bims-medica 2026-09-27 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–09–27
fourteen papers selected by
Brett Chrest, Wake Forest University

Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage.
Ketone ester supplementation in aged mice produces sex-specific cognitive and metabolic effects.
Hepatocytes promote liver metastasis of pancreatic cancer by providing serine.
Initial perturbations triggered by p53 loss in stem cells.
In Vitro Glutamine Adaptability in Murine Liver- but Not Lung-Metastasizing Triple-Negative Breast Cancer Cells.
FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.
KDM4B Maintains Pyruvate Dehydrogenase Complex Expression to Support Mitochondrial Metabolism and Survival in Cancer Cells.
Enhanced Ratiometric Indicators for (Sub)cellular Detection of Magnesium(II) Ions by Flow Cytometry.
Exploiting Metabolic Vulnerabilities in Acute Myeloid Leukemia: Rationale and Evidence for Combining Metabolic Modulators with Conventional Chemotherapy.
All the ways a cell can die - and why the variety matters.
Wired to Survive: How AML Cytogenetics Shape Apoptotic Dependence and Venetoclax Resistance.
Beyond glucose: metabolic substrate provision enhances cardiac energetics, function and stability ex vivo: a simple recipe for healthier hearts?
Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories.
Na + /K + -ATPase Blockade Reversibly Attenuates Proliferation and Metabolic Function in K562 Human Myelogenous Leukemia Cells.

bioRxiv. 2026 Sep 14. pii: 2026.09.13.750663. [Epub ahead of print]

Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage.

Ryan Elbashir, Keene L Abbott, Diya L Ramesh, Ahmed Ali, Anna Shevzov-Zebrun, Anna M Barbeau, Michelle Wu, Abigail P Ward, Yetiş Gültekin, Brian T Do, Sharanya Sivanand, Azucena Ramos, Tenzin Kunchok, Millenia Waite, Edrees H Rashan, Muhammad Bin Munim, Michael T Hemann, Matthew G Vander Heiden.

Proliferating cells must acquire nucleotides to support DNA replication, yet how cells meet these nucleotide demands for proliferation under physiological conditions remains understudied. Here, we investigated how physiological nutrient availability shapes nucleotide acquisition strategies in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL). To assess how environmental nutrients impact nucleotide metabolism, we formulated a mouse plasma-like medium (MPM) that reproduces the circulating metabolite composition of plasma from mice with B-ALL and assessed how this influenced nucleotide metabolism relative to standard culture conditions, where nucleotide acquisition has historically been studied. We find that leukemia cells cultured in MPM acquire nucleotides through salvage pathways, and that select nucleotide salvage pathways are required for proliferation under physiological conditions. Of note, this dependency on nucleotide salvage in plasma-like conditions was not caused by precursor metabolite limitation for de novo synthesis. Instead, we found that physiological folate levels are insufficient to support deoxynucleotide triphosphate (dNTP) synthesis for genome replication, leading to DNA replication stress and impaired proliferation when nucleotide salvage is disrupted. Consistently, dietary folate restriction exacerbates the impaired leukemia progression phenotype of nucleotide salvage-deficient B-ALL cells. Together, these findings demonstrate that access to folates is an endogenous limitation for nucleotide synthesis in plasma-like nutrient conditions, increasing the relevance of nucleotide salvage pathways for leukemia progression. More broadly, this work highlights how micronutrient abundance can influence metabolic dependencies and reveals that folate levels shape nucleotide metabolism under physiological conditions.

DOI: https://doi.org/10.64898/2026.09.13.750663
Geroscience. 2026 Sep 23.

Ketone ester supplementation in aged mice produces sex-specific cognitive and metabolic effects.

Kirsten J Roslund, Laurynne C Coates, Sadia Sattar Sultani, Dylan Hayes, Samantha Diaz, Jennifer M Rutkowsky, Zeyu Zhou, Jon J Ramsey, Ameer Y Taha, Carolyn M Slupsky.

