bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–11–01
eighteen papers selected by
Brett Chrest, Wake Forest University
  1. MCT1-dependent mitochondrial lactate import sustains cardiac metabolism.
  2. MCT1-mediated succinate import fuels mitochondrial metabolism and hydrogen peroxide (H2O2) production in cultured H9C2 rat cardiomyocytes.
  3. Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
  4. A roadmap for quantifying metabolism in patients with cancer.
  5. Ketone ester supplementation reduces age-associated B cell activation in aged mice without impairing antibody responses.
  6. Emerging concepts on one-carbon metabolism as a unique and actionable vulnerability in cancer.
  7. Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism.
  8. Lactate takes a shortcut into mitochondria to power the heart.
  9. Sex differences in glycine biosynthesis drives sex-specific responses to combined nutrient deprivation and pharmacological inhibition in brain tumors.
  10. A luminescence-based assay for analyzing energy metabolism in human hepatocellular carcinoma spheroids.
  11. Allosteric inhibition of human mitochondrial ClpP by hijacking the dordaviprone (ONC201) binding site.
  12. Nutrient-sensitive histone propionylation regulates T cell fate and function.
  13. Flow Cytometry Analysis of Mitochondrial Function in Muscle Stem Cells.
  14. Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition.
  15. Random mtDNA mutagenesis maps genotype-phenotype associations across metabolic contexts and lineages.
  16. Oxygen-dependent constraint of glycolysis through the mitochondrial electron transport chain.
  17. Remote Control of Excited-State Chemistry in Positive Reversibly Switchable Fluorescent Proteins.
  18. Engaging the host adaptive response to nutrient limitation delays cancer cachexia.
  1. Nature. 2026 Oct 28.
    MCT1-dependent mitochondrial lactate import sustains cardiac metabolism.
    Ahmad A Cluntun, Joseph R Visker, Jesse N Velasco-Silva, James Carrington, Luis Cedeño-Rosario, Giulia C Napoli, Ji Eon Kim, Thirupura S Shankar, Marisa J Brothwell, Rana Hamouche, Álvaro J Narbona-Pérez, Jing Ling, Ashish G Toshniwal, Hayden K Low, Corey N Cunningham, David R Eberhardt, Jing Li, Claire E Stanley, Queren A Alcantara, Tarun Yadav, Ryan L Maves, Wojciech I Swiatek, Nicholas A Offei, Bhavya Blaze, Sumangala P Shetty, Dipayan Chaudhuri, Tingting Hong, Jeffery D Rothstein, Deborah M Muoio, Joao A Paulo, Steven P Gygi, Eleni Tseliou, Sutip Navankasattusas, James E Cox, Katsuhiko Funai, Stavros G Drakos, Jared Rutter, Gregory S Ducker.
      The heart possesses a dynamic capacity to oxidize a variety of fuels, including glucose and lactate, to meet its energetic demands under diverse dietary, exertion and injury stressors1. Oxidation of carbohydrate substrates is thought to converge on the cytosolic generation of pyruvate, which is transported by the mitochondrial pyruvate carrier (MPC) for entry into the tricarboxylic acid cycle2. Here we find that glucose-derived carbon is oxidized in mouse myocardium even when the MPC is genetically ablated. Using genetic and pharmacological tools, we demonstrate that lactate monocarboxylate transporter 1 (MCT1, encoded by Slc16a1) is required for the oxidation of glucose carbon by MPC-deficient myocardium. We further observe that MCT1, traditionally localized to the plasma membrane, also resides in the inner mitochondrial membrane of mouse and human cardiomyocytes. Together with matrix-localized LDHB, MCT1 enables mitochondrial lactate conversion to pyruvate and NADH, directly fueling the electron transport chain. Loss of MCT1 impairs lactate oxidation, disrupts metabolic flexibility and accelerates the development of heart failure with increased mortality after hyperactivation of the neurohormonal axis or ischemia-reperfusion injury. Thus, the existence of a parallel lactate-based pathway for carbohydrate oxidation can sustain cardiac energetics and maintain myocardial structure and function under diverse stress conditions.
