bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–07–05
thirty-one papers selected by
Brett Chrest, Wake Forest University
  1. Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
  2. Oxaloacetate Inhibition of Succinate Dehydrogenase: Mechanism and Physiological Implications.
  3. SGLT2 inhibitors enhance ketogenesis by acting as allosteric activators of the mitochondrial enzyme HMGCS2.
  4. Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.
  5. Complex I drives glutamine-dependent TCA cycle to support viability of MYChigh breast cancer cells.
  6. Glucose and Glutamine Define Independent Activation-Braking Metabolic States in Triple Negative Breast Cancer Cells.
  7. An NADPH safety valve: De novo lipogenesis buffers biguanide-induced reductive stress.
  8. Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.
  9. Real-world safety, prognostic, and design considerations in ketogenic diet trials for pancreatic cancer.
  10. Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
  11. Physiologically relevant media are associated with overlapping metabolic responses in primary human hepatocytes and Huh7 cells.
  12. Beyond apoptosis: LSC state dictates metabolic and anti-apoptotic vulnerabilities.
  13. Metabolic Flux Analysis Reveals Cell Line-Specific Rewiring in CHO Cells Following TCA Cycle Intermediate Feeding for Bioprocess pH Control.
  14. Females Are Completely Resistant to Semaglutide-Induced Muscle Loss in ob/ob Mice.
  15. Triphenylphosphonium compounds preferentially inhibit long-chain fatty acid oxidation in cardiac mitochondria.
  16. A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.
  17. BCAA metabolism promotes lung cancer tumorigenesis by enhancing cholesterol biosynthesis.
  18. A carboxylate switch point controls long-range energy transduction in respiratory Complex I.
  19. Dysregulated sphingolipid metabolismdrives pancreatic carcinogenesis through plasma membrane Kras enrichment.
  20. Genetic and Clinical Factors Associated With Metformin Plasma Concentrations Following an Acute Metformin Challenge.
  21. Assessment of mitochondrial lipid peroxidation in cells and zebrafish using a targeted mass spectrometry probe.
  22. Branching architecture of tryptophan metabolism determines therapeutic vulnerability in acute myeloid leukemia.
  23. Ketone Bodies Derived From Medium-Chain Triglycerides Support Brain Metabolism and Function Under Hypoglycemia in Type 1 Diabetes Mellitus.
  24. A planar dimer of bovine ATP synthase.
  25. Horizontal transfer of mitochondria in cancer: The physiology reborn in disease?
  26. Synergy of a Low-methionine Diet and Reduced-dose Cisplatinum Eradicates Experimental Lung-cancer Bone Metastases in a Nude-mouse Model.
  27. Imaging post-reperfusion metabolism in porcine myocardial infarction with hyperpolarized 13C pyruvate MRI.
  28. Metabolic profiling of human melanoma cell lines with high and low metastatic capacity by 1H-NMR spectroscopy.
  29. An enzyme kinetic model for quantitative interpretation of the role of nicotinamide nucleotide transhydrogenase (NNT) in cell physiology.
  30. Platelet proteome links metabolism to reactivity in Essential Thrombocythemia.
  31. Deleterious mitochondrial heteroplasmy drives high-risk clonal hematopoiesis and hematological malignancy.
  1. Res Sq. 2026 Jun 17. pii: rs.3.rs-10007862. [Epub ahead of print]
    Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
    Daniel Pelaez, Samantha McLaughlin, Kendall Knechtel, Zelia Correa, J William Harbour.
      Cancer cells alter their metabolism to support growth and survival, most notably by fermenting glucose to lactate even in the presence of oxygen, a phenomenon known as the Warburg effect. Although this metabolic state has been recognized for decades, its bioenergetic advantages remain unclear, as fermentation produces less net ATP than mitochondrial respiration. How aerobic fermentation contributes to cellular energy balance therefore remains unresolved. Here, we show that extracellular acidification generated by lactate export creates a proton gradient across the plasma membrane that is harnessed by ectopic ATP synthases to drive intracellular ATP production. We find that ATP synthase and proton-shuttling components of the mitochondrial respiratory chain translocate to the plasma membrane in cancer cells and are preferentially oriented to exploit this gradient, linking a hallmark of aerobic fermentation directly to energy supplementation. This work provides a mechanistic resolution to the apparent energetic inefficiency of the Warburg paradigm and identifies a previously unrecognized pathway for energy complementation in cancer.
    DOI:  https://doi.org/10.21203/rs.3.rs-10007862/v1
  2. Am J Physiol Cell Physiol. 2026 Jun 29.
    Oxaloacetate Inhibition of Succinate Dehydrogenase: Mechanism and Physiological Implications.
    William I Sivitz, Liping Yu.
      As has been known for many decades, oxaloacetate (OAA) is a very potent inhibitor of succinate dehydrogenase (SDH). However, the phenomenon has received little attention for several reasons to be discussed. Although the interaction between OAA and the structure of SDH has been scrutinized, there has been little attention to the mechanism underlying OAA inhibition of SDH in respiring mitochondria or to its functional implications. In recent years, we have used more advanced methodology to examine these issues. OAA is unstable and therefore very difficult to detect by mass spectroscopy. Hence, we used a novel NMR approach to assess OAA in mitochondria of muscle, brown adipose tissue, and liver under active respiratory conditions. We also used a modification of existing technology to assess mitochondrial respiration in states apart from the extremes of state 4 and state 3. We found strong evidence that mitochondrial OAA content and inhibition of SDH is dependent on inner mitochondrial membrane potential (ΔΨ) and the effects of ΔΨ on the NADH/NADM+ redox state. Further, we examined the effects of perturbed OAA content by deleting glutamic-oxaloacetic transaminase (GOT2) which metabolizes OAA and glutamate to aspartate and α-ketoglutarate. Such deletion enhanced mitochondrial OAA and impaired metabolism through SDH. Here we review historical and recent studies addressing OAA inhibition of SDH. We also discuss the possible physiological role of OAA/SDH interaction and whole-body consequences. Further, we describe novel methodology for detection of OAA and assessment of mitochondrial function under conditions of clamped mitochondrial inner membrane potential.
    Keywords:  Mitochondria; glutamic-oxaloacetic transaminase-2; mitochondrial inner membrane potential; oxaloacetate; succinate dehydrogenase
    DOI:  https://doi.org/10.1152/ajpcell.00200.2026
  3. J Clin Invest. 2026 Jul 01. pii: e192333. [Epub ahead of print]136(13):
    SGLT2 inhibitors enhance ketogenesis by acting as allosteric activators of the mitochondrial enzyme HMGCS2.
    Abdualrahman Mohammed Abdualkader, Xiaobei Li, Yiming Yin, Chenhao Bai, Parisa Pourfarziani, Jiaheng Guan, Sora Kwon, Kyoung-Han Kim, Rami Al Batran.
      SGLT2 inhibitors boost ketone production by directly activating a liver enzyme, revealing a new mechanism that may contribute to their heart and kidney benefits.
