehydrogenase complex (PDC) deficiency results from inborn errors in the genes encoding its component proteins with largely devastating outcomes. Among its genes, the X-linked PDHA1 gene is subject to a much higher rate of mutations. Despite the analysis of many PDC-deficient subjects, no specific genotype-phenotype relationship emerges from the available data. This review focuses on the observations from animal models of primary PDC deficiency. Mouse models of systemic and brain-specific PDC deficiency closely reproduced several cerebral abnormalities observed in many PDC-deficient subjects and provide new insights into the impairment of cellular proliferation, migration and differentiation. Mouse models would be useful tools to evaluate efficacy of dietary and drug treatments. The mouse model is useful for creating tissue-specific PDC deficiency to examine the importance of PDC in carbohydrate metabolism. Other animal models of PDC deficiency have provided unique insights on the impact of PDC deficiency and are useful tools for rapid screening of drugs. All animal models utilized so far carried null mutations in the PDC genes, and hence creations of missense mutations in animals, especially in the mouse, are highly desirable to evaluate the genotype-phenotype relationship in PDC deficiency.
    Keywords:  animal models; cerebral development abnormalities; high-fat diet; murine; phenylbutyrate; pyruvate dehydrogenase complex deficiency; tissue-specific metabolic roles; zebrafish
    DOI:  https://doi.org/10.3389/fmed.2026.1861016
  23. Nat Cancer. 2026 Jul 15.
    A polyadenylation enzyme rewires metabolism to fuel AML.
    Animesh Kar, Daniel Herranz.
      
    DOI:  https://doi.org/10.1038/s43018-026-01180-9
  24. Pharmacol Res. 2026 Jul 17. pii: S1043-6618(26)00261-6. [Epub ahead of print] 108346
    Acetyl-CoA Metabolism in Skeletal Biology and Bone Disorders: From Mechanisms to Therapeutic Implications.
    Qianyu Yang, Runlin Shi, Chenyang Zhang, Wei Sun, Guangjin Chen.
      Acetyl-CoA is a central metabolite that links energy status to transcriptional regulation through protein acetylation, yet its functions in skeletal biology depend strongly on subcellular compartmentalization. Because acetyl-CoA does not freely traverse biological membranes, its mitochondrial, cytosolic, and nuclear pools are maintained through compartment-specific synthesis and exchange routes, including the citrate-SLC25A1-ACLY axis, acetylcarnitine/carnitine cycling, acetate-dependent ACSS2 activity, and local nuclear enzyme activity. This review synthesizes current evidence that three conserved modules, including glycolytic/PDC-driven mitochondrial production, CIC/ACLY-mediated citrate export, and HAT-dependent acetylation, connect carbon flux with skeletal cell fate. However, lineage-specific outcomes are shaped by local acetyl-CoA availability, acetyltransferase context, and the transcription-factor landscape, including RUNX2 (osteogenesis), SOX9 (chondrogenesis) and NFATc1 (osteoclastogenesis). Critically, compartmentalized acetyl-CoA dysregulation can contribute to different pathological states: excessacetyl-CoA supply is linked to ACLY/FAO-driven cartilage catabolism and osteoclast resorption, whereas insufficient nucleocytosolic supply is associated with impaired regenerative programs in aged or inflamed bone. This duality argues for context-specific therapeutic strategies that either restrain excess acetyl-CoA flux or restore deficient pools. We propose that the translational bottleneck is not target identification but delivery precision, advocating for localized metabolite supplementation, cell-selective ACLY/FAO inhibitors, and spatial acetylome mapping to deconvolute cell-type-specific fluxes. Moving beyond broad HDAC/HAT modulation toward compartment-resolved strategies will be essential for translating acetyl-CoA biology into effective skeletal therapies.
    Keywords:  Acetyl‑CoA; Bone diseases; Epigenetic regulation; Metabolic targeting; Skeletal metabolism; Therapeutic intervention
    DOI:  https://doi.org/10.1016/j.phrs.2026.108346
  25. Adv Exp Med Biol. 2026 ;1501 525-554
    Mass Spectrometry as a Tool for Metabolomics in Cancer.
    João S Patrício, Ana C L Guerreiro, Paulo A Gameiro, Judit Morello.
      Mass spectrometry (MS) is a highly sensitive and high-throughput analytical technology that has become central to investigating the metabolic alterations in cancer cells, enabling the discovery of diagnostic biomarkers and potential therapeutic targets. This chapter provides an overview of the key principles of MS-based metabolomics, covering the entire experimental workflow-from sample collection and preparation to data acquisition, preprocessing, normalization, statistical modeling, and pathway enrichment analysis. We also discuss current limitations and outline future directions to enhance data reproducibility, metabolite annotation, and clinical translation of MS-based results.