    DOI:  https://doi.org/10.1038/s41586-026-11182-3
  2. Biochim Biophys Acta Mol Cell Res. 2026 Oct 30. pii: S0167-4889(26)00142-4. [Epub ahead of print] 120243
    MCT1-mediated succinate import fuels mitochondrial metabolism and hydrogen peroxide (H2O2) production in cultured H9C2 rat cardiomyocytes.
    Meijing Li, Daina Zofija Avizonis, Luis B Agellon, Ryan J Mailloux.
      Endogenous myocardial succinate accretion induces oxidative distress on a massive scale by triggering a drastic spike in hydrogen peroxide (H2O2) production. Here, using the H9C2 rat cardiomyocyte cell line, we demonstrate for the first time that the import of exogenous succinate by cardiomyocytes fuels H2O2 generation through the pH-gated monocarboxylate transporter 1 (MCT1, aka SLC16A1). Succinate as a fuel depended on a slightly acidic extracellular medium (pH < 7.0), whereas exogenous succinate could not be metabolized at physiological neutrality. AZD3965 (1 μM), a highly specific MCT1 inhibitor, strongly prevented uptake of isotopically labeled succinate and its metabolism to other TCA cycle intermediates. Physiologically relevant succinate levels (50 μM) fueled both H2O2 production and oxidative phosphorylation (OxPhos), which inhibited by complex II inhibitor dimethylmalonate (DMM) or AZD3965. By contrast, pathological succinate (100 μM) increased H2O2 production, which was also sensitive to DMM and AZD3965 inhibition. Treating cells with succinate (1 mM), which reflects the concentration observed in the ischemic heart, induced H2O2 production and collapsed the mitochondrial membrane potential. In sum, our experiments show for the first time extracellular succinate fuels H2O2 biogenesis in H9C2 cardiomyocytes after its import by MCT1. These results provide new insights into how a pathological extracellular succinate buildup can trigger cardiovascular complications by promoting H2O2 production by mitochondrial RET in cardiomyocytes.
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120243
  3. Nat Metab. 2026 Oct 27.
    Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
    Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.
      Mutations in mitochondrial DNA (mtDNA) impair ETC activity and oxidative phosphorylation, but their phenotypic consequences vary with heteroplasmy levels. Whether increasing mtDNA heteroplasmy creates metabolic dependencies not present in respiratory-competent cells remains unknown. Here, we show that low pyruvate carboxylase (PC) expression creates an asparagine dependency in high-mtDNA-heteroplasmy, respiration-compromised cells. In isogenic cells carrying similar mtDNA deletions, respiration declines linearly with increasing heteroplasmy, whereas redox imbalance emerges only above 50% heteroplasmy. Above 70% heteroplasmy, integrated stress-response-associated translational defects emerge, which can be reversed by either exogenous asparagine or PC overexpression. Asparagine dependence inversely correlates with PC expression across respiration-deficient cells. Consistent with this pattern, patient-derived thyroid tumour cells harbouring a high-heteroplasmy complex I mutation and low PC levels exhibit asparagine auxotrophy and sensitivity to L-asparaginase. Together, these findings demonstrate a role for mitochondrial PC in cellular asparagine synthesis under conditions of compromised respiratory activity.
    DOI:  https://doi.org/10.1038/s42255-026-01651-4
  4. Trends Cancer. 2026 Oct 30. pii: S2405-8033(26)00239-6. [Epub ahead of print]
    A roadmap for quantifying metabolism in patients with cancer.
    Baharan Meghdadi, Daniel R Wahl, Deepak Nagrath.
      Advancements in in vivo stable isotope tracing have revolutionized our understanding of cancer metabolism, transitioning the field from static metabolomic snapshots to dynamic metabolic pathway activities. However, interpreting raw fractional enrichment data presents significant biological and analytical challenges. This review systematically examines the methodological landscape of in vivo tracing, addressing the interpretive gap created by clinical constraints, such as single-timepoint surgical sampling. We dissect how secondary circulating tracers and the inherent heterogeneity of the tumor microenvironment can confound metabolic signals. We highlight the critical transition to metabolic flux analysis as the requisite computational step to overcome these challenges and to identify targetable metabolic vulnerabilities in precision oncology.
