bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2025–08–24
six papers selected by
Brett Chrest, Wake Forest University



  1. bioRxiv. 2025 Aug 12. pii: 2025.08.10.669191. [Epub ahead of print]
      The mevalonate pathway produces sterols and isoprenoids that support cancer cell growth, yet its broader metabolic functions remain incompletely defined. Here, we show that this pathway sustains amino acid biosynthesis by promoting mitochondrial NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impairs oxidative phosphorylation, lowers the NAD⁺/NADH ratio, and suppresses de novo serine and aspartate synthesis, thereby activating the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limits purine and pyrimidine nucleotide production. Expression of the bacterial NADH oxidase LbNOX or the alternative oxidase AOX restores NAD⁺ levels and rescues statin-induced growth inhibition. These findings suggest that impaired NAD⁺ regeneration is a key mechanism contributing to the anti-proliferative activity of statins, linking the mevalonate pathway to mitochondrial electron transport- dependent control of amino acid metabolism.
    Significance: This study identifies the mevalonate pathway as a regulator of amino acid biosynthesis through mitochondrial electron transport-dependent NAD⁺ regeneration and reveals redox disruption as a key mechanism contributing to the anti-proliferative effects of statins.
    DOI:  https://doi.org/10.1101/2025.08.10.669191
  2. Future Med Chem. 2025 Aug 17. 1-14
      "Glutamine addiction" is a hallmark metabolic feature of many cancer cells. Driven by the "Warburg effect," tumor cells exhibit an increased reliance on glutamine uptake and metabolism to sustain rapid proliferation and survival. As such, precise modulation of glutamine metabolic pathways has emerged as a promising strategy for cancer therapy. Alanine - serine - cysteine transporter 2 (ASCT2), a key glutamine transporter, is frequently overexpressed in a variety of cancer cells, facilitating elevated glutamine influx to meet the metabolic demands of malignant cells. Accordingly, pharmacological inhibition of ASCT2 represents an attractive approach to reduce intracellular glutamine availability and suppress tumor cell growth. This review provides a comprehensive overview of ASCT2, including its structural and functional characteristics, recent progress in small-molecule inhibitor development, and the potential for future therapeutic applications.
    Keywords:  ASCT2; Glutamine metabolism; drug discovery; future perspectives; small-molecule inhibitors
    DOI:  https://doi.org/10.1080/17568919.2025.2546777
  3. Commun Biol. 2025 Aug 19. 8(1): 1249
      Cardiovascular diseases are often associated with impairment in mitochondrial function. However, existing respirometry measuring mitochondrial function are limited by the necessity of fresh tissue samples. This study develops a method with tailored substrate-inhibitor titration (TSIT) of mitochondrial electron transport complexes (ETC) to measure mitochondrial function in frozen cardiac samples using high-resolution respirometry. Briefly, acetyl-CoA is added to fuel the tricarboxylic acid (TCA) cycle for NADH production, enabling complex I (CI)-linked respiratory assessment. NADH is then added to measure maximum CI-linked respiratory capacity, followed by rotenone and succinate to assess complex II (CII)-linked respiratory capacity. TSIT detects mitochondrial functional differences between frozen atrial and ventricular tissue, with comparable results as measured in fresh samples. It also detects cardiac mitochondrial dysfunction across various (patho)physiological mouse models and in human frozen cardiac samples, highlighting its clinical potential. Furthermore, we provides the first evidence for SC formation between the ETC-SCs and the TCA cycle metabolon using blue native electrophoresis, underpinning why TSIT is feasible in frozen tissue. In conclusion, we establish a novel, robust, sensitive and translational method (TSIT) for assessing mitochondrial (dys)function in frozen cardiac samples from various species, enabling flexible analysis of mitochondrial function in both laboratory and clinical settings.
    DOI:  https://doi.org/10.1038/s42003-025-08608-5
  4. Biochem J. 2025 Aug 18. pii: BCJ20253237. [Epub ahead of print]482(16):
      Mitochondria are multifaceted organelles that support numerous cellular metabolic pathways, including the biosynthesis of nucleotides required for cell growth and proliferation. Owing to an ancient endosymbiotic origin, mitochondria contain multiple copies of their own genome and therefore demand sufficient (deoxy)nucleotides in the mitochondrial matrix for DNA replication and transcription into RNA. Disturbed mitochondrial deoxynucleotide homeostasis can lead to a decline in mitochondrial DNA abundance and integrity, causing mitochondrial diseases with diverse and severe symptoms. Mitochondrial nucleotides are not only required for nucleic acid synthesis but also for bioenergetics and mitochondrial enzymatic activity. This review first explores how mitochondria supply energy and anabolic precursors for nucleotide synthesis and how the mitochondrial network influences the spatial control of cellular nucleotide metabolism. Then follows an in-depth discussion of the mechanisms that supply mitochondria with sufficient and balanced nucleotides and why these mechanisms are relevant to human mitochondrial disease. Lastly, the review highlights the emergence of regulated mitochondrial nucleotide supply in physiological processes including innate immunity and discusses the implications of dysregulated mitochondrial and cytosolic nucleotide homeostasis in pathophysiology.
