bims-medica 2025-07-27 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–07–27
23 papers selected by
Brett Chrest, Wake Forest University

One-Carbon Metabolism Inhibition Depletes Purines and Results in Profound and Prolonged Ewing Sarcoma Growth Suppression.
Development of novel mitochondrial pyruvate carrier inhibitors for breast cancer treatment.
Exploiting genetic and environmental vulnerabilities to target DHODH in CNS tumors.
High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.
Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism.
PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.
ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential.
De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.
High-Fat Diet Driven Post-Operative Colon Cancer Recurrence is Dependent upon Genetic Susceptibility to Deoxycholic Acid.
Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence.
Isolation of tumor interstitial fluid for metabolic determinations.
Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.
Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
High altitude induces a shift from complex I to complex II in the brain mitochondria of newborn and adult mice.
Evaluating cholesterol de novo synthesis biomarkers: a systematic review and meta-analysis of cancer prognosis and clinical outcomes.
Myocardial kinetics of [11C]β-hydroxybutyrate in healthy pigs: Comparison of positron emission tomography imaging vs. arteriovenous balance methods.
Yeast Model System Showed That Heterologously Expressed Mutant Atp9 Has a Negative Impact on Cell Growth by Causing ATP Depletion.
Clonal hematopoiesis in myeloid malignancies and solid tumors.
PKM2 is a key regulator of cardiac lipid metabolism in mice.
Caprylic Acid Restores Branched-Chain Amino Acid Metabolism in a Mouse Cachexia Model.
Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning.
TCA cycle mode switch determines the fate of pirtobrutinib-tolerant persister cells in mantle cell lymphoma.

Cancer Res Commun. 2025 Jul 23.

One-Carbon Metabolism Inhibition Depletes Purines and Results in Profound and Prolonged Ewing Sarcoma Growth Suppression.

Sara Zirpoli, Noah Copperman, Shrey Patel, Alexander Forrest, Zhanjun Hou, Larry H Matherly, David M Loeb, Antonio Di Cristofano.

Ewing sarcoma (EWS) is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long term survival rates less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between EWS and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate (THF)-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in EWS patients. We show that both genetic and pharmacological inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2 (SHMT2), leads to substantial inhibition of EWS cell proliferation and colony-forming ability, and that this effect is primarily caused by depletion of glycine and one-carbon units required for synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor Pralatrexate, similarly yields a profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of SHMT2 dramatically impairs tumor growth in a xenograft model of EWS. Together, these data establish dependence on one-carbon metabolism as a novel and targetable vulnerability of EWS cells, which can be exploited for therapy.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0218
J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02336-1. [Epub ahead of print] 110486

Development of novel mitochondrial pyruvate carrier inhibitors for breast cancer treatment.

Tanner J Schumacher, Zachary S Gardner, Jon Rumbley, Conor T Ronayne, Venkatram R Mereddy.

  Reprogrammed metabolism of cancer cells offers a unique target for pharmacological intervention. The mitochondrial pyruvate carrier (MPC) plays important roles in cancer progression by transporting cytosolic pyruvate into the mitochondria for use in the TCA cycle. In the current study, a series of novel fluoro-substituted aminocarboxycoumarin derivatives have been evaluated for their mitochondrial pyruvate carrier (MPC) inhibition properties. Our studies indicate that the aminocarboxycoumarin template elicits potent MPC inhibitory characteristics, and specifically, structure activity relationship studies show that the N-methyl-N-benzyl structural template provides the optimal inhibitory capacity. Further respiratory experiments demonstrate that candidate compounds specifically inhibit pyruvate driven respiration without substantially affecting other metabolic fuels, consistent with MPC inhibition. Further, computational inhibitor docking studies illustrate that aminocarboxycoumarin binding characteristics are nearly identical to that of classical MPC inhibitor UK5099 bound to human MPC, recently determined by cryoEM. The lead candidate C5 elicits cancer cell proliferation inhibition specifically in monocarboxylate transporter 1 (MCT1) expressing murine breast cancer cells 4T1 and 67NR, consistent with its ability to accumulate intracellular lactate. In vivo tumor growth studies illustrate that C5 significantly reduces the tumor burden in two syngeneic murine tumor models with 4T1 and 67NR cells. These studies provide novel MPC inhibitors with potential for anticancer applications in MCT1 expressing breast cancer tumor models.

Keywords:  aminocarboxycoumarin; breast cancer; mitochondrial pyruvate carrier; tumor metabolism

DOI:  https://doi.org/10.1016/j.jbc.2025.110486
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf149

Exploiting genetic and environmental vulnerabilities to target DHODH in CNS tumors.