  The ketogenic diet (KD) elevates β-hydroxybutyrate (β-HB), an energy metabolite and signaling molecule with immunomodulatory effects, and has been associated with cognitive and metabolic effects in some preclinical and clinical studies. However, clinical evidence for ketogenic and ketone-based interventions in cognitive aging and Alzheimer's disease remains mixed, and long-term carbohydrate restriction may be difficult to implement in older adults. Dietary supplements that elevate β-HB, such as medium-chain triglycerides and ketone esters, have been proposed as alternatives to the KD, but their sex-specific effects in aging remain poorly defined. Here, we determined the effects of short-term supplementation with the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate on physical function, metabolism, and age-related memory outcomes in 24-month-old male and female C57BL/6 mice. The ketone ester-containing diet increased postprandial β-HB and lowered postprandial glucose; however, its effects on cognitive, anthropometric, inflammatory, and metabolic outcomes differed by sex. In males, the intervention changed body composition, with lower body fat and higher relative lean mass. In females, the intervention was associated with fewer Barnes maze primary errors and lower hippocampal IL-1β expression. These sex-dependent effects were accompanied by differences in fasting metabolite profiles across tissues and biofluids and by altered hippocampal oxylipins. Further studies are needed to determine whether ketone monoester supplementation has similar sex-specific effects in humans, and to define the mechanisms, physiological changes, and translational relevance of ketone-based interventions in aging.

Keywords:  Aging; Cognition; Ketogenic; Ketone; Ketone ester; β-hydroxybutyrate

DOI:  https://doi.org/10.1007/s11357-026-02546-8
Nature. 2026 Sep 23.

Hepatocytes promote liver metastasis of pancreatic cancer by providing serine.

Koelina Ganguly, Keisuke Yamamoto, Jason Rodencal, Joel Encarnacion-Rosado, Albert S W Sohn, Douglas E Biancur, Elaine Y Lin, Ruohong Wang, Carolina Alcantara Hirsch, Anthony Sorrentino, Elshaddai Z White, Paul M Grandgenett, Michael A Hollingsworth, Miwako Kakiuchi, Richard Possemato, Dafna Bar-Sagi, Mitsuhiro Fujishiro, Alec C Kimmelman.

The liver is the primary site of metastasis in pancreatic ductal adenocarcinoma (PDAC), and liver metastases are a major cause of mortality1,2. Nutrient availability in the metastatic niche influences colonization efficiency; however, the metabolic heterogeneity of disseminated tumour cells can also reshape the local microenvironment3-5. Loss of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine biosynthesis, is observed in nearly 40% of PDACs, and renders these cells dependent on exogenous serine (exSer)6. Although a neuron-tumour metabolic cross-talk supports exSer-dependent PDAC cells at the primary site6, it remains unclear how these cells adapt to the metastatic liver niche. Here we show that exSer-dependent PDAC cells reprogram neighbouring hepatocytes through a CXCL5-CXCR2 axis. Activation of CXCR2 in hepatocytes promotes PI3K-AKT signalling, leading to the sequestration of FOXO3A in the cytoplasm and derepression of PHGDH transcription, thereby enhancing serine production in hepatocytes. This hepatocyte-derived serine supports the outgrowth of exSer-dependent PDAC liver metastases. Accordingly, genetic or pharmacological inhibition of individual nodes within the CXCL5-CXCR2-PI3K-AKT-FOXO3A axis, or hepatocyte-specific deletion of Phgdh or Cxcr2, markedly reduces the liver-metastasis burden in mice and prolongs survival, particularly when dietary serine is restricted. Our findings reveal a cancer cell-hepatocyte metabolic cross-talk and identify therapeutic targets for exSer-dependent PDAC liver metastases.

DOI: https://doi.org/10.1038/s41586-026-11051-z
Genes Dev. 2026 Sep 22.

Initial perturbations triggered by p53 loss in stem cells.

Yang Fan, Amanda E Jones, Yulei Wei, Yi Ding, Chendong Yang, Ralph J DeBerardinis, Jun Wu, John M Abrams.

  p53 is frequently mutated in human cancers, but how it normally acts to prevent transformation is not fully understood. The initial events triggered by p53 loss are commonly extrapolated from cell lines, patient tumors, or mouse models in which p53 has been absent for long durations (e.g., months, years). In these contexts, collateral changes, competitive selection, and secondary adaptations may obscure the immediate impact of p53 elimination. Therefore, to inspect the direct consequences triggered by p53 loss in real time, we developed a platform that enables conditional removal of p53 in unstressed mouse embryonic stem cells. Within 48 h, activated germline programs were accompanied by altered chromatin profiles and downregulated canonical p53 targets. At the single-cell level, extensive heterogeneity was observed in the form of erupting retroelements, increased SINE accessibility, features of Warburg metabolism, and functional germ cell effectors (e.g., Dmrt1 and PGC7/Dppa3). Together, these findings expose ground state functions for p53 and establish that germline transitions, activated mobile elements, and metabolic reprogramming define acute perturbations caused by p53 loss.