    Keywords:  digital twins; in vivo isotope tracing; isotope tracing in patients; metabolic flux analysis; tumor heterogeneity; tumor metabolism
    DOI:  https://doi.org/10.1016/j.trecan.2026.10.005
  5. Res Sq. 2026 Sep 03. pii: rs.3.rs-10756850. [Epub ahead of print]
    Ketone ester supplementation reduces age-associated B cell activation in aged mice without impairing antibody responses.
    Ariel Adkisson-Floro, Ritesh Tiwari, Mitsunori Nomura, Rebeccah R Riley, Ryan Kwok, Durai Sellegounder, Mir M Khalid, Herbert G Kasler, John C Newman, Eric Verdin.
       Background: Aging in the immune system results in increased susceptibility to infections, exacerbated autoimmunity, and reduced responsiveness to vaccines. However, there are no current established interventions for immune aging. Ketogenic diets and fasting have been researched as interventions against other aspects of aging and age-related diseases, and they work in part by increasing circulating levels of ketone bodies, which have anti-inflammatory properties and can boost T cell function. Exogenous ketones, such as ketone esters, are currently being studied as a more accessible approach to obtain the benefits of ketone bodies through direct supplementation. Here, we investigated whether ketone ester supplementation improves immune function during aging. Aged (19-month-old) C57BL/6JN mice were given a diet supplemented with the ketone ester or a control diet for 15 weeks.
    Results: We found that the ketone ester diet decreased activation of B cells, especially age-associated B cells, in the spleen. The diet also reduced the proportion of age-associated B cells defined by CD11b and CD11c expression, though not of the broader CD21-CD23- population. Despite this decrease in activation, there was no impairment in antibody production, as mice on the ketone ester diet mounted a normal response to nitrophenyl-ovalbumin immunization. The ketone ester diet also reduced glucose dependence and translation in subsets of age-associated B cells. Treating splenocytes from aged mice with β-hydroxybutyrate was sufficient to suppress B cell translation and reduced mTORC1 signaling, indicating that ketone bodies act directly on B cells. β-hydroxybutyrate also decreased expression of T-bet, the signature transcription factor driving the autoimmune functions of age-associated B cells.
    Conclusions: Our study elucidates the effect of ketone esters on B cells in the context of aging and unveils a new immunoregulatory role of ketone bodies on B cells.
    Keywords:  B cell activation; Ketone ester; T-bet; age-associated B cells; immune aging; translation; β-hydroxybutyrate
    DOI:  https://doi.org/10.21203/rs.3.rs-10756850/v1
  6. ASPET Discov. 2026 ;2 100029
    Emerging concepts on one-carbon metabolism as a unique and actionable vulnerability in cancer.
    Mathew Schneider, Zhanjun Hou, Larry H Matherly.
      Metabolic reprogramming is a defining feature of cancer, and folate-mediated one-carbon (C1) metabolism occupies a central role in supporting malignant growth, survival, and immune evasion. Although cytosolic C1 enzymes have long been exploited for the therapy of a host of cancers through the use of "classical" antifolates, growing evidence suggests that mitochondrial C1 metabolism is a critical driver of tumor progression, metastasis, and redox homeostasis. Mitochondrial serine catabolism via serine hydroxymethyltransferase 2 and 5,10-methylene tetrahydrofolate dehydrogenase 2 provides formate, glycine, and reducing equivalents to sustain nucleotide and amino acid biosynthesis, biological methylation reactions, and antioxidant defenses. Dysregulation of mitochondrial C1 metabolism promotes "formate overflow", alters tumor-immune interactions, and supports metastatic signaling. This review synthesizes recent key advances in folate biology, and compartmentalized C1 metabolism, leading to the development of an exciting new generation of cytosolic- and mitochondrial-targeted therapies. We examine emerging links between C1 metabolism and the tumor microenvironment, including relationships between C1 metabolism and immune suppression, T cell infiltration, and macrophage polarization. Finally, we highlight critical unresolved questions and vexing future challenges in implementing the next generation of C1-targeted anticancer agents. Collectively, these insights underscore the remarkable biology of C1 metabolism, and mitochondrial C1 metabolism in paticular, and its potential as a multifaceted and therapeutically actionable vulnerability in cancer.
    Significance Statement: This minireview summarizes recent advances in folate biology and one-carbon (C1) metabolism. Topical areas include mechanisms of membrane transport, compartmentalization of C1 metabolism and its role in tumor biology, and the relationship between C1 biology and the tumor microenvironment. The goal of this study is to provide an evolving framework for discovery of tumor-specific vulnerabilities in C1 metabolism that can be exploited for therapy.