Eli E Bar, Julie-Aurore Losman.

  This review explores innovative therapeutic strategies for treating central nervous system (CNS) tumors by targeting their unique metabolic dependencies. This approach marks a significant departure from traditional cytotoxic treatments, focusing instead on the metabolic vulnerabilities created by the tumor's microenvironment and genetic profile. A key area of interest is the de novo pyrimidine synthesis pathway, which is crucial for DNA and RNA synthesis, DNA repair, and protein glycosylation. We highlight the potential of dihydroorotate dehydrogenase (DHODH) inhibitors, which have shown promising anti-tumor activity in preclinical models. The blood-brain barrier, while a challenge for drug delivery, may enhance the efficacy of these inhibitors by maintaining a unique metabolic environment in the brain. Specific brain tumors, such as glioblastoma multiforme, MYC-amplified medulloblastoma, and IDH mutant gliomas, exhibit heightened sensitivity to DHODH inhibition. We suggest that the unique metabolic environment of the brain could make DHODH a more effective therapeutic target for brain tumors compared to other cancer types. Despite the speculative nature of these findings, the compelling preclinical data warrant further investigation into brain-penetrant DHODH inhibitors for CNS malignancies.

Keywords:  CNS tumors; DHODH inhibitors; brain tumors; metabolic vulnerabilities; pyrimidine synthesis

DOI:  https://doi.org/10.1093/noajnl/vdaf149
Science. 2025 Jul 24. eadx3800

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

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

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

DOI: https://doi.org/10.1126/science.adx3800
Nat Commun. 2025 Jul 21. 16(1): 6700

Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.

Yingyuan Sun, Yaru Wang, Zheng Xing, Dongyu Li, Rong Wang, Baozhi Chen, Ning Zhou, Alyssa Ayala, Benjamin P Tu, Xiaofeng Qi.

The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we present the cryogenic electron microscopy (cryo-EM) structures of the human MPC1-2 complex in the mitochondrial intermembrane space (IMS)-open state and the inhibitor-bound in the mitochondrial matrix-open state. Structural analysis shows that the transport channel of MPC is formed by the interaction of transmembrane helix (TM) 1 and TM2 of MPC1 with TM2 and TM1 of MPC2, respectively. UK5099, a potent MPC inhibitor, shares the same binding site with pyruvate at the matrix side of the transport channel, stabilizing MPC in its matrix-open conformation. Notably, a functional W82F mutation in MPC2 leads to the complex in an IMS-open conformation. Structural comparisons across different conformations, combined with yeast rescue assays, reveal the mechanisms of substrate binding and asymmetric conformational changes in MPC during pyruvate transport across the inner mitochondrial membrane (IMM) as well as the inhibitory mechanisms of MPC inhibitors.

DOI: https://doi.org/10.1038/s41467-025-61939-z
Cell Chem Biol. 2025 Jul 17. pii: S2451-9456(25)00201-6. [Epub ahead of print]32(7): 902-904

Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism.

Riley J Wedan, Sara M Nowinski.

Mitochondrial NADPH is abundant, but the reason why was uncertain. In a study published in Nature Cell Biology, Kim et al.1 identified an important role of NADK2-derived mitochondrial NADPH in mitochondrial fatty acid synthesis (mtFAS) through direct quantification of the products built by mtFAS. This work opens the door to understanding how NADK2, mitochondrial NADPH, and mtFAS regulate mitochondrial function.

DOI: https://doi.org/10.1016/j.chembiol.2025.06.006
Clin Transl Med. 2025 Jul;15(7): e70404

PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.

Swagat Pradhan, Takayuki Mito, Nahid A Khan, Sofiia Olander, Aleksandra Zhaivoron, Thomas G McWilliams, Anu Suomalainen.

   BACKGROUND: Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.
METHODS: We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.
RESULTS: In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.
CONCLUSIONS: Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.

Keywords:  integrated stress response; mitochondrial disease; mitochondrial myopathy; nutrient signaling; progressive external ophthalmoplegia; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1002/ctm2.70404
Metabolites. 2025 Jul 07. pii: 461. [Epub ahead of print]15(7):

ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential.

Akane Sawai, Takeo Taniguchi, Kohsuke Noguchi, Taisuke Seike, Nobuyuki Okahashi, Masak Takaine, Fumio Matsuda.