Keywords:  ESCs; Warburg metabolism; depletion; germline; p53; perturbations; retroelements

DOI:  https://doi.org/10.1101/gad.353794.126
Cells. 2026 Sep 09. pii: 1630. [Epub ahead of print]15(18):

In Vitro Glutamine Adaptability in Murine Liver- but Not Lung-Metastasizing Triple-Negative Breast Cancer Cells.

Marjorie Anne Layosa, Keigo Tomoo, Madeline P Sheeley, Michael F Coleman, Chaylen Andolino, Michael K Wendt, Stephen D Hursting, Dorothy Teegarden.

  Background: Metabolic adaptability plays a critical role in supporting the growth and survival of metastatic breast cancer cells, and potentially supports site-specific metastasis. This study investigates the differential metabolism of glutamine and adaptability to varying glutamine levels of triple-negative breast cancer (TNBC) cells that metastasize to the lungs (metM-WntLung) or liver (metM-WntLiver). Methods: The metastatic cell lines were exposed to varying in vitro glutamine concentrations (0.5, 2, and 4 mM). Cell viability, migration, 14C-glutamine uptake, mRNA abundance of metabolic enzymes, and 13C5-glutamine cellular flux, were measured. Results: At an intermediate level of in vitro glutamine supplementation (2 mM), metM-WntLung cells exhibited greater glutamine uptake, catabolic enzyme expression, and flux of glutamine-derived carbon into the TCA cycle compared with metM-WntLiver cells. Despite this, metM-WntLiver cells were more viable and migratory than metM-WntLung cells under both higher (4 mM) and lower (0.5 mM) glutamine levels, suggesting metabolic adaptability. Exposure to ammonia upregulated ammonia-assimilating enzymes in metM-WntLiver, but not metM-WntLung cells, plausibly mitigating ammonia toxicity in higher glutamine conditions. In glutamine-deprived conditions, the metM-WntLung cells maintained higher glutamine oxidation, but the metM-WntLiver cells had higher total glutathione and GSH/GSSG ratios and enhanced resistance to oxidative stress, suggesting glutamate utilization toward glutathione synthesis. Additionally, metM-WntLiver cells utilized glucose-derived carbons through pyruvate carboxylase (PC) to maintain TCA cycle activity, with elevated PC expression and M+3-labeled oxaloacetate enrichment to a greater extent than metM-WntLung cells. PC silencing in metM-WntLiver cells enhanced cell viability under glutamine deprivation, which was reversed by inhibiting phosphoglycerate dehydrogenase (PHGDH, a key enzyme in de novo serine synthesis). We propose that PC activity compensates for low glutamine levels, including diverting glucose to adaptive pathways such as de novo serine synthesis. Conclusions: Overall, our findings demonstrate that metM-WntLiver cells, but not metM-WntLung cells, exhibit glutamine-specific metabolic plasticity, characterized by the modulation of glutamine catabolism, enhanced ammonia metabolism and antioxidant defense, and support of glucose metabolism, which are associated with better cell survival and migration under glutamine excess and deprivation.

Keywords:  TNBC; breast cancer; glutamine; glutathione; metabolic adaptation; metabolic plasticity; metastasis; organotropic metastasis; pyruvate carboxylase

DOI:  https://doi.org/10.3390/cells15181630
Cell Rep. 2026 Sep 24. pii: S2211-1247(26)01107-1. [Epub ahead of print]45(10): 118029

FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.

Manas Kohli, Aurélien Tripp, Anastasiia Shcherbakova, George Poulogiannis.