    Keywords:  (Anti)folate; 5,10-Methylenetetrahydrofolate dehydrogenase; One-carbon metabolism; Proton-coupled folate transporter; Reduced folate carrier; Serine hydroxymethyltransferase
    DOI:  https://doi.org/10.1016/j.aspetd.2026.100029
  7. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757616. [Epub ahead of print]
    Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism.
    Damon Fard, Edisa Pirani, Maria Gomez-Jenkins, Sereno Lopez-Darwin, Maria Ibrahim, Lilia Schell, Charlotte Larkin, Clara Gorgui, Clara Berdasco, Zhixian Hu, Trishna Das, Jesse Powers, Tracy G Anthony, Joshua D Rabinowitz, Benjamin J Raphael, Jessie Yanxiang Guo, Marcus D Goncalves, Tobias Janowitz, Eileen White.
      Cancer cachexia causes pathological weight loss, anorexia, and depressive symptoms, culminating in increased mortality. Using mouse models of pancreatic cancer cachexia, we identify tumor and hepatic inflammatory signaling, multi-organ energy charge depletion, and altered tryptophan metabolism. Metabolomic profiling and stable isotope tracing revealed altered tryptophan fates: serotonin depletion and kynurenine accumulation across tumor, liver, muscle and spleen. Kynurenine accumulation involved accelerated conversion of tryptophan to kynurenine with slowed downstream conversion to kynurenic acid. Restoring serotonin activity pharmacologically or metabolically normalized feeding, locomotion, and depression-like behavior, but wasting, tumor burden, and survival remained unchanged. Blocking kynurenine production or kynurenine-mediated AhR activation pharmacologically produced similar results. Thus, in cancer cachexia, the tryptophan pathway is subverted to deplete serotonin and accumulate kynurenine. This subversion contributes to cachexia-associated behavioral and feeding defects but not lethal systemic catabolism.
    Highlights: Tumors divert tryptophan from serotonin toward kynurenine accumulation in cachexiaSerotonin depletion contributes to behavioral alterations in cancer cachexiaKynurenine accumulation reduces feeding and activity via aryl hydrocarbon receptorCombined pathway targeting preserves fat mass but wasting remains unaltered.
    DOI:  https://doi.org/10.64898/2026.10.08.757616
  8. Nature. 2026 Oct 28.
    Lactate takes a shortcut into mitochondria to power the heart.
    Trace Thome, Zolt Arany.
      
    Keywords:  Cell biology; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-026-03261-2
  9. Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag245
    Sex differences in glycine biosynthesis drives sex-specific responses to combined nutrient deprivation and pharmacological inhibition in brain tumors.
    Camryn Marquez, Jianyun Lu, Kevin Cho, Shanshan Zhang, Jingqin Luo, Joshua B Rubin, Gary J Patti, Joseph E Ippolito.
       Background: Glioblastoma (GBM) is the deadliest brain tumor. Generally, male GBM occurs at higher incidence and demonstrates shorter overall survival compared to females. Targetable drivers of this phenomenon remain undisclosed, preventing the integration of sex differences into the design of targeted therapeutics.
    Methods: Here, we utilized metabolite tracing, pharmacological blockade, and nutrient deprivation to profile and target putative sex differences in cellular proliferation driven by the synthesis of glycine and nucleotides from glucose.
    Results: Utilizing an established murine model of GBM (Nf1-/- DNp53), we observed male biases in de novo glycine biosynthesis and in the cellular response to inhibition of this pathway in nutrient-replete media. Additionally, we illustrated that removal of exogenous glycine or nucleotide salvage metabolites enhanced inhibition efficacy in both male and female tumor cells. Collectively, our paradigm targets sex differences in the endogenous synthesis of glycine, which coordinates with cellular uptake of exogenous glycine or nucleotide salvage metabolites, to stall nucleotide biosynthesis and cellular proliferation.
    Findings: These data suggest inhibition of de novo glycine biosynthesis may elicit a sex-biased therapeutic response in GBM. Additionally, this work opens the door to future studies involving dietary restriction of glycine in combination with pharmacological inhibition of de novo glycine biosynthesis as a means to improve outcomes in patients with brain tumors.