    Keywords:  Biomarkers; Cancer diagnosis; MS-based metabolomics; Mass spectrometry (MS)
    DOI:  https://doi.org/10.1007/978-3-032-12166-0_19
  26. bioRxiv. 2026 Jul 07. pii: 2026.07.06.736842. [Epub ahead of print]
    SLC16A6 is a tyrosine transporter for the melanosome.
    Corey N Cunningham, Alex J Bott, Charles H Adelmann, Matthew Shields, Katarina E Heyden, Jonathan G Van Vranken, Álvaro Jesús Narbona-Pérez, Juan A Cantres-Vélez, Guillaume Adelmant, Nathan M Krah, Steven P Gygi, David M Sabatini, Jared Rutter.
      Cells enable specialized metabolism by compartmentalizing metabolic pathways into distinct organelles, which requires the membrane transport of metabolites. In melanocytes, the amino acid tyrosine is imported into developing melanosomes for the synthesis of the UV-protective pigment melanin 1,2 . In spite of extensive biochemical characterization, the identity of the melanosomal tyrosine transporter remains unknown. Here, we identify SLC16A6 as an orphan melanosome-localized metabolite transporter. Genetic screens reveal that SLC16A6 expression is driven by the SOX10-MITF axis, the well-characterized master regulatory program governing melanogenesis and melanosomal homeostasis 3,4 . By redirecting SLC16A6 to the plasma membrane with an S240A mutation 5 , we demonstrate that SLC16A6 transports tyrosine, a process competitively inhibited by other bulky amino acids. We further determine that SLC16A6 is sufficient for in vitro melanosomal tyrosine uptake. Genetic depletion of SLC16A6 triggered loss of melanosome biogenesis and function as well as depletion of most melanosomal components. Collectively, these findings establish SLC16A6 as a melanosomal tyrosine transporter that is essential for melanosome biogenesis.
    DOI:  https://doi.org/10.64898/2026.07.06.736842
  27. Int J Mol Sci. 2026 Jun 26. pii: 5804. [Epub ahead of print]27(13):
    Mitochondrial Voltage-Dependent Anion Channel: From a Passive Pore to a Cellular Hub Through Protein Complexation.
    Megha Rajendran, Sergey M Bezrukov, Tatiana K Rostovtseva.
      The voltage-dependent anion channel (VDAC) is the primary conduit for ion and metabolite transport across the mitochondrial outer membrane. Positioned at the interface between the cytosol and the mitochondrial compartment, VDAC is uniquely accessible to proteins on both sides of the membrane, making it an interaction hub whose biophysical properties and signaling functions are shaped by protein complexation in addition to its intrinsic pore specialization. Mammals express three isoforms-VDAC1, VDAC2, and VDAC3-sharing a conserved β-barrel scaffold with about 70% identity. However, minor differences in the sequence lead to drastic changes in VDAC isoform affinity with other proteins. Here, we review the molecular mechanisms and physiological consequences of VDAC complexation with a set of well-characterized partners: hexokinase, dimeric tubulin, α-synuclein, mitochondria-associated membrane proteins, B-cell lymphoma 2 (BCL-2) family proteins, and the translocase of the outer membrane (TOM) protein import complex. For each complex, we evaluate the available structural, biophysical, and genetic evidence for isoform specificity, highlight where mechanistic understanding is most advanced, and identify open questions. A consistent principle emerges across all complexes: functionally nonredundant isoform contributions are primarily governed by differential partner affinity and complexation, rather than by differences in pore architecture alone. This framework has direct implications for mitochondria-associated pathologies, including cancer, cardiovascular disease, and neurodegeneration, as well as for the rational design of VDAC-targeting therapeutics.
    Keywords:  BCL-2 family proteins; TOM complex; VDAC; hexokinase; mitochondrial-associated membrane (MAM); tubulin; α-synuclein
    DOI:  https://doi.org/10.3390/ijms27135804
  28. Nutrients. 2026 Jun 27. pii: 2100. [Epub ahead of print]18(13):
    Investigation of an ALDH1A1-Specific Inhibitor, FSI-TN42, as a Treatment for Obesity in Female Mice.
    Jisun Paik, Haley Martin, Andy Jinpyo Kim, Kelsie Neumann, Jessica M Snyder, John K Amory.