  Eukaryotic cells generate ATP primarily via oxidative and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often use both pathways as aerobic glycolysis, even in the presence of oxygen. However, its role in cell survival remains poorly understood. Objectives: In this study, aerobic glycolysis was compared between the Warburg effect in breast cancer cells (MCF7) and the Crabtree effect in a laboratory strain of Saccharomyces cerevisiae (S288C). Methods: The metabolic adaptations of MCF7 and S288C cells were compared following treatment with electron transport chain inhibitors, including FCCP, antimycin A, and oligomycin. Results: MCF7 and S288C cells exhibited strikingly similar metabolic rewiring toward substrate-level phosphorylation upon inhibitor treatment, suggesting that mitochondrial oxidative phosphorylation and cytosolic substrate-level phosphorylation communicate through a common mechanism. Measurement of mitochondrial membrane potential (MMP) and ATP concentrations further indicated that cytosolic ATP was transported into the mitochondria under conditions of reduced electron transport chain activity. This ATP was likely utilized in the reverse mode of H+/ATPase to maintain MMP, which contributed to the avoidance of programmed cell death. Conclusions: These results suggest that the ATP supply to mitochondria plays a conserved role in aerobic glycolysis in yeast and mammalian cancer cells. This mechanism likely contributes to cell survival under conditions of fluctuating oxygen availability.

Keywords:  Saccharomyces cerevisiae; aerobic glycolysis; breast cancer cells; metabolic rewiring; mitochondrial membrane potential; programmed cell death; reverse mode of H+/ATPase

DOI:  https://doi.org/10.3390/metabo15070461
EMBO Mol Med. 2025 Jul 24.

De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.

Duo Xu, Yanyun Gao, Shengchen Liu, Shiyuan Yin, Tong Hu, Haibin Deng, Tuo Zhang, Balazs Hegedüs, Thomas M Marti, Patrick Dorn, Shun-Qing Liang, Ralph A Schmid, Ren-Wang Peng, Yongqian Shu.

  Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.

Keywords:  De Novo Pyrimidine Synthesis; Metabolic Diversity; Neurofibromin 2 (NF2); Pleural Mesothelioma (PM); Synthetic Lethality

DOI:  https://doi.org/10.1038/s44321-025-00278-4
Cancer Lett. 2025 Jul 22. pii: S0304-3835(25)00512-9. [Epub ahead of print] 217943

High-Fat Diet Driven Post-Operative Colon Cancer Recurrence is Dependent upon Genetic Susceptibility to Deoxycholic Acid.

Ryan Morgan, Mohammad Amin Bayat Tork, Zitong Lin, Claire Wild, Luke R Frietze, Sihao Huang, Meejeon Roh, Andrea Olivas, Colin W Steele, Tao Pan, Benjamin D Shogan.

  The development of postoperative recurrent tumors or metastasis following surgical resection of colorectal cancer remains a major obstacle to colon cancer cure. While a high-fat diet is a risk factor for the development of recurrence, studies that examine the molecular mechanism by which diet drives postoperative tumors have been lacking. Here, using a murine model that mimics postoperative tumor formation, we show that the tumorigenic influence of a high-fat diet strongly depends on the genetic backbone of the primary tumor cells. We identify deoxycholic acid as a major contributor to the promotion of tumor recurrence only when the primary cancer cell has an APC-driving mutation. We investigate the deoxycholic acid effect on the proliferation of organoids and identify the organoid response to deoxycholic acid treatment, including the transcriptome expression and transfer RNA abundance, modification, and charging. The integrated analysis of mRNA and tRNA sequencing results reveals enhanced decoding of codons in proliferation-promoting genes. Our results provide a new understanding of how both diet and tumor genetics together lead to postoperative colorectal cancer recurrence.

Keywords:  Bile Acid; Cancer Genetics; Colorectal Cancer; High-Fat Diet; Protein synthesis; Recurrence

DOI:  https://doi.org/10.1016/j.canlet.2025.217943
Cell Rep. 2025 Jul 17. pii: S2211-1247(25)00797-1. [Epub ahead of print]44(8): 116026

Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence.

Sung-Jen Wei, Joseph Schell, Wei Qian, Martin Silguero, Agne Baseviciene, Wan Hsi Chen, Rolando Trevino, E Sandra Chocron, Meredith M Ogle, Mahboubeh Varmazyad, Gloria M Martinez, Diego Cruz, Brandon Lorenzana, Felix F Dong, Haiyan Jiang, Alia Nazarullah, Robert A Beardsley, Kumar Sharma, Jenny Chang, Erin Munkácsy, Nobuo Horikoshi, David Gius.