    Keywords:  Diabetes; Endocrinology; Fatty acid oxidation; Glucose metabolism; Metabolism
    DOI:  https://doi.org/10.1172/JCI192333
  4. Sci Adv. 2026 Jul 03. 12(27): eaee5417
    Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.
    Celia de la Calle Arregui, Anderson R Frank, Kelvin Mun, Jiwoong Kim, Kuntal Majmudar, Justin A Bishop, Cheryl Lewis, Yang Xie, David G McFadden.
      Oncocytic (Hürthle cell) carcinoma of the thyroid (OCT) is characterized by widespread loss of heterozygosity (LOH), mitochondrial accumulation, and recurrent mitochondrial DNA mutations leading to impairment of complex I. Here, we establish and characterize a novel OCT cell line, UT946, which displays severe mitochondrial electron transport chain dysfunction and a Warburg metabolic phenotype. Using a series of cytoplasmic hybrids, we establish that the complex I defect in UT946 stems from a nuclear-encoded loss-of-function mutation in the complex I subunit NDUFS1. To our surprise, the mutation in NDUFS1 was inherited as a recessive germline allele that underwent LOH in the tumor to expose functional loss of complex I. A reanalysis of 91 OCT tumor genomes revealed that LOH-driven exposure of recessive germline mutations in complex I subunits was a recurrent mechanism underlying complex I inactivation in OCT. These findings unveil a previously unidentified germline-driven mechanism of complex I loss and metabolic reprogramming in cancer and provide further evidence of the selective pressure for complex I impairment in OCT.
    DOI:  https://doi.org/10.1126/sciadv.aee5417
  5. Cell Rep. 2026 Jul 02. pii: S2211-1247(26)00707-2. [Epub ahead of print]45(7): 117629
    Complex I drives glutamine-dependent TCA cycle to support viability of MYChigh breast cancer cells.
    Johanna M Anttila, Mariel Savelius, Linda Id, Daniel Nicorici, Juhi Somani, Antti O Hiltunen, Pauliina M Munne, Aino Peura, Martina Peltonen, July Aung, Ryan Awadhpersad, Ellisiv Nyhamar, Bina Prajapati, Hanna Ala-Hongisto, Prson Gautam, Mika J Välimäki, Topi A Tervonen, Karina Šapovalovaitė, Raman Devarajan, María Victoria Ruiz Pérez, Minna Mutka, Panu Kovanen, Laura Niinikoski, Tuomo Meretoja, Johanna Mattson, Päivi Heikkilä, Krister Wennerberg, Marie Arsenian-Henriksson, Jukka Westermarck, Tero Aittokallio, Andrei Goga, Christopher B Jackson, Anni I Nieminen, Juha Klefström.
      In many cancers, stably elevated MYC levels drive sustained activation of anabolic programs and the cell cycle, creating opportunities for the synthetic-lethal targeting of MYChigh tumors. Enhanced mitochondrial respiration is a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains the TCA cycle by regenerating NAD+ through complex I-mediated oxidation of NADH, supporting the anabolic demand of MYC-driven cells. Metabolic carbon tracing reveals that MYC shifts the TCA cycle carbon source from glucose to glutamine. Inhibition of the glutamine-fueled TCA cycle using NAD+-depleting complex I inhibitors promotes MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYChigh tumors, combined inhibition of complex I and glutaminolysis produces persistent suppression of tumor growth. Altogether, the elevated respiration of MYChigh cells supports a glutamine carbon-enriched TCA cycle that meets anabolic demand, rendering MYChigh tumors selectively vulnerable to mitochondrial respiration and glutaminolysis inhibitors.
    Keywords:  CP: cancer; CP: metabolism; MYC; TCA cycle; breast cancer; cancer; complex I; glutamine; metabolism; mitochondria; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.celrep.2026.117629
  6. Cancer Genomics Proteomics. 2026 Jul-Aug;23(4):23(4): 629-648
    Glucose and Glutamine Define Independent Activation-Braking Metabolic States in Triple Negative Breast Cancer Cells.
    Elizabeth A Mazzio, Renee Reams, Ramesh B Badisa, Jean Baptiste Lamango, Zonelle Hanley, Karam F A Soliman.
       BACKGROUND/AIM: Cancer metabolism is often viewed as a cooperative reliance on glucose and glutamine; however, whether these nutrients can enforce discrete, non-overlapping metabolic states remains unclear. This study aimed to isolate nutrient-specific regulatory programs.
    MATERIALS AND METHODS: MDA-MB-231 human breast cancer cells were cultured under four distinct metabolic environments: glucose/glutamine nutrient-repleted (fed), dual glucose/glutamine deficiency, and isolated repletion of either glucose or glutamine. Groups were evaluated for integrated transcriptomic, metabolomic, and lipidomic profiles to identify only the non-redundant, nutrient-enforced architectures.
    RESULTS: The data show a mutually restrictive mechanistic state. Glutamine functions as a metabolic architect, restoring glycolytic enzyme transcripts (without lactate production), while inducing PDK1/3 which would decouple glycolysis from the TCA cycle. These changes are concomitant with a glutamine flux toward reductive TCA-driven lipogenesis, citric acid overflow, sterol synthesis (SREBF1/2), structural membrane expansion (phospholipids/sphingolipids) and the unique production of alanine as a nitrogen pool, independent of glycolytic flux. Conversely, glucose alone acts as the executor, licensing chromatin engagement, DNA replication, and mitotic progression. Glucose alone resolved ER stress, restored hexose-phosphate-derived glycosylation (mannose-6-phosphate), enabled lactic acid production, and diverted excess carbon into a triglyceride storage pool (>40% of lipids). Notably, each nutrient suppressed core elements of the other's program, revealing a reciprocal activation-braking system. Interestingly, ATP yield from glucose or glutamine alone were comparable, but not arbitrary; instead, aligned with the functional state of the cell. Glucose alone supported glycolytic phosphorylation and proliferative execution, as marked by lactate accumulation, whereas glutamine alone supported Krebs cycle-related phosphorylation, characterized by citrate accumulation and the maintenance of cellular structure and membrane infrastructure.
    CONCLUSION: Glucose and glutamine enforce a balance of two independent, reciprocally regulated metabolic states. This data provides a systems-level explanation for metabolic resilience in cancer and may lead to the identification of nutrient-specific targets for combination therapy.
    Keywords:  Cancer metabolism; ER stress; PDK; Warburg effect; anaplerosis; breast cancer; glucose–glutamine reciprocity; glutaminolysis; lipid remodeling; metabolic plasticity; nutrient-enforced metabolic states; oxidative phosphorylation; pyruvate dehydrogenase kinase; substrate-level phosphorylation; transcriptional state control
    DOI:  https://doi.org/10.21873/cgp.20593
  7. Mol Cell. 2026 Jul 02. pii: S1097-2765(26)00384-9. [Epub ahead of print]86(13): 2446-2448
    An NADPH safety valve: De novo lipogenesis buffers biguanide-induced reductive stress.
    Harrison J Tom, Gerta Hoxhaj.