    Keywords:  cancer; glioblastoma; glycine; metabolism; sex differences
    DOI:  https://doi.org/10.1093/noajnl/vdag245
  10. Methods. 2026 Oct 24. pii: S1046-2023(26)00214-8. [Epub ahead of print]257 14-24
    A luminescence-based assay for analyzing energy metabolism in human hepatocellular carcinoma spheroids.
    Norapat Nitaramorn, Porntida Kobpornchai, Kasem Kulkeaw.
      Cancer cells often exhibit elevated glycolysis even when oxygen is available, a phenomenon known as the Warburg effect and a potential therapeutic target. Three-dimensional (3D) cell culture systems mimic tumor masses, but whether cancer cells cultured in 3D retain this glycolytic dependence remains unclear. This study examined changes in metabolic pathway dependence using small-molecule inhibitors of glycolysis and mitochondrial ATP synthesis as an indirect approach, and investigated effects of metformin, an emerging antitumor metabolism drug, in a hepatocellular carcinoma cell line. Human hepatocellular carcinoma G2 (HepG2) cells were cultured as hemispherical aggregates. Following metformin pretreatment, small-molecule inhibitors targeting glycolysis, the tricarboxylic acid cycle, and mitochondrial ATP synthesis were applied. After metformin treatment, ATP levels were significantly decreased in the 2D monolayers, whereas ATP levels were unchanged in the 3D hemispheroids. Following the addition of small-molecule inhibitors, glucose dependence of HepG2 monolayers and hemispheroids remained unchanged compared with the vehicle control. In addition, inhibition of mitochondrial ATP synthase did not significantly reduce ATP levels in the 3D configuration. Overall, HepG2 cells in hemispheroids remained glucose-dependent for ATP production, although ATP response to metformin was reduced. Therefore, using 3D spheroids to test anti-Warburg drugs requires careful interpretation, considering different metabolic responses compared with 2D monolayers. Direct flux analysis is needed to further evaluate metabolic pathway dependence.
    Keywords:  ATP; Cancer cell line; Hepatoma carcinoma HepG2 cell; Spheroid; Warburg effect
    DOI:  https://doi.org/10.1016/j.ymeth.2026.10.009
  11. Nat Commun. 2026 09 28. pii: 11175. [Epub ahead of print]17(1):
    Allosteric inhibition of human mitochondrial ClpP by hijacking the dordaviprone (ONC201) binding site.
    Monica M Goncalves, Adwaith B Uday, Iain D G Watson, Anh M Chau, Shiva Kalhor-Monfared, Benson Wan, Taira Kiyota, S Quinn W Currie, Yulia Jitkova, Yue Feng, Matthew Diamandas, Dakai Ling, Mary Ma, Ross S Mancini, Zhezhou Wang, Matias Casás-Selves, Dhananjay Joshi, Mohammed Mohammed, Ratheesh Subramaniam, Evelyne Lima Fernandes, Yongran Yan, Neil Pomroy, Rose Hurren, Marcela Gronda, Algirdas Velyvis, Andrei K Yudin, Mark A Reed, Gil Prive, Ahmed Aman, Methvin Isaac, Richard Marcellus, David Uehling, Aaron D Schimmer, Natalie Zeytuni, Siavash Vahidi.
      ClpP protease maintains proteostasis in human mitochondria and is overexpressed in cancers such as acute myeloid leukemia (AML). While activators such as dordaviprone (ONC201) have reached the clinic, the development of ClpP inhibitors has been hampered by paradoxical activation upon orthosteric inhibitor binding. Here, we report a series of quinazolinone-based compounds that allosterically inhibit human ClpP with nanomolar potency. Cryo-EM and H/D exchange mass spectrometry reveal that our lead compound binds sub-stoichiometrically to a distal hydrophobic pocket ~30 Å from the active sites, disrupts a conserved inter-subunit cluster, and induces a conformational change that misaligns the catalytic triad, thereby inactivating ClpP. The binding site of our quinazolinone-based inhibitors partially overlaps with that of the activator dordaviprone. In a xenograft mouse model of leukemia, our lead compound significantly reduced tumor burden following short-term oral administration. Our findings identify a regulatory hotspot in human ClpP and a mechanistically distinct inhibition strategy.