  Metabolic reprogramming is a hallmark of cancer, yet dynamic metabolic flux has been difficult to study systematically. Here, we present FluxAtlas, a pan-cancer atlas of metabolic flux generated from genome-scale metabolic modeling of over 10,000 tumors across 28 The Cancer Genome Atlas (TCGA) cancer types. By integrating enzyme constraints and nutrient diffusion limits, we reveal conserved and tissue-specific metabolic rewiring, including alterations in bile acid recycling, urea metabolism, and amino acid biosynthesis. We identify a bile acid-associated program that remodels glutathione homeostasis and drives gastrointestinal-specific lipid metabolism. Comparisons with matched normal models uncover tumor-selective metabolic dependencies, such as increased reliance of renal cancers on de novo purine synthesis. Under nutrient limitation, modeling predicts convergence on glutamine-dependent aspartate synthesis while preserving tissue-specific metabolic states. Machine learning models based on fluxomics predict patient survival and highlight biotin uptake as a prognostic biomarker. FluxAtlas defines the functional metabolic landscape of human cancer and is accessible at https://software.icr.ac.uk/app/flux-atlas.

Keywords:  CP: cancer; CP: metabolism; FluxAtlas; cancer; genome-scale metabolic modeling; metabolic flux; metabolic reprogramming; prognostic biomarkers; therapeutic targets

DOI:  https://doi.org/10.1016/j.celrep.2026.118029
Epigenomes. 2026 Sep 16. pii: 59. [Epub ahead of print]10(3):

KDM4B Maintains Pyruvate Dehydrogenase Complex Expression to Support Mitochondrial Metabolism and Survival in Cancer Cells.

Sachiko Sato, Arif Ul Hasan, Mami Obara, Eiichi Taira.

  Background/Objectives: Metabolic reprogramming is a hallmark of cancer and requires coordinated regulation of glycolysis and mitochondrial metabolism. The pyruvate dehydrogenase complex (PDC) links these pathways by catalyzing the conversion of pyruvate to acetyl-CoA, yet the epigenetic mechanisms regulating PDC expression remain poorly understood. We investigated whether the histone demethylase KDM4B regulates PDC expression and mitochondrial metabolism in cancer cells. Methods: Human colorectal carcinoma (HCT-116), cervical adenocarcinoma (HeLa), melanoma (G-361), and non-malignant human proximal tubule epithelial (HK-2) cells were analyzed using glucose-response assays, RNA sequencing, RT-qPCR, immunoblotting, metabolic assays, fluorescence imaging, and cell viability analyses. KDM4B was disrupted by small interfering RNA (siRNA) and the selective inhibitor NCGC00244536. Results: Glucose availability induced coordinated upregulation of the PDC subunits PDHA1, DLD, and DLAT and was associated with increased proliferation and KDM4B expression in cancer cells. Both genetic depletion and pharmacological inhibition of KDM4B suppressed PDC expression and increased the repressive histone mark H3K9me3. Exploratory RNA-seq analysis revealed coordinated metabolic transcriptional reprogramming characterized by induction of glycolytic genes and suppression of PDC, the tricarboxylic acid cycle, and electron transport chain genes, together with increased PDK1 and reduced PDP1 expression, consistent with impaired mitochondrial glucose oxidation. These changes were accompanied by reduced pyruvate dehydrogenase activity, extracellular pyruvate accumulation, ATP depletion, impaired glucose uptake, mitochondrial depolarization, caspase-3 activation, increased lactate dehydrogenase release, reduced viability, and diminished proliferative capacity. These effects were generally more pronounced in the cancer cell models than in HK-2 cells. Conclusions: Our findings identify KDM4B as a regulator associated with maintenance of PDC expression and mitochondrial glucose metabolism in cancer cells. KDM4B inhibition suppresses PDC abundance and activity and is accompanied by metabolic dysfunction, mitochondrial depolarization, and reduced cell survival. These findings support a model in which the KDM4B-PDC axis may contribute to metabolic homeostasis and survival in cancer cells and suggest that this pathway may represent a potential therapeutic vulnerability.

Keywords:  KDM4B; cancer metabolism; epigenetic regulation; histone demethylase; metabolic reprogramming; mitochondrial metabolism; pyruvate dehydrogenase complex

DOI:  https://doi.org/10.3390/epigenomes10030059
ACS Sens. 2026 Sep 21.

Enhanced Ratiometric Indicators for (Sub)cellular Detection of Magnesium(II) Ions by Flow Cytometry.