  While a ketogenic diet (KD) can improve certain health parameters, evidence from murine and clinical studies suggests that these effects may be dependent on multiple variables. One understudied variable is the role of sex in the response to a KD. Here, we show that a KD-induced increase in p53, p21, and cellular senescence is only observed in male mice, except when they are given estrogen, and in female mice administered tamoxifen. Male, but not female, mice on a KD exhibit an increase in markers of oxidative stress and acetylation of mitochondrial proteins, including manganese superoxide dismutase (MnSOD). Notably, the increases in p53, p21, cellular senescence, MnSOD acetylation, and oxidative stress in male mice on a KD were all prevented by estrogen treatment. In addition, several established antioxidants and an MnSOD chemical mimetic also prevented KD-induced cellular senescence. These results suggest sex specificity in the effects of a KD, with important clinical implications.

Keywords:  CP: Metabolism; MnSOD; SOD2; acetylation; antioxidant; cellular senescence; estrogen; ketogenic diet; oxidative stress; sex difference

DOI:  https://doi.org/10.1016/j.celrep.2025.116026
Methods Cell Biol. 2025 ;pii: S0091-679X(24)00241-3. [Epub ahead of print]196 177-192

Isolation of tumor interstitial fluid for metabolic determinations.

Ainhoa Ruiz-Iglesias, Ángel García-Aldea, Elena Nonnast, Rosa M Peregil, Santos Mañes.

  Neoplastic cells are characterized by alterations in metabolic pathways, typically leading to an aberrant use of glycolysis even under aerobic conditions - a phenomenon known as the Warburg effect. One consequence of this metabolic shift is the production of lactate, an oncometabolite often found at elevated levels in tumors. Lactate not only fuels the growth of cancer cells but also promotes angiogenesis, immune escape, and metastasis, thereby contributing to tumor progression and resistance to therapy. This highlights the importance of lactate in cancer metabolism and underscores the need for methods to measure it. In this study, we describe various centrifugation and elution protocols to isolate interstitial fluid and measure lactate in experimental tumors. These tumors were generated in immunocompetent mice using the MC38 colon cancer cell line. We propose that, with minor modifications, the methods here described could be successfully adapted for use with tumors originating from other human or murine cell lines. Furthermore, these methods could potentially enable the detection of other oncometabolites in the tumor microenvironment, which could have significant implications for both basic research and therapeutic strategies.

Keywords:  Extracellular space; Glycolysis; Lactate; Oncometabolites; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.mcb.2024.11.004
J Cell Physiol. 2025 Jul;240(7): e70066

Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.

Adam Chatoff, Daniel S Kantner, Nathaniel W Snyder, Lori Rink.

  Succinate dehydrogenase (SDH) is both Complex II in the electron transport chain (ETC) and a key metabolic enzyme in the tricarboxylic acid cycle. SDH is a heterotetrameric enzyme consisting of four subunits SDHA, SDHB, SDHC, and SDHD, all encoded in the nuclear genome. In addition, the SDH complex requires two assembly factors, SDHAF1 and SDHAF2, which are required for assembly of SDHA and SDHB onto the inner mitochondrial-embedded subunits SDHC and SDHD. Once assembled, SDH catalyzes the conversion of succinate to fumarate coupled to the reduction of ubiquinone to ubiquinol via FAD/FADH2 and ultimately the generation of ATP via ATP synthase through a functioning ETC. Given the unique dual metabolic role of SDH, loss of activity results in major metabolic rewiring, potentially uncovering metabolic vulnerabilities that could be targeted for pharmacological manipulation in disease states. SDH is a tumor suppressor and SDH-loss is a driver of oncogenesis for cancers including pheochromocytomas, paragangliomas, gastrointestinal stromal tumors, and clear cell renal cell carcinomas. SDH deficiency also plays a role in the pathogenesis in non-neoplastic diseases, including Leigh syndrome and other neurometabolic disorders. Considering the implications of SDH function in both normal physiology and disease, understanding SDH function has fundamental and translational implications. This review seeks to summarize SDH deficiency, focusing on the role SDH plays in metabolism, the metabolic consequences of SDH deficiency, the proteomic consequences of SDH loss, thereby highlight potential therapeutic vulnerabilities in SDH-deficient cells.

Keywords:  Complex II; clear cell renal cell carcinoma; electron transport chain; gastrointestinal stromal tumors; leigh syndrome; pheochromocytomas/paragangliomas; succinate dehydrogenase; tricarboxylic acid cycle

DOI:  https://doi.org/10.1002/jcp.70066
Res Sq. 2025 Jul 15. pii: rs.3.rs-7042684. [Epub ahead of print]

Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.

