bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–09–06
eleven papers selected by
Brett Chrest, Wake Forest University
  1. Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
  2. Transforming neural activity to operate without glucose metabolism using brain-derived ketone bodies.
  3. Assessing cellular metabolic dynamics with two-photon NAD(P)H fluorescence polarization microscopy.
  4. Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
  5. Charge Detection Native Mass Spectrometry for Quantitative Insights into Heterogeneous Protein Interactions.
  6. L-Glutamine in combination with first-line gemcitabine and nab-paclitaxel in advanced pancreatic ductal adenocarcinoma: an open-label, single-arm, phase 1 GlutaPanc trial.
  7. L-Glutamine's potential to enhance chemotherapy efficacy in advanced pancreatic cancer.
  8. Redox and structural determinants of mitochondrial complex III inhibition by triphenylphosphonium-conjugated atovaquone analogs.
  9. Oxygen-dependent subcellular redistribution of PHD3 links the hypoxic microenvironment to mitochondrial metabolic reprogramming in ccRCC.
  10. FDA grants accelerated approval to BCL-2 inhibitor sonrotoclax for mantle cell lymphoma.
  11. Mitochondrial Respiration in Peripheral Blood Cells Links to Metabolic Flexibility and Physical Performance in Ageing.
  1. Elife. 2026 Sep 02. pii: RP106976. [Epub ahead of print]14
    Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
    Marisa J Brothwell, Guoshen Cao, J Alan Maschek, Annelise M Poss, Alek D Peterlin, Liping Wang, Talia B Baker, Justin L Shahtout, Piyarat Siripoksup, Quentinn J Pearce, Jordan M Johnson, Fabian M Finger, Alexandre Prola, Sarah A Pellizzari, Gillian L Hale, Allison M Manuel, Shinya Watanabe, Edwin R Miranda, Kajsa E Affolter, Trevor S Tippetts, Linda S Nikolova, Ran Hee Choi, Stephen T Decker, Mallikarjun Patil, J Leon Catrow, William L Holland, Sara M Nowinski, Daniel S Lark, Kelsey H Fisher-Wellman, Patrice N Mimche, Kimberley Evason, James E Cox, Scott A Summers, Zach Gerhart-Hines, Katsuhiko Funai.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to metabolic dysfunction-associated steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in humans and in mice. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also promoted electron leak primarily at sites IIIQO and IIF of the electron transport chain (ETC), reduced the formation of I + III2 + IV respiratory supercomplex, and disrupted the propensity of coenzyme Q to become reduced. Thus, low mitochondrial CL disrupts the ETC to promote oxidative stress and contributes to the pathogenesis of MASH.
    Keywords:  cardiolipin; cell biology; human; liver; mitochondria; mouse
    DOI:  https://doi.org/10.7554/eLife.106976
  2. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2613981123
    Transforming neural activity to operate without glucose metabolism using brain-derived ketone bodies.
    Hafsa Yaseen, Karissa Cisneros, Rebecca Wright, Nikolaus Bueschke, Joseph M Santin.
      The vertebrate brain is exquisitely sensitive to disruptions in glucose metabolism, and failure of adequate glucose delivery causes neurological dysfunction. Here, we identified an animal with the capacity to defy this rule: We show that neural circuits in frogs, animals with seemingly typical glucose demands, can stop metabolizing glucose by, in part, shifting to ketone bodies made exclusively within the brain after emergence from hibernation. This involves ketone body synthesis and transport from astrocytes to neurons to power synaptic transmission, along with the upregulation of gene expression that controls fatty acid catabolism and ketone body transport. Brain-derived ketone bodies also prevent decrements in activity that occur during hypoxia. These results provide insight into how frogs restart brain circuits following months of underwater hibernation when facing severe hypoxia and hypoglycemia that otherwise strongly impair neural performance in most animals. More broadly, they reveal the vertebrate brain has the capacity to serve as its own fuel reserve during the cessation of glucose metabolism, switching seamlessly to locally sourced ketone bodies while maintaining neural activity. This reframes glucose metabolism in the vertebrate brain not as a hard-wired necessity, but as a plastic trait that can in some cases be entirely abandoned.
    Keywords:  brain metabolism; hypoxia; ketone body; metabolic plasticity; synapse
    DOI:  https://doi.org/10.1073/pnas.2613981123
  3. Sci Adv. 2026 Sep 04. 12(36): eaed6844
    Assessing cellular metabolic dynamics with two-photon NAD(P)H fluorescence polarization microscopy.
    Lu Ling, Jack C Crowley, Matthew L Tan, Jennie A M R Kunitake, Adrian A Shimpi, Rebecca M Williams, Lara A Estroff, Claudia Fischbach, Warren R Zipfel.