    Keywords:  metabolism; mitochondria; mitochondrial disease; nucleotide salvage; nucleotide transport; nucleotides
    DOI:  https://doi.org/10.1042/10.1042/BCJ20253237
  5. PeerJ. 2025 ;13 e19879
       Background: High-resolution respirometry is commonly used in skeletal muscle research and exercise science to measure mitochondrial respiratory function in both permeabilized muscle fibers and isolated mitochondria. Due to the low throughput and high cost of the most used respirometer, the Oroboros 2k (O2k), multiple experiments are often conducted within the same chamber in short succession. Despite this, no methodological consideration has been given for the potential contamination of inhibitors, used to investigate the contribution of specific complexes within the electron transport chain, between experiments.
    Methods: We first assessed the potential effect of inhibitor contamination on mitochondrial respiration experiments by evaluating the ability of the currently recommended wash protocol to remove rotenone and compared its efficacy against a simplified wash protocol of sequential rinses. Secondly, we assessed the potential effect of inhibitor contamination on mitochondrial respiration measured before and after a single session of high-intensity interval exercise, with and without the use of rotenone between experiments.
    Results: The currently recommended protocol for washing chambers was insufficient for removing rotenone. Following exercise, a decrease in mitochondrial respiration was observed exclusively in chambers exposed to rotenone between experiments.
    Discussion: Our findings highlight an important methodological consideration regarding the measurement of mitochondrial respiratory function using high-resolution respirometry, with inhibitor contamination potentially affecting the conclusions derived from experiments conducted in close succession. Future studies investigating mitochondrial respiratory function should assess the necessity of using inhibitors such as rotenone, ensure thorough wash procedures between experiments, and explicitly report the washing protocols used.
    Keywords:  Bioenergetics; Exercise; Exercise-induced adaptation; Mitochondria; Oroboros O2k; Permeabilized fibers; Protocol development; Respiration; Rotenone
    DOI:  https://doi.org/10.7717/peerj.19879
  6. Biotechnol J. 2025 Aug;20(8): e70087
      Human Embryonic Kidney 293 (HEK293) cells are currently one of the preferred host cell lines for the production of biologics, specifically, AAV-based viral vectors. These fast-growing cells consume significant amounts of nutrients and often convert them into byproducts such as lactate and ammonia. In fed-batch cultures, accumulation of lactate and ammonia to high levels can inhibit cell proliferation. In this study, we demonstrate that lactate and ammonia accumulation alone doesn't fully explain the growth inhibition observed in HEK293 fed-batch cultures. Growth inhibition was noted even when the residual levels of these byproducts were well controlled. Instead, we show that several previously unknown compounds accumulate in HEK293 cell fed-batch cultures, some of which can inhibit HEK293 cell growth either individually or synergistically. Many of these newly identified compounds are intermediates or byproducts of amino acid catabolism. When residual levels of the source amino acids for these novel byproducts were controlled in the low concentration range (∼1 mM) in HEK293 fed-batch cultures, lactate accumulated to higher levels, causing growth inhibition. This prompted the use of High-end pH Delivery of Glucose (HIPDOG), a control strategy that limits lactate production by keeping low residual concentrations of glucose. In HIPDOG cultures, controlling the source amino acids at low concentrations resulted in lower accumulations of the corresponding growth-inhibitory byproducts when compared to the control HIPDOG conditions with typical levels of amino acids. This led to higher viable cell densities (VCD) and viabilities in low amino acid conditions. Strategies that reduce byproduct accumulation, whether classical or novel byproducts, in HEK293 fed-batch processes can result in enhanced VCDs, potentially leading to higher volumetric productivities.
    Keywords:  HEK293 cells; HIPDOG; amino acid catabolic byproducts; ammonia; fed‐batch culture; growth inhibitory byproducts; lactate; low amino acid process
    DOI:  https://doi.org/10.1002/biot.70087