Tim Heden, Melina Mancini, Cameron McCall, Robert Noland, Wagner Dontas.

Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.

DOI: https://doi.org/10.21203/rs.3.rs-7042684/v1
J Exp Biol. 2025 Jul 22. pii: jeb.250422. [Epub ahead of print]

High altitude induces a shift from complex I to complex II in the brain mitochondria of newborn and adult mice.

Maud Demarest, Fernanda Aliaga-Raduan, Christian Arias-Reyes, Marcelino Gonzales, Edith M Schneider Gasser, Jorge Soliz, Vincent Joseph.

  Species living at high altitude (HA) often exhibit optimized oxygen utilization at adulthood, however, the plasticity of metabolic pathways during postnatal development remains unclear. Because mice, but not rats are commonly found at HA, we investigated mitochondrial oxygen consumption rates (OCR) in the cerebral cortex across postnatal development and at adulthood at sea level (SL, Quebec, Canada) under normoxia or hypoxia (13.5% O2), and at HA (La Paz, Bolivia, 3600m) after 50 generations of residency. At postnatal day 7 (P7), 14 (P14), 21 (P21) and in adults (P60-90), fresh tissue samples were used to assess mitochondrial OCR under states of proton LEAK (OCRLEAK(N)) and oxidative phosphorylation (OXPHOS) using substrates for complex I (N pathway - OCRN), complex II (S pathway - OCRS), and complexes I+II (NS pathways - OCRNS). Our results showed 1) At HA, rats exhibit higher OCR at P7, P14, and at adulthood compared to their SL counterparts, and 2) HA residency induces a shift from the N pathway to the S pathway at all ages in mice. Finally, these responses were absent in SL animals exposed to postnatal hypoxia, highlighting the importance to study HA-living species. These findings emphasize key metabolic shifts, with implications for understanding responses to hypoxia in species showing divergent success at HA.

Keywords:  Brain cortex; High altitude; Mitochondria; Postnatal development; Rodents.

DOI:  https://doi.org/10.1242/jeb.250422
BMC Cancer. 2025 Jul 24. 25(1): 1208

Evaluating cholesterol de novo synthesis biomarkers: a systematic review and meta-analysis of cancer prognosis and clinical outcomes.

Eman Taha Osman Ali, Nouh Saad Mohamed, Emmanuel Edwar Siddig, Mai Abdul Rahman Mohammed Masri.

   BACKGROUND: While systemic cholesterol levels are generally associated with cancer risk and progression in various tumors, studies of cholesterol de novo synthesis by cancer cells in various tumor settings were limited. This meta-analysis aims to provide a comprehensive understanding of the role of cholesterol de novo synthesis pathway in cancer, focusing on key markers related with this metabolic reprogramming in cancer tissues.
METHODS: A systematic review and meta-analysis were conducted using data from multiple databases, including PubMed, EMBASE, and Cochrane Library. Studies were included if they examined the expression of cholesterol synthesis markers in solid tumors and reported hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS), or recurrence-free survival (RFS). Data extraction and quality assessment were performed by two independent researchers. Pooled HRs and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models.
RESULTS: Twenty studies involving 4,343 patients were included. High expression of cholesterol metabolism and esterification markers was significantly associated with worse prognosis in overall survival (OS: HR 2.38, 95% CI 1.97-2.87, p < 0.0001) and disease-free survival (DFS: HR 2.44, 95% CI 1.69-3.51, p < 0.0001). However, no significant association was observed for recurrence-free survival (RFS: HR 0.95, 95% CI 0.28-3.24, p = 0.9), with substantial heterogeneity (I² = 89%). Elevated expressions of enzymes correlated with more aggressive tumor characteristics, including lymph node metastasis and larger tumor size.
CONCLUSIONS: High expression of cholesterol metabolism markers in solid tumors is linked to poorer survival and aggressive disease features. Among these, SQLE and SOAT1 stand out as the most robust predictors and potential therapeutic targets, emphasizing the critical role of cholesterol metabolic reprogramming in cancer progression.

Keywords:  Cholesterol synthesis; Metabolic reprogramming; Prognostic markers; Solid tumors

DOI:  https://doi.org/10.1186/s12885-025-14633-8
Nucl Med Biol. 2025 Jul 19. pii: S0969-8051(25)00062-9. [Epub ahead of print]148-149 109053

Myocardial kinetics of [11C]β-hydroxybutyrate in healthy pigs: Comparison of positron emission tomography imaging vs. arteriovenous balance methods.