    DOI:  https://doi.org/10.1038/s41467-026-78140-5
  12. bioRxiv. 2026 Oct 06. pii: 2026.10.01.756002. [Epub ahead of print]
    Nutrient-sensitive histone propionylation regulates T cell fate and function.
    Alison Jaccard, Kelly Rome, Qihua Yang, Shuo Zhang, Noah Ford, Adam Chatoff, Tran Ngoc Van Le, Michael Noji, Andrea Andress Huacachino, Stephanie Stransky Lauar, Carlos Pondevida, Krittin Trihemasava, Laura V Pinheiro, Sanat Bhadsalve, Eun Kyung Ko, Charles Salinas, Mariola M Marcinkiewicz, Brian C Capell, Golnaz Vahedi, Simone Sidoli, Roddy S O'Connor, Will Bailis, Nathaniel W Snyder, Kathryn E Wellen.
      Tissue microenvironments differ widely in nutrient composition; yet how local nutrient conditions shape epigenetic programs that direct immune cell fate is poorly understood. We identify histone lysine propionylation (Kpr) as a chromatin mechanism linking nutrient availability to T cell fate decisions. Proteomic analysis reveals that Kpr is broadly reduced in exhausted T cells. H3K18pr is enriched at stemness-associated loci in effector T cells and depleted upon exhaustion. Isoleucine and propionate supply propionyl-CoA in T cells, and restricted nutrient availability within the tumor microenvironment limits histone Kpr, promoting T cell exhaustion. Disrupting isoleucine catabolism in T cells further suppresses Kpr, without altering histone acetylation, and impairs T cell function and antitumor immunity in a manner rescued by propionate. Dietary supplementation of isoleucine and propionate increases Kpr in tumor infiltrating lymphocytes, limits exhaustion, and improves tumor control. These findings establish a microenvironment-chromatin axis crucial for antitumor immunity and amenable to nutritional intervention.
    DOI:  https://doi.org/10.64898/2026.10.01.756002
  13. Methods Mol Biol. 2027 ;3093 167-184
    Flow Cytometry Analysis of Mitochondrial Function in Muscle Stem Cells.
    Lucia Acampora, Melania Murolo, Shahragim Tajbakhsh, Barbara Gayraud-Morel.
      Mitochondrial metabolism plays a central role in regulating muscle stem cell (MuSC) quiescence, activation, and differentiation, with dynamic metabolic transitions accompanying changes in cell fate and function. Flow cytometry-based analysis of mitochondrial function provides a rapid and accessible approach to characterize metabolic states at the single-cell level. Here, we present a detailed protocol to analyze mitochondrial activity, particularly by assessing mitochondrial membrane potential and mitochondrial mass in freshly isolated MuSCs and myoblasts using the fluorescent dyes TMRE and MitoTracker Deep Red in cytometry. This method is compatible with antibody-based identification of MuSCs and includes controls using mitochondrial uncouplers to validate ΔΨm-dependent staining. This protocol enables reliable discrimination between quiescent, activated, and differentiating muscle cells and can be applied to study physiological and pathological conditions in different contexts, including injury, aging, and diseases.
    Keywords:  Flow cytometry; Metabolism; MitoTracker; Mitochondria; Satellite cells; Skeletal muscle; Stem cells; TMRE
    DOI:  https://doi.org/10.1007/978-1-0716-5643-3_13
  14. Cancer Res. 2026 Oct 27.
    Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition.
    Nathan J Coffey, Sara M Demczyszyn, Yizheng Xue, Zian Zhang, Nicolas Skuli, Nicholas P Lesner, Romain Riscal, Yanqing Jiang, Xu Han, Madeleine Carens, Morgan Brown, Laura C Kim, Brian Keith, Zoltan Arany, M Celeste Simon.