      In this issue, Ahsan et al.1 reveal that de novo lipogenesis averts biguanide-induced reductive stress by consuming reduced nicotinamide adenine dinucleotide phosphate, reframing fatty acid synthesis as a conserved redox safety valve that determines whether biguanide-driven metabolic stress remains adaptive or turns lethal.
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.013
  8. Nat Commun. 2026 Jul 01.
    Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.
    Abhisha Sawant Dessai, Nadya A Elhalawany, Tao Dai, Justine J Jacobi, Christian Prechtl, Alphonse N Dimeck, Sierra R Morton, Mark D Long, Prashant K Singh, Nagireddy Putluri, Mariana Lopes, Song Liu, Dominic J Smiraglia, Katerina V Gurova, Peder J Lund, Leah A Gates, Sung Yun Jung, Subhamoy Dasgupta.
      Mitochondria remain at the core of cell metabolism, whereas the nucleus integrates cellular and environmental signals to activate genes. However, the mechanisms that directly link cellular metabolism to gene regulation are not well understood. Here we show, a metabolic pathway in the nucleus controls acetylation of histones by nuclear localization of mitochondrial enzymes aconitase (ACO2) and isocitrate dehydrogenase (IDH2). Metabolic tracing studies show that IDH2 and ACO2 catalyze reductive carboxylation of α-ketoglutarate to rapidly synthesize citrate to increase nuclear acetyl-CoA pool. Genetic and proteomic analyses reveal nuclear IDH2 and ACO2 form a complex with KAT2A/GCN5 for acetylation of histones to increase chromatin accessibility and activation of proliferative genes. Robust nuclear expressions of ACO2 and IDH2 drive aggressive tumors indicating the tumorigenic potential of IDH2-ACO2-KAT2A axis. Altogether, our work reveals a paradigm coupling a nuclear metabolic pathway with histone acetylation to control of gene expression that accentuates hyperproliferative phenotype in tumors.
    DOI:  https://doi.org/10.1038/s41467-026-74786-3
  9. Cancer. 2026 Jul 01. 132(13): e70509
    Real-world safety, prognostic, and design considerations in ketogenic diet trials for pancreatic cancer.
    Howard W Bruckner, Elisheva Knopf.
      
    DOI:  https://doi.org/10.1002/cncr.70509
  10. J Gen Physiol. 2026 Sep 07. pii: e202613979. [Epub ahead of print]158(5):
    Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
    Yaw Akosah, Ioannis Azoidis, Dane D Jensen, Paolo Bernardi, Evgeny V Pavlov.
      Along with the membrane potential and respiration, mitochondrial matrix volume is a critical parameter that determines mitochondrial function. Mitochondria undergo constant changes in matrix volume and crista dynamics, and in processes that are critical for normal metabolic rates and pathophysiological responses. Changes in matrix volume cannot be easily measured by conventional fluorescence imaging techniques due to the size of the suborganellar structures, which are below resolution. This challenge was successfully resolved in studies of isolated mitochondria with the use of scattered light. Here, we use dark-field imaging, which relies on scattered light contrast, to measure matrix volume dynamics in living cells. We demonstrate that mitochondrial volume changes can be easily detected as changes in intensity of the scattered light following matrix volume modulation with K+ ionophores or by onset of the permeability transition. Specifically, we found that stimulation of K+ influx leads to an increase in mitochondrial matrix volume, while stimulation of K+ efflux leads to matrix shrinkage, and that activation of the permeability transition leads to high-amplitude mitochondrial swelling in wild-type but not in cells lacking subunit c of ATP synthase. These results directly demonstrate the dynamic nature of mitochondrial matrix volume and its link to physiological and pathological ion transport.
    DOI:  https://doi.org/10.1085/jgp.202613979
  11. Physiol Rep. 2026 Jul;14(13): e70989
    Physiologically relevant media are associated with overlapping metabolic responses in primary human hepatocytes and Huh7 cells.
    Eloise Cross, Felix Westcott, Kieran Smith, Shilpa R Nagarajan, Fabio Sanna, Kaitlyn M J H Dennis, Leanne Hodson.
      The initiation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD) is challenging to study in vivo in humans, and robust in vitro high-fidelity disease models are limited. Although primary human hepatocytes (PHH) are often considered to be the gold standard, immortalized hepatic cell lines are often utilized because of their scalability and experimental tractability. Therefore, the aim of this study was to compare the metabolic responses of PHHs with our characterized Huh7-based model when exposed to the physiologically relevant fatty acid (FA) mixtures. PHH and Huh7 cells were treated with 2% human serum and a combination of sugar and FAs enriched in either unsaturated (OPLA) or saturated (POLA) FAs for 4 or 7 days, respectively. Stable isotope tracers were utilized to investigate basal changes in hepatocyte metabolism in response to different treatment regimes. Changes in cell viability, media biochemistry, intracellular metabolism, lipid droplet morphology, and gene expression were quantified. Huh7 cells had greater viability than PHH, while NEFA uptake and triglyceride secretion were similar. Both OPLA and POLA increased the proportion of large lipid droplets in Huh7 cells, whereas only OPLA produced comparable effects in PHH. Despite higher baseline TG in PHH, both models showed similar lipid composition, de novo lipogenic responses, and glycogen levels. Compared to Huh7 cells, PHH exhibited higher media 3-hydroxybutyrate, lower media lactate, reduced glucose uptake, and donor-dependent transcriptomic variability. Our data demonstrate that Huh7 cells are metabolically adaptable and, when cultured in physiologically relevant media, metabolic readouts are more similar to those observed in PHH cells, thus making Huh7 a potentially useful workhorse model to investigate relevant pathways that may underpin the development of MASLD. Progress in MASLD research is constrained by limited access to human liver tissue and the scarcity of robust in vitro models. Although PHHs are considered the gold standard, they can be limited by poor viability and donor-to-donor variability. Huh7 cells are metabolically flexible and can recapitulate key metabolic responses of PHH when exposed to physiologically-relevant chronic culture conditions, making them an alternative to PHH that is a scalable and reproducible model for investigating intrahepatic triglyceride (IHCTG) accumulation and MASLD progression.
    Keywords:  in vitro; liver; metabolism; primary human hepatocytes
    DOI:  https://doi.org/10.14814/phy2.70989
  12. Cell Stem Cell. 2026 Jul 02. pii: S1934-5909(26)00206-7. [Epub ahead of print]33(7): 1054-1056
    Beyond apoptosis: LSC state dictates metabolic and anti-apoptotic vulnerabilities.
    Juan L Coelho-Silva, João A Machado-Neto.
      Two studies1,2 published in the last issue of Cell Stem Cell reveal that leukemic stem cell (LSC) identity in acute myeloid leukemia (AML) encodes both anti-apoptotic dependencies and metabolic survival programs. They reframe LSC-directed therapy: eradication may require combinatorial targeting of BCL-2 family proteins and ferroptosis-suppressive ketogenesis in a cell-state-specific manner.