Mette Louise Gram Kjærulff, Mie Ringgaard Dollerup, Aage Kristian Olsen Alstrup, Nigopan Gopalasingam, Lars Poulsen Tolbod, Ole Lajord Munk, Lars Christian Gormsen, Erik Nguyen Nielsen.

   BACKGROUND: Accurate assessment of myocardial ketone uptake and oxidation is essential for understanding cardiac metabolism. This study aims to validate positron emission tomography (PET) imaging as a non-invasive method for quantifying myocardial ketone metabolism, using the invasive arteriovenous (AV) balance method as reference.
METHODS: Myocardial ketone uptake was assessed using [11C]β-hydroxybutyrate ([11C]OHB) PET imaging in a porcine model. Blood samples were collected from arterial and coronary sinus sites, and kinetic parameters were calculated to evaluate the relationship between PET-derived and AV balance-derived measurements. Myocardial perfusion was assessed using [15O]water PET scans. The procedures were conducted during a graded infusion of ketone salt.
RESULTS: A strong positive correlation between PET-derived and AV balance-derived measurements of myocardial OHB uptake was observed (r = 0.97; p < 0.0001), indicating that [11C]OHB PET imaging can reliably assess myocardial ketone metabolism. The correlation between the rate constant k2 and the [11C]CO2 fraction in coronary sinus blood was near-significant, moderate and positive (r = 0.71; p = 0.08), suggesting potential for k2 as a marker of myocardial ketone oxidation.
CONCLUSION: [11C]OHB PET imaging is a non-invasive tool for assessing myocardial ketone metabolism, providing valuable insights into ketone uptake and oxidation in vivo, with potential for extrapolation to human data.

Keywords:  Arteriovenous balance; Beta-hydroxybutyrate; Ketone metabolism; Positron emission tomography; Tracer kinetics

DOI:  https://doi.org/10.1016/j.nucmedbio.2025.109053
Biol Pharm Bull. 2025 ;48(7): 1070-1078

Yeast Model System Showed That Heterologously Expressed Mutant Atp9 Has a Negative Impact on Cell Growth by Causing ATP Depletion.

Takeshi Ito, Kenta Terai, Hidetaka Kosako, Yasuo Shinohara.

  Depletion of ATP is a promising strategy for controlling or killing pests, pathogens, and cancer cells. In eukaryotic cells, mitochondrial F1Fo-ATP synthase plays a central role in oxidative phosphorylation and has therefore been considered as a suitable target for this strategy against pests, pathogenic fungi, and some cancer cells. Membrane-embedded Atp9 (subunit c) is a crucial subunit of the F1Fo-ATP synthase ring oligomer (c-ring) that, together with Atp6, directly mediates proton translocation, which drives ATP synthesis. Substitution of the proton-binding residue of Atp9, i.e., glutamic acid, with glutamine abrogates ATP synthase function. Importantly, a single mutated Atp9 subunit in the c-ring is sufficient for inactivation. We hypothesized, therefore, that heterologous expression of mutant Atp9 in cells would result in the assembly of a nonfunctional complex and, consequently, depletion of ATP. Using a yeast model system, we verified the hypothesis through a series of biochemical analyses and thus validated this approach as a strategy for depleting intracellular ATP in target cells and organisms.

Keywords:  ATP synthase; inactivation; mutant; subunit c; yeast model system

DOI:  https://doi.org/10.1248/bpb.b24-00787
Nat Cancer. 2025 Jul 18.

Clonal hematopoiesis in myeloid malignancies and solid tumors.

Xiurong Cai, Robert L Bowman, Jennifer J Trowbridge.

Clonal hematopoiesis (CH) results from clonal expansion of hematopoietic stem cells. In specific contexts, CH is linked with an increased risk of blood cancers and mortality in individuals with solid tumors. To understand the mechanisms and clinical relevance of this association, it is crucial to explore the reciprocal relationship between CH and cancer. Here, we provide an updated summary of the mechanisms known to drive CH in blood cancers and solid tumors. In addition, we review proposed strategies to intercept CH and examine their impact on solid tumor-directed therapies, including immunostimulatory therapies.

DOI: https://doi.org/10.1038/s43018-025-01014-0
Mitochondrion. 2025 Jul 22. pii: S1567-7249(25)00067-4. [Epub ahead of print] 102070

PKM2 is a key regulator of cardiac lipid metabolism in mice.

Katie C Y Lee, Allison L Williams, Anastasia Fujimoto, Mariana Gerschenson, Connor Schuller, Noemi Polgar, Naghum Alfulaij, Briana K Shimada, Lucia A Seale, Ralph V Shohet.