      Altered metabolism enables adaptive advantages for cancer cells, driving the need for improved methods for noninvasive long-term monitoring of cellular metabolism. Here, we present a fast live-cell NADH imaging method that provides a real-time measurement of the fractional level of unbound NADH and show that it is a robust indicator of a cell's metabolic status. The method, two-photon fluorescence polarization ratiometric microscopy (FPRM), is easy and inexpensive to implement and more than an order of magnitude faster than fluorescence lifetime imaging microscopy (FLIM), a common means of assessing bound and unbound NADH levels. We show that FPRM returns instrument-independent ratiometric parameters that correlate with the expected metabolic changes arising from pharmaceutical and environmental perturbations. By correlating FPRM-returned parameters with cell morphology and migration in two- and three-dimensional collagen matrices, we demonstrate the technique's versatility in typical bioengineered platforms used in cancer metabolism research.
    DOI:  https://doi.org/10.1126/sciadv.aed6844
  4. Cancer Discov. 2026 Sep 01. 16(9): 1727-1729
    Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
    Silvia Tiberti, Katayoun Rezvani, May Daher.
      Zhou and colleagues identify mitochondrial complex I activity, mediated through NDUFA9, as a critical determinant of natural killer (NK) cell metabolic fitness and antitumor function in glioblastoma. Their study links impaired oxidative phosphorylation to glutamine dependence, epigenetic repression of effector programs, and loss of NK cell activity, highlighting mitochondrial fitness as an actionable axis for improving cellular immunotherapy in solid tumors. See related article by Zhou et al., p. 1924.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1267
  5. Anal Chem. 2026 Sep 01. 98(34): 24761-24774
    Charge Detection Native Mass Spectrometry for Quantitative Insights into Heterogeneous Protein Interactions.
    Ziyu Zhang, Duong T Bui, Ling Han, Elena N Kitova, Joseph O Primeau, Rajneesh K Bains, Edward N Schmidt, Matthew S Macauley, Takashi Angata, Stephen G Withers, Howard S Young, Lara K Mahal, John S Klassen.
      Native mass spectrometry (nMS) is a powerful label-free method for detecting biomolecular complexes, resolving stoichiometry, and quantifying affinity (Kd). However, signal overlap in heterogeneous systems often limits its accuracy. Charge detection (CD)-nMS, which independently measures the mass-to-charge ratio and charge of individual ions, overcomes this challenge, enabling quantitative analysis of polydisperse and high molecular weight complexes with unresolved charge states. Here, we systematically validate CD-nMS for precise Kd determination using soluble protein-ligand complexes of known Kd and extend its application to quantify glycan ligand binding by a highly glycosylated immune lectin. We then demonstrate the implementation of slow mixing mode (SLOMO), a time-resolved mixing method that corrects for nonuniform response factors of interacting species, using CD-nMS to enable robust quantification of protein-protein interactions. Finally, we apply SLOMO-CD-nMS to directly detect and quantify bacterial toxin binding to glycolipids embedded in membrane-like assemblies, a capability not accessible with conventional nMS. These measurements uncovered previously unrecognized assembly pathways and demonstrate, for the first time, that SLOMO-CD-nMS can resolve and quantify multivalent lectin engagement with glycolipids in a native-like membrane context. Collectively, these results establish CD-nMS, alone or in combination with SLOMO, as a broadly applicable assay for quantitative characterization of complex biomolecular interactions across soluble, glycosylated, and membrane-associated systems.
    DOI:  https://doi.org/10.1021/acs.analchem.6c00996
  6. Nat Cancer. 2026 Aug 31.
    L-Glutamine in combination with first-line gemcitabine and nab-paclitaxel in advanced pancreatic ductal adenocarcinoma: an open-label, single-arm, phase 1 GlutaPanc trial.
    Jun Gong, Hayato Muranaka, So Yung Choi, Mourad Tighiouart, Shrikant Bhute, Ezinne R Aja, Jonathan P Jacobs, Aleksandr Stotland, Jennifer Van Eyk, Omer H M Elmadbouh, Mouad Edderkaoui, Sunao Tanaka, Hideki Furuya, Arsen Osipov, Jeremy Lorber, Sandrine Billet, Alexzandra Morris, Johanna Ten Hoeve-Scott, Thomas Graeber, Stephen J Pandol, Andrew Hendifar, Neil A Bhowmick.