    DOI:  https://doi.org/10.1016/j.stem.2026.05.014
  13. Biotechnol Bioeng. 2026 Jun 28.
    Metabolic Flux Analysis Reveals Cell Line-Specific Rewiring in CHO Cells Following TCA Cycle Intermediate Feeding for Bioprocess pH Control.
    Sarah A Sacco, Kevin J Ruiz-Márquez, Rachel Moen, Irina Trenary, Xiaolin Zhang, Xiaowen Wang, Malik Padellan, Henry Lin, Jamey D Young.
      Chinese hamster ovary (CHO) cells are the leading host for recombinant therapeutic protein production in the biopharma industry. In this study, we investigated how feeding acidic forms of tricarboxylic acid (TCA) cycle intermediates-malic acid, succinic acid, and α-ketoglutaric acid-affects cell culture performance and metabolism in two industrial IgG-producing CHO cell lines. These intermediates were used as pH control agents to replace conventional CO2 sparging, enabling simultaneous modulation of the bioreactor environment and cell metabolism. Carbon-13 metabolic flux analysis (13C-MFA) revealed substantial rewiring of central carbon and nitrogen metabolism under all fed conditions, with distinct responses between cell lines. Intermediate-fed cultures exhibited enhanced TCA cycle fluxes, reduced glucose dependency, decreased lactate accumulation, and altered routing of pyruvate. Notably, α-ketoglutaric (α-KG) acid feeding triggered divergent nitrogen assimilation phenotypes: one cell line enhanced glutamine biosynthesis and ammonium clearance, while the other accumulated glutamate with minimal glutamine production. These metabolic adaptations were accompanied by shifts in redox balance and delayed but measurable increases in cell-specific IgG productivity. Our findings highlight the compound- and cell line-specific nature of metabolic responses to TCA cycle intermediate feeding and support its use for pH control and bioprocess optimization.
    DOI:  https://doi.org/10.1002/bit.70287
  14. Diabetes. 2026 Jul 02. pii: db260229. [Epub ahead of print]
    Females Are Completely Resistant to Semaglutide-Induced Muscle Loss in ob/ob Mice.
    Subhasmita Rout, Takuya Karasawa, Shinya Watanabe, Amandine Chaix, Micah J Drummond, Katsuhiko Funai, Ran Hee Choi.
       ARTICLE HIGHLIGHTS: Female C57BL/6 J mice are relatively resistant to weight gain, which complicates the study of sex-specific metabolic responses. So, we used ob/ob mice to examine semaglutide-induced weight loss in both sexes. We wanted to determine whether semaglutide-induced weight loss produces sex-specific effects on skeletal muscle mass and function in ob/ob mice. Semaglutide had minimal effects on skeletal muscle mass and strength in ob/ob mice. In particular, females were completely resistant to loss of muscle mass. These findings reveal that semaglutide exerts sex-specific effects, highlighting a need for further research into the molecular mechanisms driving these distinct protective outcomes.
    DOI:  https://doi.org/10.2337/db26-0229
  15. Res Sq. 2026 Jun 19. pii: rs.3.rs-9944913. [Epub ahead of print]
    Triphenylphosphonium compounds preferentially inhibit long-chain fatty acid oxidation in cardiac mitochondria.
    Anna Faakye, Satoshi Matsuzaki, Venkateswararao Eeda, Vibhudutta Awasthi, Kenneth Humphries.
      Triphenylphosphonium (TPP) is a lipophilic molecule widely used in targeting compounds into the mitochondria. Despite its wide use, TPP has known mitochondrial toxicity, the characteristics of which are not completely defined. In this study, we sought to determine if the effects of TPP and TPP conjugates on mitochondrial function occur in a substrate dependent manner. To do so, we treated isolated mouse heart mitochondria with TPP, commercially available TPP derivatives MitoTEMPO and MitoSOX, and a test compound (TPP-aspirin). All TPP conjugates, except MitoTEMPO which was relatively inert, preferentially inhibited mitochondrial respiration when it was supported by palmitoyl carnitine as compared to pyruvate. This substrate selectivity was not explained by differential effects on membrane potential or electron transport chain activities, as both were largely preserved at concentrations of compounds that inhibited respiration. To identify the site of inhibition, we measured fatty acid oxidation directly and found that TPP and its conjugates significantly inhibited β-oxidation activity in energized mitochondria. CPT1 activity was unaffected, localizing the inhibition to the inner mitochondrial compartment. Finally, acute treatment of AC16 cells with TPP showed the same preferential inhibition of oxygen consumption rates when comparing fatty acids to pyruvate, without the loss of cell viability. Cumulatively, these results show that TPP and TPP-conjugate effects on mitochondrial function have substrate dependency by targeting fatty acid oxidation.
    DOI:  https://doi.org/10.21203/rs.3.rs-9944913/v1
  16. Science. 2026 Jul 02. 393(6806): 90-97
    A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.
    Michael Cross, Stefan Kotschi, Warren Wu, Fedra Luciano-Mateo, Young-Yon Kwon, Ezequiel Dantas, Taha Niazi, Shijia Chen, Ali Rashidfarrokhi, Ray Pillai, Jack Sanford, Jeshua Kim, Juliya Hsiang, Begona Gamallo-Lana, Adam C Mar, Yuan Hao, Sahith Rajalingam, Annie Huang, Jackie Shan, Habon A Issa, Maria Gomez, Alice R Wang, Xiang Zhao, Tobias Janowitz, Eileen White, Yin Liu, Kwok-Kin Wong, Leopoldo N Segal, Sheng Hui, Marcus D Goncalves, Robert C Froemke, Thales Papagiannakopoulos.
      Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.
    DOI:  https://doi.org/10.1126/science.adz4196
  17. Cell Rep. 2026 Jul 03. pii: S2211-1247(26)00719-9. [Epub ahead of print]45(7): 117641
    BCAA metabolism promotes lung cancer tumorigenesis by enhancing cholesterol biosynthesis.
    Huimin Ma, Erbao Zhang, Jiaying Cai, Dong Hang, Xiaoyang Ma, Yi Yang, Meng Zhu, Qi Sun, Jianv Huang, Jing Zhang, Guang Huang, Chang Zhang, Chen Jin, Yating Fu, Lingnan Gong, Chong Shen, Xiangfeng Lu, Yue Jiang, Juncheng Dai, Guangfu Jin, Dongfeng Gu, Xu Qian, Hongbing Shen, Hongxia Ma.
      Metabolic dysregulation has been established as a key driver in tumorigenesis, but its underlying mechanisms in lung cancer remain poorly characterized. In this study, we performed nested case-control analyses in two prospective cohorts (208 and 144 matched pairs) to examine associations between plasma metabolites and lung cancer risk. Untargeted metabolomics identified circulating metabolites of the branched-chain amino acid (BCAA) pathway as significantly associated with lung cancer risk. An animal study demonstrated that a high-BCAA diet accelerated lung cancer progression in the KrasG12D/+ mice model. Among the three BCAAs, leucine contributed much more to promoting lung cancer growth. Mechanistically, AUH-mediated acetyl-CoA production from leucine metabolism fuels cholesterol synthesis, promoting lipid raft formation and EGFR redistribution and activation, thereby driving lung tumorigenesis. Moreover, atorvastatin blocked leucine-induced tumor progression in mice. Overall, our findings provide experimental evidence that leucine-driven BCAA metabolic reprogramming promotes lung tumorigenesis via cholesterol metabolism, revealing a potential therapeutic target.