  Deficiencies in lipid metabolism can have severe consequences for cardiac function. We previously showed that regulating glucose flux by pyruvate kinase 2 (PKM2) affects lipid synthesis and droplet abundance in cardiomyocytes. This study aims to examine how PKM2 regulates lipid metabolism in the heart. Indirect calorimetry suggested similar whole-body metabolism of PKM2 knockout (PKM2-/-) and control (PKM2fl/fl) young mice (2-3 months), but indicated that lipids were utilized to a greater degree in aged (1-year) PKM2-/- mice compared to controls. Metabolic chamber studies also revealed an overall negative energy balance that contributed to reduced exercise tolerance in aged PKM2-/- mice. Metabolomics showed substantially lower carnitine levels in PKM2-/- cardiomyocyte fractions (CM), alongside increased circulating and cardiac dicarboxylic acids, as well as reduced mitochondrial palmitate oxidation in PKM2-/- CM. We also noted a sex-specific difference in which female PKM2-/- mice exhibited greater high-fat diet (HFD)-induced hyperglycemia and weight gain compared to PKM2fl/fl females, while male PKM2-/- mice fed an HFD were comparatively leaner than their PKM2fl/fl counterparts. PKM2-/- mice have aberrations in lipid metabolism that worsen with age, shifting whole-body metabolism towards a preference for lipid utilization. This may lead to a decline in aerobic capacity during exercise in aged PKM2-/- mice. PKM2-/- CM also display compromised mitochondrial lipid metabolism due to carnitine deficiency. Challenging PKM2-/- mice with a HFD revealed sex-dependent differences in glycemic control and body weight. Our results indicate a role for PKM2 in sustaining the homeostasis of cardiac and whole-body lipid metabolism that contributes to overall physiological fitness.

Keywords:  Cardiomyocyte; Fatty acid oxidation; Metabolism

DOI:  https://doi.org/10.1016/j.mito.2025.102070
Curr Issues Mol Biol. 2025 May 01. pii: 325. [Epub ahead of print]47(5):

Caprylic Acid Restores Branched-Chain Amino Acid Metabolism in a Mouse Cachexia Model.

Isao Kawahara, Rina Fujiwara-Tani, Takuya Mori, Shota Nukaga, Ryoichi Nishida, Yoshihiro Miyagawa, Kei Goto, Hitoshi Ohmori, Kiyomu Fujii, Yi Luo, Takamitsu Sasaki, Chie Nakashima, Ruiko Ogata, Hiroki Kuniyasu.

  Cancer-associated sarcopenia is closely linked to the prognosis of cancer patients, making its management a critical aspect of cancer treatment. Branched-chain amino acids (BCAAs) are known to promote skeletal muscle growth in healthy individuals; however, their efficacy in cancer patients remains controversial. In this study, we investigated the effects of BCAAs on cancer-associated sarcopenia to identify the underlying mechanisms that may suppress their effectiveness. In both a mouse cachexia model and an in vitro cachexia model, BCAAs did not significantly reduce oxidative stress, improve oxidative phosphorylation, suppress cytokine production, or enhance muscle mass and maturation, as observed in non-cancer-bearing models. Furthermore, treatment with 5-fluorouracil exacerbated sarcopenia in the mouse cachexia model, independent of tumor weight reduction, and this deterioration was not ameliorated by a BCAA-supplemented diet. The ineffectiveness of BCAAs was attributed to impaired BCAA catabolism, characterized by the decreased expression of branched-chain α-ketoacid dehydrogenase (BCKD) and increased levels of its inactive phosphorylated form, which were driven by elevated expression of BCKD kinase. These metabolic alterations were induced by high-mobility group box-1 (HMGB1). Notably, caprylic acid reversed these impairments in BCAA metabolism, thereby restoring BCAA efficacy. Our findings suggest that enhancing BCAA metabolism may improve their therapeutic potential in the treatment of cancer-associated sarcopenia.

Keywords:  branched-chain amino acids; branched-chain α-ketoacid dehydrogenase; cancer sarcopenia; caprylic acid

DOI:  https://doi.org/10.3390/cimb47050325
Cell Mol Gastroenterol Hepatol. 2025 Jul 19. pii: S2352-345X(25)00134-1. [Epub ahead of print] 101593

Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning.