      Metabolic reprogramming is a well-described hallmark of clear cell renal cell carcinoma (ccRCC). Gene copy number variation and altered gene expression data suggest enhanced branched-chain amino acid (BCAA) transamination and reduced BCAA oxidation are highly selected traits in ccRCC. Surprisingly, we found that genetic modulation of BCAA oxidation had little effect on experimental ccRCC cell growth in vitro and in vivo. In contrast, BCAA transamination in ccRCC cells was essential for the generation of glutamate-derived glutathione and cell viability when glutamine was limiting. Thus, BCAA transamination conferred resistance to states of low glutamine or treatment with the glutaminase inhibitor CB-839 by providing glutathione independent of glutamine breakdown. Targeting BCAA transamination in vitro and in vivo sensitized ccRCC to CB-839 mediated glutaminase inhibition by decreasing glutathione biosynthesis and redox homeostasis. These findings reveal that BCAA transamination maintains critical glutamate and glutathione levels in glutamine-deprived ccRCC, explaining why CB-839 treatment has been ineffective in ccRCC clinical trials and demonstrate an approach to treat ccRCC by targeting BCAA transamination to create a vulnerability to glutaminase inhibition.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0563
  15. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757705. [Epub ahead of print]
    Random mtDNA mutagenesis maps genotype-phenotype associations across metabolic contexts and lineages.
    Amir Giladi, Ron Baik, Chih-Yao Chung, Minsoo Kim, Josephine Adams, Rahul Saha, Max Land, Ruobing Cui, Emily DeBitetto, Megan E Kelley, Craig B Thompson, Ed Reznik, Roshan Sharma, Ronan Challinge, R Stefan Isaac, Josi Peterson, Alexander van Oudenaarden, Agnel Sfeir.
      Mitochondrial DNA (mtDNA) mutations cause inherited disease, accumulate with age, and recur in tumors, yet their effects remain unresolved because existing models interrogate one engineered allele at a time. We developed mtDIVE, a random C→T mutagenesis platform for pooled mitochondrial forward genetics in human epithelial cells and zebrafish embryos. mtDIVE generates genotypes ranging from single substitutions to >100 mutations per molecule, impairs respiration, and causes lineage-specific developmental delay. Coupling single-cell transcriptomics with mtDNA genotyping revealed that selection on mutant genomes and their transcriptional consequences depend on metabolic state and developmental lineage. Obligate OXPHOS eliminates highly mutated cells by apoptosis, whereas glycolytic conditions promote their competitive displacement. Individual loci exert modest but non-redundant effects that predict cell state beyond aggregate mutation burden, and cancer-recurrent variants are enriched among mutations linked to reduced mitochondrial transcription. Thus, mtDIVE links mtDNA genotypes to cellular phenotypes, separating the consequences of mutation identity from mutational load.
    DOI:  https://doi.org/10.64898/2026.10.08.757705
  16. Sci Adv. 2026 Oct 30. 12(44): eaed1177
    Oxygen-dependent constraint of glycolysis through the mitochondrial electron transport chain.
    Andrea Guajardo-Grence, María Fernández-Lamadrid, Greta Moschini, Lidia Marin-Algeciras, Claudia Mesa-Ciller, Rosa Andreu Martínez, Lucía Fernández-Arroyo, Rebeca Vázquez Muñoz, María José Calzada, Noa Beatriz Martín-Cófreces, José Antonio Enríquez, Katrien De Bock, Julián Aragonés.
      Hypoxia-inducible factors (HIFs) are constitutively active in clear cell renal cell carcinoma (ccRCC) cells. Here, we investigated whether these cells could still respond to hypoxia independently of canonical HIF activation. We found that hypoxia provokes a NADH reductive stress that attenuates lactate release when the supply of extracellular pyruvate becomes limited, a response that was restored by the ectopic expression of the cytosolic and mitochondria-targeted NADH oxidase (LbNOX). Suppression of the mitochondrial electron transport chain (mtETC) alone is sufficient to attenuate glycolytic flux when extracellular pyruvate is limited, a situation consistent with metabolomic data from human ccRCCs. Furthermore, this response can be mimicked by pharmacological or genetic inhibition of mitochondrial complex IV (CIV) activity and restored by the mitochondrial-targeted alternative oxidase (AOX). Therefore, our data suggest that cells can respond to low oxygen tension through a mitochondrial-dependent elevation of NADH/NAD+, resulting in the suppression of glycolysis when pyruvate availability is compromised.
    DOI:  https://doi.org/10.1126/sciadv.aed1177
  17. J Phys Chem Lett. 2026 Oct 29. 17(43): 12339-12347
    Remote Control of Excited-State Chemistry in Positive Reversibly Switchable Fluorescent Proteins.