Michael Brady, Mu-Chun Liu, Veronika Shchepetkina, Daniela Buccella.

  Magnesium(II) plays essential roles in cellular physiology, yet the inner workings of its cellular distribution and transport remain challenging to study due to the scarcity of tools for Mg2+-selective detection with high spatiotemporal resolution and compatible with high-throughput analysis. We report herein MagZet2, a next-generation ratiometric fluorescent sensor featuring a quinoline dicarboxylate motif with an expanded dynamic range for Mg2+ detection by fluorescence microscopy and flow cytometry. MagZet2 displays excellent Mg2+/Ca2+ selectivity and an apparent dissociation constant, K'd = 0.4 mM, well matched to physiological free Mg2+ concentrations in mammalian cells. By conjugation to HaloTag, we further engineer MagZet2 into chemigenetic indicators that retain desirable photophysical properties of the small molecule counterpart while enabling genetically encoded control of subcellular localization. Using a hybrid sensor, MagZet2(L2)Halo, we demonstrate the first organelle-resolved Mg2+ detection by flow cytometry, a technique that does not inherently offer spatial resolution. Finally, we apply MagZet2(L2)Halo to monitor Mg2+ uptake kinetics in live Caco-2 cells, revealing transport dynamics that parallel those measured using destructive 25Mg transport assays while offering improved temporal resolution and compatibility with live-cell analysis. Together, these results establish MagZet2 and its chemigenetic derivatives as powerful tools for organelle-resolved, high-throughput interrogation of free Mg2+ in living cells.

Keywords:  flow cytometry; fluorescence microscopy; fluorescent indicator; live cell imaging; metal ions; metal transport

DOI:  https://doi.org/10.1021/acssensors.6c01904
Pharmaceuticals (Basel). 2026 Sep 01. pii: 1384. [Epub ahead of print]19(9):

Exploiting Metabolic Vulnerabilities in Acute Myeloid Leukemia: Rationale and Evidence for Combining Metabolic Modulators with Conventional Chemotherapy.

Usman Ali Shams, Fawad Inayat, Muhammad Asif Zeb, Maryam, Sulaiman Shams, Muhammad Jawad Ullah, Silvia Jiménez-Morales.

  Acute myeloid leukemia (AML) represents a heterogeneous group of hematological malignancies characterized by uncontrolled proliferation of myeloid progenitors and accumulation of immature blasts in the bone marrow. Metabolic reprogramming is now recognized as a core hallmark of AML, generating dependencies that distinguish leukemic cells from normal hematopoietic stem and progenitor cells and that can be exploited therapeutically. In this review we follow a single connected line of argument: we first place metabolic rewiring within the broader hallmarks of cancer, then describe the principal metabolic programs altered in AML and the specific features that distinguish AML from other malignancies. We next examine the inhibitors and drugs that target each of these pathways, linking every drug class to its mechanism of synergy with chemotherapy, the preclinical and clinical evidence available, and its association with outcome in AML. We then consider multi-target (combination) therapy as a distinct opportunity, and finally the principal challenges that remainsafety and tolerability, the metabolic heterogeneity and plasticity of AML, and the design of biomarker-guided trials. Multiple classes of metabolic drugs are discussed, including glycolysis inhibitors, oxidative phosphorylation inhibitors, glutamine metabolism antagonists, fatty acid oxidation modulators, and redox-active compounds. Despite significant challenges, targeting cellular metabolism represents a promising strategy to enhance therapeutic outcomes in patients with AML.

Keywords:  acute myeloid leukemia; chemotherapy; drug combination; glutamine metabolism; glycolysis; metabolic reprogramming; oxidative phosphorylation; targeted therapy

DOI:  https://doi.org/10.3390/ph19091384
Nature. 2026 Sep;657(8133): 870-872

All the ways a cell can die - and why the variety matters.

Amber Dance.



Keywords:  Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1038/d41586-026-02929-z
Genes (Basel). 2026 Sep 15. pii: 1122. [Epub ahead of print]17(9):

Wired to Survive: How AML Cytogenetics Shape Apoptotic Dependence and Venetoclax Resistance.

Arnold Rojas, Sahil Jethi, Tulin Budak-Alpdogan, Manoj K Pandey.