    Keywords:  AUH; CP: cancer; CP: metabolism; EGFR signaling; branched-chain amino acids; cholesterol; leucine; lung cancer; metabolomics; tumorigenesis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117641
  18. Nat Commun. 2026 Jul 01. pii: 5737. [Epub ahead of print]17(1):
    A carboxylate switch point controls long-range energy transduction in respiratory Complex I.
    Adel Beghiah, Patricia Saura, Terezia Kovalova, Franziska Hoeser, Thorsten Friedrich, Ville R I Kaila.
      Complex I is a highly intricate membrane-bound protein complex that powers the cellular energy metabolism by a long-range ( > 300 Å) proton-coupled electron transfer (PCET) reaction. Here, we investigate the highly debated coupling mechanism of Complex I by probing the charge transfer reaction along its functionally central carboxylate pathway (E-channel). By combining biophysical and site-directed mutagenesis experiments with high-resolution (2.6-2.8 Å) cryo-electron microscopy (cryo-EM) and multiscale simulations, we identify a conserved carboxylate switch point (D79NuoA) that mediates proton transfer by establishing a kinetic gate and couples the redox chemistry to proton pumping. We find that mutation of the identified site, as found in patients suffering from severe neurodegenerative disorders, drastically perturbs the charge transfer mechanism, and results in a 20% PCET activity. Our combined findings illustrate mechanistic principles of molecular gates underlying long-range charge transfer reactions, and show how disease mutations perturb the function of conserved switch points in energy transduction.
    DOI:  https://doi.org/10.1038/s41467-026-74767-6
  19. Gut. 2026 Jul 03. pii: gutjnl-2025-337363. [Epub ahead of print]
    Dysregulated sphingolipid metabolismdrives pancreatic carcinogenesis through plasma membrane Kras enrichment.
    Ahmed Alnatsha, Jianying Xu, Tahib Habshi, Qi Li, Klea Rickú, Prince Allawadhi, Didem Saka, Ruoxan Dai, Yuxing Xue, Hang Nguyen, Helena Stadler, Theresa Weltermann, Quan Zhou, Nicole Schreiner, Yonggan Xue, Victoria Rittinghausen, Steffen Ormanns, Fredrick Klauschen, Danmei Zhang, Stefan Böck, Martin Benoit, Najib Ben Khaled, Shibojyoti Lahiri, Axel Imhof, Andreas Klingl, Anjali Jaiswal, Girija P Sahoo, Ivonne Regel, Sebastian Mueller, Rupert Öllinger, Roland Rad, Claus Belka, Tanja Bange, Kirsten Lauber, Julia Mayerle, Ujjwal M Mahajan.
       BACKGROUND: As key constituents of cellular sphingolipid pools, sphingomyelin (SM) and ceramide (CER) are central to the regulation of cancer cell death and survival. The metabolic flux between these two lipids is a vital component of the cellular stress response, yet the underlying regulatory mechanisms in cancer remain elusive. Acid sphingomyelinase (SMPD1) facilitates the conversion of SM to CER, functioning as a key enzymatic driver of CER-mediated signalling.
    OBJECTIVES: Herein, we aim to evaluate the role of SMPD1-driven sphingolipid metabolism in pancreatic carcinogenesis.
    DESIGN: A targeted quantitative analysis of the plasma metabolome was conducted involving patients with pancreatic ductal adenocarcinoma (PDAC, n=202) and matched control subjects (n=204). Multiplex immunohistochemistry was performed on resected PDAC (n=122) to identify expression of SMPD1 with tumour and immune cell markers. CRISPR/Cas9 driven Smpd1-deleted murine cell lines were generated and subsequently assessed for their carcinogenic potential in vitro. The effects of Smpd1 deletion on tumour formation were evaluated using both syngeneic orthotopic and metastatic murine models.
    RESULTS: Here, we demonstrate that tumour cell-autonomous expression of SMPD1, in pancreatic ductal adenocarcinoma (PDAC), is associated with poorer patients' outcomes. Smpd1 ablation in murine PDAC cells resulted in reduced proliferation and migration in vitro and decreased metastases and tumour burden in vivo. Integrated transcriptomic, metabolomic and proteomic studies revealed that SMPD1 abrogation impairs KrasG12D oncogenic signalling and, thus, reduces tumour burden. Reduced plasma membrane interaction of KrasG12D was associated with SMPD1-dependent sphingolipid metabolism. Notably, the SMPD1 inhibitor (ARC39) potently synergised with the KrasG12D inhibitor (MRTX1133).
    CONCLUSION: In summary, SMPD1 regulated plasma membrane sequestration of KrasG12D represents a potential therapeutic target within the Kras signalling pathway for intractable PDAC.
    Keywords:  BASIC SCIENCES; PANCREAS; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2025-337363
  20. J Clin Endocrinol Metab. 2026 Jul 03. pii: dgag262. [Epub ahead of print]
    Genetic and Clinical Factors Associated With Metformin Plasma Concentrations Following an Acute Metformin Challenge.
    Bryan Kuo, Stella Nam, Varinderpal Kaur, Farah Jones, Josep M Mercader, Sook Wah Yee, Jose C Florez, Shylaja Srinivasan, Josephine H Li.
      The glycemic response to metformin is highly variable, yet the genetic determinants of metformin pharmacokinetics remain poorly characterized. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), an ancestrally diverse cohort, we evaluated clinical and genetic factors associated with plasma metformin concentrations. Plasma metformin concentrations were measured in 745 participants who completed a standardized acute metformin challenge in SUGAR-MGH. Higher metformin concentrations were associated with older age (β=2.5 ng/mL per year, p = 0.02), lower eGFR (β=-3.5 ng/mL per ml/min/1.73m2, p = 4.5 × 10-4), and lower BMI (β=-7.3 ng/mL per kg/m2, p = 1.3 × 10-4). African ancestry was associated with lower metformin concentrations compared to European ancestry (β=-72.6 ng/mL, p = 0.036). A genome-wide association study (GWAS) identified four African ancestry-specific genetic variants significantly associated with higher metformin concentrations (p < 5 × 10-8) as well as several suggestive loci near genes implicated in glucose metabolism, including USP36 and DGKB. Top variants associated with metformin concentration were not associated with glycemic response endpoints following the metformin challenge, including fasting glucose at Visit 2, change in HOMA-IR, and change in fasting insulin between visits. Previously reported metformin transporter variants showed no significant associations with metformin concentration. These findings represent the first GWAS of metformin plasma concentrations and provide a novel resource for future studies of metformin pharmacogenetics.