      Exogenous L-glutamine has preclinical antitumor activity although formal clinical translation has not been attempted. We conducted a single-arm phase 1 trial to assess the safety and preliminary efficacy of clinical-grade, US Food and Drug Administration-approved L-glutamine therapy with gemcitabine and nab-paclitaxel (GA) in participants with treatment-naive, advanced pancreatic cancer (n = 16). The primary endpoint was to determine the recommended phase 2 dose (RP2D) by adaptive Bayesian design across standard doses of GA and a dose range of 0.1-0.3 g kg-1 twice-daily oral L-glutamine. Secondary endpoints included safety and preliminary efficacy of the study combination. The primary endpoint was met with the RP2D reached at maximum doses of L-glutamine and GA. The grade ≥3 treatment-related adverse event rate was 66.7%, primarily from GA. Addition of L-glutamine to GA induced tumor shrinkage in 94% of subjects with a best overall response rate (ORR) of 44% (12.5% complete response). Median progression-free survival and overall survival (OS) were 8.5 months (95% confidence interval (CI) 6-not reached (NR)) and 22 months (95% CI 11-NR), respectively. L-Glutamine induced distinct metagenomic and metabolomic signatures on exploratory analyses in glutamine-treated subjects as a single agent, while the combination of L-glutamine and GA nearly doubled the ORR and tripled the OS compared to historical GA alone (ClinicalTrials.gov registration: NCT04634539 ).
    DOI:  https://doi.org/10.1038/s43018-026-01225-z
  7. Nat Cancer. 2026 Sep 01.
    L-Glutamine's potential to enhance chemotherapy efficacy in advanced pancreatic cancer.
      
    DOI:  https://doi.org/10.1038/s43018-026-01231-1
  8. Redox Biol. 2026 Aug 28. pii: S2213-2317(26)00369-1. [Epub ahead of print]97 104370
    Redox and structural determinants of mitochondrial complex III inhibition by triphenylphosphonium-conjugated atovaquone analogs.
    Bruna Rafaela Pereira Resende, Gang Cheng, Gabriel Canard, Didier Siri, Vanessa Leone, Micael Hardy, Balaraman Kalyanaraman.
      Growing evidence indicates that cancer cell mitochondria remain functional and represent attractive therapeutic targets. Mitochondria-targeted drug delivery commonly uses triphenylphosphonium (TPP+)-conjugated compounds, which preferentially accumulate in cancer cell mitochondria because of their highly negative membrane potential. Many TPP+-conjugated agents inhibit mitochondrial electron transport chain complexes I and II, suppressing mitochondrial respiration and cancer cell proliferation. Recent studies suggest that electron-withdrawing substituents, such as trifluoromethyl groups, on the TPP+ phenyl rings alter electron density around the phosphorus center, enhancing mitochondrial uncoupling activity and antiproliferative effects. To determine how TPP+ electronic substituents influence redox properties, mitochondrial complex III interactions, and biological activity, we used mitochondria-targeted atovaquone (Mito-ATO) as a model system. Atovaquone (ATO), a hydroxy-1,4-naphthoquinone and the only FDA-approved mitochondrial complex III inhibitor, is currently undergoing clinical evaluation for cancer therapy. We synthesized a series of mitochondria-targeted ATO derivatives (MitoR-ATOs) containing electron-donating or electron-withdrawing substituents on the TPP+ moiety. Their effects on enzymatic superoxide generation were assessed by EPR spin trapping, mitochondrial oxygen consumption by Seahorse XF96 analysis, complex III Qi-site binding by computational modeling, and cancer cell proliferation using IncuCyte live-cell imaging. Unexpectedly, several MitoR-ATO derivatives emerged as potent complex III inhibitors through enhanced binding at the Qi site. Structure-activity relationship analysis revealed that the intrinsic redox properties of TPP+-conjugated MitoR-ATO analogs alone do not predict biological activity. Instead, accurate prediction of the therapeutic efficacy of mitochondria-targeted complex III inhibitors requires integrating redox properties with computational analyses of ligand-protein interactions at the mitochondrial complex III Qi site.
    Keywords:  Atovaquone; Cancer; Mitochondrial complex III; Redox-cycling; Superoxide
    DOI:  https://doi.org/10.1016/j.redox.2026.104370
  9. Exp Mol Med. 2026 Sep 02.
    Oxygen-dependent subcellular redistribution of PHD3 links the hypoxic microenvironment to mitochondrial metabolic reprogramming in ccRCC.
    Jaelim Sim, Soyeon Lim, Changjun Lee, Hani Jieun Kim, Wonseok Lee, Hyeonki Kim, Hojun Lee, Kimyeong Kim, Mahesh Kumar Teli, Kyeong Beom Jo, Jacob Wright, Jee Soo Park, Myung Eun Lee, Minsun Jung, Minsoo Noh, Dae-Kyum Kim, Mi-Hyun Kim, Dong Wook Choi, Tae Su Choi, Won Sik Ham, Hunsang Lee, Haejin Yoon.
      Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic dysregulation, with both prolyl hydroxylase domain protein 3 (PHD3) and pyruvate carboxylase (PC) independently implicated in disease progression. Although each influences patient outcomes, a direct mechanistic interplay between these two regulators has remained elusive. Here, we uncover a novel regulatory axis involving PHD3 and PC by identifying an unexpected subcellular behavior of PHD3, namely, its dual localization to the cytosol and the mitochondrial matrix. We show that mitochondrial import of PHD3 is associated with its intracellular clustering, a process modulated by PHD3 hydroxylase activity and oxygen levels. Once in the matrix, PHD3 directly hydroxylates PC, suppressing its enzymatic activity. In ccRCC with elevated PHD3 expression, this modification restricts anaplerotic flux into the tricarboxylic acid cycle, leading to impaired proliferation, reduced metastasis, and enhanced apoptosis. Together, our findings provide a new framework for targeting cancer metabolism by establishing a previously unrecognized mechanistic link between PHD3-mediated oxygen sensing within the tumor microenvironment and the regulation of ccRCC mitochondrial metabolism through the subcellular re-localization of PHD3.
    DOI:  https://doi.org/10.1038/s12276-026-01814-z
  10. Cancer. 2026 Sep 01. 132(17): e70537
    FDA grants accelerated approval to BCL-2 inhibitor sonrotoclax for mantle cell lymphoma.
    Leah Lawrence.
      
    DOI:  https://doi.org/10.1002/cncr.70537
  11. J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70361
    Mitochondrial Respiration in Peripheral Blood Cells Links to Metabolic Flexibility and Physical Performance in Ageing.
    Donna Li, Catrin Herpich, Christopher Bishop, Marie Aleithe, Antonia Peil, Nele Krüger, Jannes Felsner, Lea Göger, Maximilian Kleinert, Kristina Norman.
       BACKGROUND: Age-related declines in energy metabolism, muscle strength and physical performance have been linked to lower mitochondrial respiratory capacity. Peripheral blood mononuclear cell (PBMC) respiration offers a minimally invasive marker of systemic bioenergetics, yet its relationship to whole-body metabolic flexibility remains unclear. This study examined whether PBMC respiratory capacity is associated with substrate utilization during submaximal exercise, muscle strength and physical function in healthy older adults.
    METHODS: PBMC mitochondrial respiratory capacity was quantified by high-resolution respirometry assessing ROUTINE, LEAK and MAX states. Postprandial substrate oxidation during steady-state treadmill walking at 60% of VO2max (oxygen uptake) was quantified by indirect calorimetry, and fat and carbohydrate oxidation rates were calculated using standard stoichiometric equations. Metabolic flexibility was defined as lower respiratory exchange ratio (RER) and higher relative fat oxidation at a fixed workload. Muscle strength was determined by handgrip dynamometry and one-repetition maximum leg extension. Physical function was evaluated by gait speed and five-repetition chair rise time. Associations were tested with linear and logistic regression adjusted for age, sex, skeletal muscle index, physical activity and high-sensitive C-reactive protein concentrations. Exploratory K-means clustering identified mitochondrial respiration phenotypes.
    RESULTS: Fifty community-dwelling older adults (22 men, 28 women; age 70 ± 4 years) were examined. Higher ROUTINE respiration was correlated with RER (rho = -0.335, p = 0.020), fat utilization (rho = -0.334, p = 0.019), grip strength (rho = 0.302, p = 0.033) and gait speed (rho = 0.324, p = 0.022). Adjusted regression analyses confirmed the association of ROUTINE respiration with greater fat oxidation (β = 0.212, 95% CI 0.049; 0.375), lower RER (β = -0.160, 95% CI -0.300; -0.020) and higher gait speed (β = 0.153, 95% CI 0.028; 0.277). Similar associations were found for ATP-linked respiration. Cluster analysis identified high- and low-respiration phenotypes. Compared with the high-respiration group the low-respiration group showed lower CMJ height (OR: 0.204, 95% CI 0.055; 0.763) and quadriceps strength (OR: 0.373, 95% CI 0.155; 0.897).
    CONCLUSIONS: In healthy older adults, higher PBMC ROUTINE respiration was associated with a more fat-dominant substrate utilization profile during submaximal exercise, greater muscle strength and faster gait speed. PBMC respiratory capacity may reflect systemic bioenergetic status relevant to exercise substrate utilization and physical performance in ageing.
    Keywords:  ageing; metabolic flexibility; metabolism; mitochondrial respiratory capacity
    DOI:  https://doi.org/10.1002/jcsm.70361
This page is being maintained by Thomas Krichel. It was last updated on 2026‒09‒06 at 14:13.