    Anam Fatima, Danielle Rosenberger, YongLe He, James N Iuliano, Gregory M Greetham, Partha Malakar, Andras Lukacs, Peter J Tonge, Stephen R Meech.
      Positive reversibly switchable fluorescent proteins (+rsFPs) are genetically encoded fluorescent labels allowing super-resolution microscopy without the fading inherent in the better established negative (-) rsFPs. Typically, switching is initiated by an ultrafast excited-state isomerization reaction. Here, we investigate the ultrafast photophysics of four structurally similar variants of the archetypal +rsFP Padron, including Padron0.9, Padron2, Kohinoor, and a newly reported "reverse" Kohinoor mutant (Kohinoor S176F) using ultrafast optical and vibrational spectroscopy. Padron0.9 exhibits an efficient excited-state proton transfer (ESPT) reaction in parallel with photoisomerization, whereas Kohinoor and Padron2 do not. Remarkably, introducing the single reverse mutation S176F in Kohinoor restores Padron-like ESPT dynamics, even though the mutation is remote from the proton donor. This result demonstrates that a single amino acid residue near to, but not in direct H-bonded interaction with, the chromophore can govern the fate of excited states. TRIR measurements reveal distinct changes in the local hydrogen-bonding network and chromophore-protein interactions associated with ESPT-active variants and further reveal a key role for H-bonding between the chromophore and an arginine residue through a study of the R66K mutant of Padron0.9. Overall, these results show that subtle mutations shift the excited state between proton transfer and photoisomerization pathways, providing mechanistic insight into photoswitching in rsFPs, thus guiding the design of improved fluorescent proteins for superresolution bioimaging.
    DOI:  https://doi.org/10.1021/acs.jpclett.6c02808
  18. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757672. [Epub ahead of print]
    Engaging the host adaptive response to nutrient limitation delays cancer cachexia.
    Maria Gomez-Jenkins, Trishna Das, Maria Ibrahim, Damon Fard, Sereno Lopez-Darwin, Justine Raeber, Jesse Powers, Zhixian Hu, Hirak Sarkar, Eduardo CararoLopes, Akshada Sawant, Gabriela Reyes-Castellanos, Wenyun Lu, Hantao Qiang, Aslihan Sen, Young-Yon Kwon, Selina Wadhera, Honiyah Armughan, Shang Shi, Joshua D Rabinowitz, Sheng Hui, Tracy G Anthony, Michael A Skinnider, Benjamin J Raphael, Marcus D Goncalves, Tobias Janowitz, Eileen White.
      Cancer cachexia is a debilitating wasting syndrome associated with involuntary weight loss, reduced appetite and food intake, adipose and muscle atrophy, and systemic inflammation with induction of a myriad of candidate cachexia factors. Using a multi-omic approach in a genetically engineered mouse model of lung cancer cachexia, we found that early circulating metabolic alterations preceded overt weight loss. Although both cachexia and fasting are characterized by a reduction in food intake, we show that the systemic metabolic changes in cachexia are distinct, indicating a lack of induction in the normal protective response to negative energy balance during cachexia. Cancer cachexia causes profound hepatic reprogramming, and activation of inflammatory programs, alongside muscle atrophy and elevation of circulating cytokines. However, targeting individual candidate cachectic factors such as IL-6, TNF-α, GDF15, CCL2, LIF, and IL17A failed to rescue weight loss or prolong survival. In contrast, caloric restriction initiated prior to tumor induction elicited a program of protection during tumor progression that attenuated multi-tissue inflammatory and catabolic transcriptional responses, preserved lean mass, and prolonged survival. Together, these findings suggest that metabolic preconditioning broadly dampens systemic inflammation and delays the onset and progression of cancer cachexia.
    HIGHLIGHTS: Despite both fasting and cachexia involve reduced nutrient intake, the metabolic alterations are distinct.Cachexia induces a systemic inflammatory response.Single targeting of implicated cachectic factors fails to rescue weight loss or survival in cancer cachexia.Caloric restriction pre-conditioning to enforce the protective response to nutrient limitation attenuates cachexia.
    DOI:  https://doi.org/10.64898/2026.10.08.757672
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