      Background/Objectives: Retinoic acids (RA) are involved in regulation of weight and energy metabolism. Mice lacking a RA synthesis enzyme, ALDH1A1, are resistant to diet-induced obesity. We previously identified an ALDH1A1-specific inhibitor, FSI-TN42 (N42), and demonstrated its efficacy in suppressing weight gain in male C57BL/6 mice fed a high-fat diet (HFD). In this report, we evaluated whether N42 is similarly effective in female mice. Methods: Two studies were performed. In the first study, C57BL/6 female mice were fed a HFD for 12 weeks to induce obesity, after which half were switched to a HFD supplemented with N42 (1 g/kg diet). A control group of mice was maintained on a low-fat purified diet throughout the study. Body weight was determined weekly, and fasting or fed blood glucose was determined at 4-8-week intervals. In the second study, obese female C57BL/6 mice were transitioned from a HFD to either (1) a moderate-fat diet (MFD) or (2) MFD + N42 for 9 weeks. Results: N42 significantly suppressed weight gain in female mice maintained on a HFD. However, it did not enhance weight loss when administered alongside a MFD diet, which alone induced significant weight loss comparable to mice fed a control diet throughout the study. Conclusions: The ALDH1A1 inhibitor N42 suppresses weight gain in female mice, consistent with prior findings in male mice. However, unlike in males, N42 did not enhance weight loss under conditions of caloric reduction, likely due to more profound weight loss induced by the lower-calorie diet in female mice.
    Keywords:  ALDH1A1; mouse model; obesity; treatment
    DOI:  https://doi.org/10.3390/nu18132100
  29. Front Cell Dev Biol. 2026 ;14 1854542
    Standardised dual-flow cytometry workflows for quantitative assessment of mitochondrial superoxide and mitochondrial mass in live cancer cells and primary multiple myeloma cells.
    Eugenia Giglio, Martina Giuseffi, Marzia Sichetti, Marisabel Mecca.
      Mitochondrial metabolism plays a critical role in carcinogenesis and cancer progression. Quantitative assessment of mitochondrial function in live cells remains technically challenging because existing biochemical assays lack single-cell resolution, and microscopy-based approaches are limited in throughput and quantitative reproducibility. Here we describe a robust and reproducible standardised dual-flow cytometry protocol for simultaneous quantitative assessment of mitochondrial superoxide production and mitochondrial mass in live cancer cells and primary patient-derived multiple myeloma plasma cells using MitoSOX Green and MitoTracker Red. The protocol provides a step-by-step workflow comprising preparation of cultured cancer cells or isolation of primary CD138+ plasma cells, optimised probe staining, viability discrimination, standardised flow cytometry acquisition and gating, and quantitative fluorescence normalisation. Compared with conventional mitochondrial assays requiring cell lysis or imaging-based analysis, this approach enables high-throughput, quantitative mitochondrial profiling at single-cell resolution in heterogeneous populations while preserving cellular integrity. The procedure incorporates defined staining conditions, instrument calibration guidance, quality-control criteria and normalisation strategies to improve reproducibility across experiments and laboratories. The workflow yields robust fluorescence measurements with low technical variability and enables discrimination of mitochondrial oxidative activity relative to mitochondrial content, facilitating analysis of mitochondrial dysfunction, oxidative stress responses and treatment-induced mitochondrial perturbations. The method is compatible with multiparametric flow cytometry and can be adapted to diverse cell types and experimental systems. The complete protocol requires ∼6-8 h for cultured cells or 8-12 h when primary cell isolation is included and can be implemented by researchers with standard cell culture and flow cytometry expertise.
    Keywords:  MitoSOX; MitoTracker; ROS; flow cytometry; live cancer cells; mitochondrial mass; mitochondrial superoxide
    DOI:  https://doi.org/10.3389/fcell.2026.1854542
  30. Cell Chem Biol. 2026 Jul 16. pii: S2451-9456(26)00237-0. [Epub ahead of print]33(7): 894-896
    BACH1 meets its match: Heme licenses BACH1 destruction to tune ferroptosis.
    Dylan Calhoon, Javier Garcia-Bermudez.
      In a recent issue of Molecular Cell, Ahmed and colleagues1 show that heme enables CRL2-FEM1B to recognize and degrade BACH1, linking metabolite-assisted substrate recruitment to ferroptosis regulation. This mechanism connects heme sensing, ubiquitin-mediated proteolysis, and transcriptional control of ferroptosis-protective genes, revealing a potential vulnerability in lung cancer.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.06.013
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