  Acute myeloid leukemia (AML) is cytogenetically and phenotypically heterogeneous, and this diversity contributes to differences in how patients respond to therapies that target apoptosis. Venetoclax, a selective BCL-2 inhibitor, has been demonstrated to improve outcomes when combined with hypomethylating drugs (HMAs) such as azacitidine or decitabine; nonetheless, clinical trials have indicated that resistance and recurrence are prevalent. This review examines the current evidence linking chromosomal abnormalities and cellular differentiation state to mitochondrial apoptotic pathways, with an emphasis on how these factors influence dependence on certain anti-apoptotic BCL-2 family proteins. We summarize how specific cytogenetic subtypes and high-risk groups (including monosomy 7/del(7q) and complex karyotype/TP53-altered AML) frequently show stress-adaptive signaling and reliance on multiple anti-apoptotic pathways, which can limit the durability of response to BCL-2 inhibition. Lineage-associated dependencies are also examined, such as monocytic differentiation (which leads to increased MCL-1 reliance) and erythroid/megakaryocytic differentiation, which has been associated with increased BCL-XL dependence and venetoclax resistance. Finally, we discuss the therapeutic implications of dependence mapping, including venetoclax combinations and direct MCL-1/BCL-XL targeting, and propose promising biomarker strategies that can detect dependence shifts early and guide appropriate treatment selection.

Keywords:  BCL-2 family proteins; BH3 mimetics; acute myeloid leukemia; cytogenetics; mitochondrial apoptosis; targeted therapy; therapeutic resistance; venetoclax

DOI:  https://doi.org/10.3390/genes17091122
Cardiovasc Res. 2026 Sep 21. pii: cvag212. [Epub ahead of print]

Beyond glucose: metabolic substrate provision enhances cardiac energetics, function and stability ex vivo: a simple recipe for healthier hearts?

Zoe Hoare, Yu Jin Chung, Edward C T Waters, Abbie Hayes, Katie Tompkins, Christopher O'Shea, Davor Pavlovic, Richard Southworth, Thomas R Eykyn, Michael J Shattock.

AIMS: In 1932, Hans Krebs and Kurt Henseleit introduced a bicarbonate-based solution for liver perfusion containing only 5.55 mM glucose. This bicarbonate-based Krebs-Henseleit buffer (KHB) has been frequently modified over many years but typically includes only glucose as a substrate, often to hyperglycaemic levels. However, despite its popularity, hearts perfused under these conditions are close to the limits of substrate and oxygen availability and unable to sustainably respond to increased demand. The aim of the present study was to compare the function, stability and energetics of hearts perfused with standard glucose-containing KHB with those perfused with a Full Metabolic Buffer (FMB) containing a physiologically appropriate range of substrates, including (in mM): fatty acids (0.4), lactate (1), pyruvate (0.1), glucose (5), glutamate (0.5), β-hydroxybutyrate (4), and insulin (5 mIU/L).
METHODS AND RESULTS: Isolated rat hearts were perfused with either KHB or FMB, followed by isoprenaline (1 μM for 20 mins) to induce stress. Cardiac function was measured via an intraventricular balloon, while energetics and metabolism were assessed with 31P and 1H NMR spectroscopy while action potential/calcium transients were assessed with cardiac optical mapping. An adapted FMB was also developed for culturing isolated cardiomyocytes, and glycolytic flux in these cells was measured with 2H NMR spectroscopy. In hearts perfused with FMB, basal left ventricular developed pressure was higher (160 ± 7 mmHg vs. 126 ± 6 mmHg in KHB), PCr/ATP ratio was elevated (1.67 ± 0.1 vs. 1.28 ± 0.05), Gibbs free energy of ATP hydrolysis was increased -2.9 ± 0.3 kJ/mol more negative, and mitochondrial membrane potential was more polarized by -19 ± 7 mV. Under stress, Langendorff-perfused FMB hearts maintained contractile function with fewer arrhythmias and maintained higher PCr/ATP ratio. The metabolic profile was significantly different between hearts perfused with either buffer, with higher levels of key mitochondrial metabolites such as succinate and fumarate in FMB hearts. FMB supressed pacing induced calcium transient duration alternans compared to KHB perfused hearts.
CONCLUSION: Compared to KHB, FMB provides substantial advantages for cardiac energetics, metabolism, and function, and is therefore a more appropriate buffer to use in cardiovascular metabolism studies.