Raja Gopal Reddy Mooli, Yerin Han, Ericka J Fiorenza, Karthik Balakrishnan, Jitendra Singh Kanshana, Suchita Kumar, Fiona M Bello, Anoop R Nallanagulagari, Shreya Karra, Junyan Tao, Evan R Delgado, Lihong Teng, Alison B Kohan, Aatur D Singhi, Michael Jurczak, Sadeesh K Ramakrishnan.

   BACKGROUND AND AIMS: Liver-derived ketone bodies play an essential in energy homeostasis during fasting by supplying fuel to both the brain and peripheral tissues. Ketogenesis also helps to remove excess acetyl-CoA generated from fatty acid oxidation, thereby protecting against diet-induced hepatic steatosis. Despite this, the role of ketogenesis in fasting-associated hepatocellular lipid metabolism has not been thoroughly investigated.
METHODS: We utilized mice with liver-specific knockout of HMGCS2 mice to determine how ACSL1-mediated esterification contributes to fasting-induced steatosis and performed biochemical assays, gene expression profiling, Western blotting, and histological analyses. We further investigated the association between HMGCS2 expression, lipid re-esterification, and steatosis using human primary hepatocytes and liver samples from MASH patients.
RESULTS: We show that ketogenic insufficiency, achieved through disrupting hepatic HMGCS2, worsens liver steatosis in both fasted chow-fed and high-fat-fed mice. Our findings indicate that hepatic steatosis arises from increased fatty acid partitioning to the endoplasmic reticulum (ER) for re-esterification, a process mediated by acyl-CoA synthetase long-chain family member 1 (ACSL1). Mechanistically, the accumulation of acetyl-CoA due to impaired hepatic ketogenesis drives the elevated translocation of ACSL1 to the ER. Furthermore, our study reveals heightened ER-localized ACSL1 and lipid re-esterification in human MASH cases exhibiting impaired hepatic ketogenesis. We also demonstrate that L-carnitine, which buffers excess acetyl-CoA, reduces ER-associated ACSL1 and alleviates hepatic steatosis.
CONCLUSION: Hepatic ketogenesis plays a crucial role in maintaining intracellular acetyl-CoA balance, regulating lipid partitioning, and preventing the development of fasting-induced hepatic steatosis.

Keywords:  Ketogenesis; fasting; fatty liver; hepatic steatosis; lipid esterification

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101593
Blood. 2025 Jul 23. pii: blood.2024026919. [Epub ahead of print]

TCA cycle mode switch determines the fate of pirtobrutinib-tolerant persister cells in mantle cell lymphoma.

Wei Wang, Qingsong Cai, Yang Liu, Lei Nie, Heng-Huan Lee, Fangfang Yan, Yue Fei, Yixin Yao, Yijing Li, Lin Tan, Philip L Lorenzi, Ying-Nai Wang, Jun Yao, Zhihong Chen, Joseph McIntosh, Cheng-Tai Yu, Preetesh Jain, Vivian Jiang, Jovanny Vargas, Xiaolin Li, Tianci Zhang, Shaoying Li, David Santos, Selvi Thirumurthi, Erin Heather Seeley, Lukas Mikolaj Simon, Christopher R Flowers, Chi Young Ok, Michael L Wang.

Bruton's tyrosine kinase inhibitors (BTKi) and cell therapy have successfully been used to treat mantle cell lymphoma (MCL); however, therapy resistance inevitably emerges. Cancer cells can progressively develop stable resistance by traversing through a transient drug-tolerant persister (DTP) state. The mechanisms enabling DTP cells to reversibly adapt to therapies and evolve to acquire heterogeneity remain poorly understood, and characterizing DTP cells in MCL continues to pose a challenge for clinic translation. Here using pirtobrutinib, a recently FDA-approved non-covalent BTKi, we identified pirtobrutinib-tolerant persister cells exhibiting morphological variability by presenting a unique population of enlarged cells (Giant cells) with reversible fate transitions. During treatment, Giant cells enter a non-proliferative, dedifferentiated state, addicted to an activated cytosolic tricarboxylic acid (TCA) cycle coupled with the malate-aspartate shuttle to engage in biosynthesis. Upon drug removal, the TCA cycle shifts to oxidative catabolism, promoting Giant cells to differentiate into regular-sized cells. Throughout the transition, acetyl-CoA modulates cell fate by fine-tuning stemness. Our biphasic model demonstrates that the metabolic switch governs the phenotypic plasticity of DTP cells in MCL, resulting a dynamic presence of DTP cells across various developmental states in response to systemic therapies. Targeting Giant cells prior to their differentiation offers a promising strategy to overcoming therapy resistance in MCL.

DOI: https://doi.org/10.1182/blood.2024026919