    Keywords:  Genome-wide association study; Metformin; Pharmacogenetics; Type 2 diabetes
    DOI:  https://doi.org/10.1210/clinem/dgag262
  21. Cell Chem Biol. 2026 Jun 30. pii: S2451-9456(26)00194-7. [Epub ahead of print]
    Assessment of mitochondrial lipid peroxidation in cells and zebrafish using a targeted mass spectrometry probe.
    Shinpei Uno, Stuart T Caldwell, Hiran A Prag, Chak Shun Yu, Lucie J Lamačová, María Torres-López, Andrew M James, Ana Lopez, Taylor A Woetzel, Angeleen Fleming, David C Rubinsztein, Richard C Hartley, Michael P Murphy.
      Mitochondrial lipid peroxidation is a major component of oxidative damage and is also thought to contribute to ferroptosis. Lipid peroxidation is generally assessed from the accumulation of oxidized end products, such as 4-hydroxynonenal (HNE). However, these report on damage throughout the cell and are affected by changes in how oxidized phospholipids are turned over. To overcome these constraints, we developed MitoLiPOX, a mitochondria-targeted mass spectrometry probe. Mitochondria targeting and detection sensitivity were achieved by incorporating a lipophilic triphenylphosphonium cation. Responsiveness to lipid peroxidation was brought about by building in a bis-allylic carbon-hydrogen bond mimic that, upon oxidation and processing, generated a single product, MitoLiPOX-OH. LC-MS/MS quantification of MitoLiPOX-OH followed by normalization to the amount of MitoLiPOX present enabled ratiometric quantification of mitochondrial lipid peroxidation. We then used MitoLiPOX to assess mitochondrial lipid peroxidation during ferroptosis in vitro and in zebrafish in vivo.
    Keywords:  exomarker; lipid peroxidation, ferroptosis; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1016/j.chembiol.2026.05.015
  22. Cell Death Dis. 2026 Jun 30.
    Branching architecture of tryptophan metabolism determines therapeutic vulnerability in acute myeloid leukemia.
    Tomasz Pienkowski, Marianna Ciwun, Anna Tankiewicz-Kwedlo, Aleksandra Golonko, Lukasz Bolkun, Jaroslaw Piszcz, Waldemar Priebe, Dariusz Pawlak.
      Acute myeloid leukemia (AML) exhibits metabolic reprogramming that supports immune evasion and treatment resistance. The kynurenine pathway (KP) is a key regulator of tumor-immune interactions, yet its downstream organization and clinical relevance in AML remain unclear. Here, we combined in vitro models with patient serum profiling to determine whether KP branching patterns are associated with treatment response. Extracellular KP metabolites were quantified in AML cell lines (HL-60 and MOLM-14) following induction regimens, and quantified circulating KP metabolites in patient serum samples collected from AML patients before and after induction therapy. Treatment was associated with normalization of tryptophan depletion and kynurenine accumulation in responders, indicating partial restoration of systemic KP homeostasis. Notably, baseline (pre-treatment) samples from patients who were later classified as non-responders exhibited a distinct metabolic phenotype characterized by persistent kynurenine elevation, increased anthranilic and kynurenic acid levels, and enrichment of 3-hydroxykynurenine flux, suggesting preferential engagement of oxidative and immunomodulatory KP branches. Among evaluated metabolic indices, the 3-hydroxykynurenine-to-kynurenine ratio demonstrated the strongest discriminatory capacity for distinguishing response to induction therapy (DA: daunorubicin + cytarabine; DAC: daunorubicin + cytarabine + cladribine), outperforming individual metabolite measurements and highlighting functional pathway flux rather than absolute metabolite abundance as a determinant of clinical outcome.
    DOI:  https://doi.org/10.1038/s41419-026-09050-z
  23. Diabetes. 2026 Jul 01. pii: db260293. [Epub ahead of print]
    Ketone Bodies Derived From Medium-Chain Triglycerides Support Brain Metabolism and Function Under Hypoglycemia in Type 1 Diabetes Mellitus.
    Domenico Tricò, Lihong Jiang, Daniel Spicer, Kathleen Page, Renata Belfort de Aguiar, Sarita Naik, Mary Savoye, Donna M Caseria, Jagriti Arora, Graeme F Mason, Todd Constable, Douglas L Rothman, Raimund I Herzog.
      Impaired cognitive function caused by insulin-induced hypoglycemia is a complication of type 1 diabetes mellitus (T1DM) for which no protective strategies are currently available. In this first-in-human mechanistic study using magnetic resonance spectroscopy, the direct contribution of the infused ketone β-hydroxybutyrate (BHB) to brain metabolism during clamped hypoglycemia was greater in participants with T1DM than healthy participants. In a randomized dietary intervention trial of participants with T1DM and recurrent hypoglycemia, receiving medium-chain triglycerides (MCTs) as a dietary ketone precursor was associated with higher working memory performance and greater regional brain activation during clamped hypoglycemia compared with an isocaloric standard diet. Counterregulatory hormone responses to hypoglycemia were not affected by MCT supplementation. We conclude that ketone bodies are well suited to support brain metabolism in persons with T1DM experiencing insulin-induced hypoglycemia. Dietary MCT supplementation raising BHB may represent a novel strategy to prevent hypoglycemia-induced brain injury in this vulnerable patient population.
    ARTICLE HIGHLIGHTS: There are currently no strategies to prevent cognitive impairment caused by insulin-induced hypoglycemia in type 1 diabetes mellitus (T1DM). We examined whether β-hydroxybutyrate (BHB) supports brain metabolism during clamped hypoglycemia and whether dietary medium-chain triglycerides (MCTs), by raising BHB availability, elicit this protective effect. BHB contributed more to brain metabolism in participants with T1DM than in healthy control participants, and long-term MCT supplementation improved working memory and brain activation during hypoglycemia. Dietary MCT supplementation may protect against hypoglycemia-related cognitive deficits in T1DM.
    DOI:  https://doi.org/10.2337/db26-0293
  24. Cell Death Differ. 2026 Jul 03.
    A planar dimer of bovine ATP synthase.
    Chimari Jiko, Atsuki Nakano, Yosuke Teshirogi, Eiki Yamashita, Genji Kurisu, Daron Standley, Tohru Terada, Kaoru Mitsuoka, Ken Yokoyama, Christoph Gerle.
      Mammalian mitochondrial ATP synthase typically organizes into rows of V-shaped dimers that impose significant membrane curvature essential for mitochondrial cristae formation. Using gentle, column-free purification combined with single-particle cryo-electron microscopy, we have identified a previously unrecognized planar dimeric form of bovine ATP synthase exhibiting minimal membrane bending. This planar dimer is characterized structurally by anti-parallel arrangement of two ATP synthase complexes linked by a straight conformation of inhibitory factor 1 (IF1), a sharp contrast to the kinked IF1 observed in tetrameric assemblies. Molecular dynamics simulations confirm that transitioning between straight and kinked IF1 conformations occurs without significant energetic barriers. The planar dimer also displays distinct peripheral stalk positioning relative to its adjacent α subunit. These structural divergences suggest a specialized function and a distinct localization for planar ATP synthase dimers, providing structural support for a division of labor within mitochondrial ATP synthase populations.