DOI: https://doi.org/10.1093/cvr/cvag212
bioRxiv. 2026 Sep 15. pii: 2026.09.09.750228. [Epub ahead of print]

Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories.

Wenyu Tang, Haoyu Xu, Steven Beck, Marcus T Cicerone, Sung Min Han, Wei-Wen Chen.

Mitochondrial dysfunction is a hallmark of aging, yet how mitochondrial states are remodeled across tissues and subcellular compartments in vivo remains elusive. Progress has been limited, in part, because mitochondrial physiology is highly sensitive to experimental perturbations, underscoring the need for minimally disruptive measurement strategies. Here, we establish a tissue-resolved, in vivo framework for the quantitative analysis of mitochondrial states in live, intact Caenorhabditis elegans without confounding effects from mounting-induced hypoxia. This platform couples two-photon fluorescence lifetime imaging microscopy (2p-FLIM) with a custom segmentation pipeline, MitoSLIT, to track functional and structural features across multiple tissues and single neurons. By integrating membrane potential-associated TMRM intensity, lifetime-based microenvironmental metrics, and morphological descriptors, we uncover localized metabolic heterogeneity masked by conventional intensity analysis. Leveraging this framework, we mapped physiological aging against mitochondrial shifts induced by acute stress and fission-fusion mutations. Our analyses reveal that mitochondrial aging is highly tissue-specific, executing distinct trajectories across cell types. Extending the framework to genetically identified neurons revealed age-dependent divergence between somatic and axonal mitochondrial states, accompanied by structural remodeling and a late shift in optical redox ratio. Together, our findings demonstrate that mitochondrial populations do not converge on a uniform bioenergetic endpoint during aging, but rather follow highly compartmentalized, tissue-specific spatiotemporal trajectories in vivo .

DOI: https://doi.org/10.64898/2026.09.09.750228
bioRxiv. 2026 Sep 17. pii: 2026.09.11.751086. [Epub ahead of print]

Na + /K + -ATPase Blockade Reversibly Attenuates Proliferation and Metabolic Function in K562 Human Myelogenous Leukemia Cells.

Simon R Bowden, Eli T Colton, Amber D Norgaard, McKenzie M Haas, Erynn R Dunnigan, Carly J Goven, Grace O Goven, Thomas J Hinnenkamp, Keagan D Walker, Theresa M Ballance, Blaise I Kathol, Elizabeth R Murphy, Kristian M Van Slyke, Rylie J Webb, Ashlin B Schaefbauer, Emily R Biggane, Joseph P Biggane.

The Na + /K + -ATPase consumes a substantial portion of cellular ATP to maintain essential electrochemical gradients, yet its role in regulating cancer cell proliferation and phenotypic plasticity remains complicated by its dual function as an ion transporter and a scaffolding receptor. Here, we investigate the physiological consequences of pharmacological NKA blockade using digoxin in K562 human chronic myelogenous leukemia cells. Submicromolar digoxin exposure induced a concentration-dependent attenuation of cell proliferation (IC 50 = 151.0 nM) and a statistically significant depression of metabolic reducing capacity without impairing cell viability. Competitive supplementation with extracellular potassium salts produced a surmountable rightward shift in digoxin sensitivity, confirming that growth inhibition is driven by on-target NKA pump occupancy rather than non-specific interactions. Furthermore, this cytostatic growth attenuation and metabolic depression were found to be fully reversible upon drug clearance. K562 cells are largely refractory to canonical kinase-overdrive stress checkpoints as they harbor constitutive BCR-ABL tyrosine kinase activity alongside non-functional TP53 and a homozygous deletion of CDKN2A (p16 INK4a ). Consequently, these findings suggest that NKA perturbation attenuates K562 growth primarily through ion dyshomeostasis and secondary active transport constraints rather than scaffold-mediated signaling. Overall, we present a novel model for elucidating the role of the NKA in cancer proliferation and dissecting the mechanistic underpinnings of ion-mediated alterations in cancer cell physiology.

DOI: https://doi.org/10.64898/2026.09.11.751086