    DOI:  https://doi.org/10.1038/s41418-026-01797-4
  25. Trends Cell Biol. 2026 Jun 29. pii: S0962-8924(26)00102-9. [Epub ahead of print]
    Horizontal transfer of mitochondria in cancer: The physiology reborn in disease?
    Gustavo Ayala, Simon Grelet.
      Intercellular mitochondria transfer has emerged as a new form of cell-to-cell communication with profound consequences for cellular fate. A growing body of evidence defines mitochondria transfer between cells as a new pathological program in which cancer cells appropriate functional mitochondria from donor cells, thereby co-opting conserved physiological mechanisms of energy allocation to gain bioenergetic and phenotypic advantages. Our recent work demonstrates the prevalence of mitochondria transfer at the nerve-cancer interface, with neurons, though not exclusively, serving as a prominent source of the organelle. This suggests an unrecognized role of the nervous system in systemic energy redistribution and indicates that tumors may exploit this ancient, physiologically grounded mechanism to fuel progression and metastasis.
    Keywords:  cancer neurometabolism; kleptoplasmy; mitochondria transfer
    DOI:  https://doi.org/10.1016/j.tcb.2026.06.003
  26. In Vivo. 2026 Jul-Aug;40(4):40(4): 1979-1986
    Synergy of a Low-methionine Diet and Reduced-dose Cisplatinum Eradicates Experimental Lung-cancer Bone Metastases in a Nude-mouse Model.
    Yohei Asano, Kohei Mizuta, Yuta Miyashi, Qinghong Han, Shukuan Li, Byung Mo Kang, Jin Soo Kim, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Kentaro Igarashi, Takashi Higuchi, Sei Morinaga, Hiroyuki Tsuchiya, Satoru Demura, Robert M Hoffman.
       BACKGROUND/AIM: Bone metastasis of lung cancer is highly recalcitrant, and current treatment is palliative. Methionine addiction is a fundamental hallmark of cancer, known as the Hoffman effect, and is targeted by methionine restriction (MR). The present study aimed to evaluate the efficacy of MR combined with low-dose cisplatinum on an experimental nude-mouse model of bone metastasis of lung cancer.
    MATERIALS AND METHODS: The A549 human lung-adenocarcinoma cell line was used in the present study. An experimental bone-metastasis model was established by implanting A549 cells into the tibia of nude mice. The mice were then randomly assigned to four groups: untreated control; standard-dose cisplatinum (6 mg/kg, intraperitoneally, weekly); combination of low-dose cisplatinum (3 mg/kg, intraperitoneally, weekly) and an MR diet; and an MR diet only. Tumor growth and body weight were monitored during the 3-week treatment period.
    RESULTS: The combination of low-dose cisplatinum and an MR diet had the most tumor inhibition efficacy of all treatment groups, with tumors essentially being eradicated by the end of the treatment period. The combination of MR and low-dose cisplatinum showed superior efficacy compared to standard-dose cisplatinum. Furthermore, weight loss was observed only in the mice treated with standard-dose cisplatinum, whereas mice treated with the combination of low-dose cisplatinum and an MR diet maintained body weight comparable to that of the MR-alone group.
    CONCLUSION: MR enhanced the efficacy of low-dose cisplatinum, while mitigating treatment-associated toxicity in a lung-cancer experimental bone-metastasis model. The present findings suggest that metabolic targeting of methionine addiction is a promising therapeutic strategy enabling effective chemotherapy dose reduction in bone-metastatic lung cancer.
    Keywords:  A549; Hoffman effect; Methionine addiction; bone metastasis; cisplatinum; combination; lung cancer; methionine-restricted diet; nude mice; synergy
    DOI:  https://doi.org/10.21873/invivo.14350
  27. J Cardiovasc Magn Reson. 2026 Jul 03. pii: S1097-6647(26)00090-6. [Epub ahead of print] 102772
    Imaging post-reperfusion metabolism in porcine myocardial infarction with hyperpolarized 13C pyruvate MRI.
    Nikolaj Bøgh, Esben Søvsø Szocska Hansen, Jakob Lindhardt, Rasmus Stilling Tougaard, Christoffer Laustsen, Won Yong Kim.
       BACKGROUND: Reperfusion injury after primary percutaneous coronary intervention is a potential target for improving treatment of myocardial infarction. Reperfusion represents a sudden metabolic challenge of the ischemic myocardial tissue, which is thought to be a driver of reperfusion injury that is difficult to evaluate with current technologies.
    METHODS: We investigated the use of metabolic magnetic resonance imaging with hyperpolarized [1-13C]pyruvate for investigation of post-reperfusion metabolism in a pig model of acute myocardial infarction. To induce ischemia, 15 pigs had a coronary balloon placed in the left anterior descendent for one hour. Seven animals underwent mechanical preload reduction in effort to investigate the effects of increased salvage. After three hours of reperfusion, the animals were scanned with hyperpolarized [1-13C]pyruvate MRI to image the balance between mitochondrial and glycolytic metabolism.
    RESULTS: Larger conversion from [1-13C]pyruvate to [1-13C]lactate, representing glycolytic metabolism, was observed in the area-at-risk (P <.001). Similar, but non-significant, hypermetabolism was observed for conversion of [1-13C]pyruvate to [13C]bicarbonate (P =.07), representing mitochondrial metabolism. Conversion from [1-13C]pyruvate to [1-13C]alanine seemed to decrease in the group with preload reduction but increase in the sham group. The observed hypermetabolism correlated with the amount of salvaged myocardium (r =.7, P <.01), but not with the size of the area-at-risk.
    CONCLUSION: This study shows that the salvaged myocardium becomes hypermetabolic and glycolytic after reperfusion, and that a metabolic MRI may be a valuable tool in attempts to modulate post-reperfusion metabolism in preclinical and clinical research alike.
    Keywords:  hyperpolarized MRI; myocardial infarction; pyruvate; reperfusion injury
    DOI:  https://doi.org/10.1016/j.jocmr.2026.102772
  28. PLoS One. 2026 ;21(7): e0352639
    Metabolic profiling of human melanoma cell lines with high and low metastatic capacity by 1H-NMR spectroscopy.
    Nima Rezvani Kakhki, Zita Hegedűs, József Tóvári, Arash Mirzahosseini, Béla Noszál, Márta Kraszni.
       BACKGROUND: Melanoma is one of the most aggressive forms of skin cancer due to its high metastatic potential and mortality rate. Although understanding of metabolic reprogramming in melanoma has advanced, the connection between metabolic alterations and metastatic capacity remains incomplete.
    AIM: This study aimed to characterize the metabolic profiles of human melanoma cell lines with high (HT168-M1) and low (WM983B) metastatic potential, and to compare them with each other and also with the metabolic profile of normal human fibroblasts (MRC-5), in order to identify key metabolites and metabolic pathways associated with metastatic behavior.
    METHODS: Non-targeted metabolomic profiling using ¹H-NMR spectroscopy was applied to hydrophilic extracts of the three cell lines. Multivariate statistical analyses (PCA and PLS-DA) were used to identify discriminating metabolites, and pathway analysis was performed to determine altered metabolic networks.
    RESULTS: Several metabolic pathways were significantly altered in melanoma cells compared to fibroblasts, including starch and sucrose metabolism, alanine, aspartate and glutamate metabolism, and glutathione metabolism. Metabolites showing more than two-fold differences included elevated UDP-glucose, ATP, glycerophosphocholine, GTP, creatine and glutathione in the melanoma cells, and reduced glucose, glutamine and 1-methylnicotinamide in fibroblasts. Comparison of the metabolites of melanoma cell lines with differing metastatic potential revealed changes in taurine and hypotaurine, β-alanine-, glutathione-, and amino acid metabolism. Metabolites showing the largest concentration changes were UDP-glucose, glutathione, NAD+, alanine and β-alanine.
    CONCLUSION: Metabolomic profiling revealed distinct metabolic reprogramming between melanoma and normal fibroblasts, characterized by enhanced glycolysis and glutathione-dependent antioxidant defense. Highly metastatic melanoma cells demonstrated stronger redox adaptation and altered amino acid utilization, with elevated glutathione and glutamate and reduced NAD⁺ and pyruvate, indicating a metabolic shift toward oxidative stress resistance.
    DOI:  https://doi.org/10.1371/journal.pone.0352639
  29. Free Radic Biol Med. 2026 Jul 02. pii: S0891-5849(26)00916-0. [Epub ahead of print]
    An enzyme kinetic model for quantitative interpretation of the role of nicotinamide nucleotide transhydrogenase (NNT) in cell physiology.
    Zhuohui Gan, Inge van der Stelt, Sander Grefte, Maria Suarez Diez, Werner J H Koopman, Jaap Keijer.
      Nicotinamide Nucleotide Transhydrogenase (NNT) connects mitochondrial bioenergetics and redox homeostasis. It catalyzes a reversible reaction that couples proton transport across the mitochondrial inner membrane (MIM) to hydride transfer between mitochondrial NAD(H) and NADP(H). Understanding NNT kinetics is essential to decipher the link between NNT and mitochondrial functioning. Based on the protein structure and the molecular mechanism of NNT, we deduced that the kinetic mechanism of NNT can be described by a "ping-pong" mechanism. Integrated with its thermodynamic features, we established a mathematical model to describe its enzyme kinetics. The model successfully simulated experimental results obtained in submitochondrial particles. Further model analyses suggest that NNT operates in the forward mode under most physiological conditions, whereas reverse-mode action occurs under specific conditions, including mitochondrial membrane potential depolarization. Additionally, our analyses suggest that during physiological conditions, the NNT-mediated reaction is more sensitive to changes in redox homeostasis than changes in mitochondrial bioenergetics, as evidenced by a larger effect of the redox ratio of NADP(H) than that of NAD(H).
    Keywords:  NADH; NADPH; NNT; kinetics; mitochondria; modelling
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.001
  30. Mol Cell Proteomics. 2026 Jun 29. pii: S1535-9476(26)00113-1. [Epub ahead of print] 101617
    Platelet proteome links metabolism to reactivity in Essential Thrombocythemia.
    Xiomara Guerrero-Carreño, Sanne Smits, Alfonso Esteban Lasso, Martina Samiotaki, Virtu Calabuig Navarro, Francisco José Iborra, Frida Rantanen, Alberto Alvarez-Larrán, Anna Angona Figueras, Beatriz Bellosillo, Adolfo J Sáen Marín, Valentin García Gutiérrez, Dick Dekkers, Jeroen Demmers, Francisca Ferrer-Marín, Juan Carlos Hernández-Boluda, Antonios Matsakas, Celina Benavente Cuesta, Peter Vandenberghe, Petros Papadopoulos.
      Essential thrombocythemia (ET) is a myeloproliferative neoplasm in which JAK2, CALR, and MPL mutations are associated with distinct clinical phenotypes. Here, we analyzed the platelet proteome of ET patients by mass spectrometry, combined with functional assays, to investigate platelet activation. Compared with healthy controls, ET platelets showed altered abundance of mitochondrial and metabolic proteins, including reduced levels of tricarboxylic acid (TCA) cycle enzymes and a relative enrichment of glycolytic signatures. Acetylsalicylic acid (ASA) decreased the abundance of metabolic proteins in CALR Type1 platelets, whereas JAK2 V617F platelets showed only minor, heterogeneous increases restricted to a subset of proteins and samples. In functional assays, JAK2 V617F platelets showed aggregation responses similar to or lower than those of healthy controls, whereas untreated CALR Type2 platelets showed higher CD62P expression, indicating a more activated phenotype than the other ET groups. These findings indicate that ET platelets display mutation-associated proteomic and functional differences and suggest that an altered metabolic state may contribute to platelet reactivity.
    Keywords:  CALR; JAK2; essential thrombocythemia; platelet activation; platelet proteome
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101617
  31. medRxiv. 2026 Jun 24. pii: 2026.06.22.26356227. [Epub ahead of print]
    Deleterious mitochondrial heteroplasmy drives high-risk clonal hematopoiesis and hematological malignancy.
    Dan E Arking, Tryggvi McDonald, Wen Shi, Daniela Puiu, Jeremy V Arking, Sergiu Pasca, Yun Soo Hong, Lukasz Gondek.
      Mitochondrial DNA (mtDNA) heteroplasmy, the coexistence of multiple mtDNA variants within cells, accumulates with age and is associated with hematological malignancies and mortality. However, whether predicted deleterious heteroplasmies causally contribute to cancer or merely represent passenger mutations remains unresolved. Here, leveraging ∼36,000 first-degree relative pairs from the UK Biobank and All of Us Research Program cohorts, we deconvolute overall heteroplasmy metrics into those that are shared across family members (representing inherited variants) and those that are not (representing de novo variants) to establish a Mendelian randomization framework for assessing causality. We show that shared heteroplasmies exhibit strong purifying selection, with reduced predicted deleteriousness compared to not shared variants, and that 90% of an individual's deleterious heteroplasmy burden is somatically acquired. Critically, shared deleterious heteroplasmy burden, fixed at conception and thus temporally upstream of potential confounders, is significantly associated with hematological malignancies (RR=2.81, 95% CI 1.29-6.13), with effect sizes concordant with the not shared heteroplasmy burden. Furthermore, shared deleterious heteroplasmy specifically associates with high-risk clonal hematopoiesis of indeterminate potential (CHIP), particularly spliceosome mutations, suggesting mitochondrial dysfunction promotes clonal expansion of specific CHIP subtypes. Finally, we identify ultra-rare individual mtDNA variants associated with hematological malignancies, a hallmark of driver mutations. These findings establish mtDNA heteroplasmies, including inherited variants, as causal contributors to hematological malignancy risk and demonstrate that most disease-relevant burden is acquired during life, identifying potential opportunities for prevention and therapeutic intervention in individuals at elevated risk for hematological cancer, particularly of myeloid origin.
    DOI:  https://doi.org/10.64898/2026.06.22.26356227
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