bims-mibica 2026-09-20 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–09–20
fourteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells.
Cysteine excess triggers a mitochondrial iron-dependent cell death.
Therapeutic Co-targeting of Oxidative Phosphorylation and Pyrimidine Synthesis Restores Gemcitabine Response in Pancreatic Ductal Adenocarcinoma.
Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML.
DHODH inhibition drives albumin-mediated drug resistance through TERF2IP lactylation-activated macropinosome-mitochondria contact.
Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.
Tamoxifen and Colchicine Alter Mitochondrial Respiration to Induce Cell Death in Low-metastatic Breast Cancer Cells.
The Methionine-Mitochondria Axis in Cancer: Metabolic Cross-Talk and Therapeutic Vulnerabilities.
Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.
Specific targeting of cancer cell mitochondria with a malaria drug improves pancreatic cancer outcome.
Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.
Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
Divergent transcriptional programs and constrained metabolic states reveal selective metabolic dependencies in chemoresistant luminal breast cancer.
RAS seals fate in AML besieged by FLT3 and BCL2 inhibitors.

Blood. 2026 Sep 17. pii: blood.2026034181. [Epub ahead of print]

IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells.

Aykut Demir, Maximilian Mönnig, Nesrine Aroua, Eleni Besiridou, Valentin Schmidt, Kristina Müller, Simon Renders, Fabian Schulte, Alireza Pouya, Alexander Waclawiczek, Aino-Maija Leppä, Karolin Stumpf, Markus Sohn, Dominic Depke, Patrick Wuchter, Darja Karpova, Elisa Donato, Halvard Bonig, Carolin Andresen, Michael Büttner, Gernot Poschet, Daniel Hübschmann, Nicola Zamboni, Tim Sauer, Andreas Trumpp, Carsten Müller-Tidow, Simon Raffel.

Targeting metabolic dependencies of leukemic stem cells (LSC) may open avenues to improve outcomes of patients suffering from acute myeloid leukemia (AML). LSCs rely heavily on an active tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation whereas healthy hematopoietic stem and progenitor cells (HSPCs) possess more metabolic flexibility. Here, we identify the TCA cycle enzyme isocitrate dehydrogenase 3 (IDH3) as a critical and selective regulator of LSC maintenance. IDH3 is more abundant in LSCs compared to healthy HSPCs, and TCA cycle activity correlates with inferior clinical outcomes of AML patients. Knockdown of IDH3A, the catalytic subunit of the complex, impairs colony-forming potential and bone marrow organoid as well as in vivo engraftment of AML, while sparing healthy hematopoiesis. Mechanistically, IDH3A downregulation reduces TCA cycle flux and leads to accumulation of intracellular citrate, impairing both glycolysis and oxidative phosphorylation. The resulting bioenergetic crisis activates AMPK and suppresses mTORC1, leading to reduced translational activity and an imbalance of anti-apoptotic proteins. Consequently, IDH3A-KD cells show enhanced susceptibility to BCL2 inhibition by venetoclax in vitro and in vivo. In a clinical cohort, LSCs from patients resistant to venetoclax/azacitidine (Ven/Aza) exhibit transcriptomic programs indicative of active TCA cycle and glycolysis. We demonstrate that downregulation of IDH3A activity and subsequent citrate accumulation directly affect these pathways and shift AML stem cells towards a metabolic state of increased vulnerability. In summary, we establish IDH3 as a metabolic rheostat in LSCs and suggest targeting the IDH3A-citrate axis to overcome Ven/Aza resistance of AML patients.

DOI: https://doi.org/10.1182/blood.2026034181
Nat Metab. 2026 Sep 15.

Cysteine excess triggers a mitochondrial iron-dependent cell death.

Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.

Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.

DOI: https://doi.org/10.1038/s42255-026-01616-7
Transl Res. 2026 Sep 13. pii: S1931-5244(26)00195-7. [Epub ahead of print]

Therapeutic Co-targeting of Oxidative Phosphorylation and Pyrimidine Synthesis Restores Gemcitabine Response in Pancreatic Ductal Adenocarcinoma.

Wenhui Ouyang, Jie Wang, Jie Chen, Zemin Fang, Ting Wei, Jiazi Qian, Shanying Gui.

  Gemcitabine resistance remains a major barrier to effective therapy in pancreatic ductal adenocarcinoma (PDAC), and current combination regimens show potential to overcome this resistance. Here, we identify the mitochondrial ribosomal proteins MRPS22 and MRPL3 as key metabolic gatekeepers that maintain mitochondrial OXPHOS and pyrimidine metabolism, thereby promoting pancreatic cancer cell proliferation and chemoresistance. Across independent cohorts, high MRPS22/MRPL3 expression associates with poorer survival. Depletion of either gene in PDAC curtailed cell proliferation and xenograft growth, which might be due to an impaired mitochondria function, including destabilized respiratory super-complex assembly, diminished ATP production, and increased oxidative stress. Multi-omics profiling revealed a broad reduction of central-carbon intermediates and a pronounced blockade of de novo pyrimidine synthesis at the dihydroorotate dehydrogenase (DHODH) node. MRPS22 depletion hampered nucleotide-pool generation, and exogenous deoxynucleotides partially rescued PDAC cell growth when MRPs were knocked down. Pharmacologic OXPHOS inhibition increased gemcitabine sensitivity, whereas gemcitabine-resistant derivatives exhibited heightened OXPHOS activity and upregulated mitochondrial ribosomal programs. Co-targeting OXPHOS (antimycin A) or DHODH (brequinar) with gemcitabine produced Loewe synergy in vitro and suppressed growth of gemcitabine-resistant xenografts without affecting body weight. Collectively, these findings established MRPS22/MRPL3 as translation-level drivers of PDAC metabolic fitness and nominate OXPHOS/DHODH blockade as a rational combination strategy to overcome gemcitabine resistance.

Keywords:  Chemoresistance; Chemotherapy; Mitochondrial ribosomal protein; Pancreatic ductal adenocarcinoma; Pyrimidine metabolism

DOI:  https://doi.org/10.1016/j.trsl.2026.09.009
JCI Insight. 2026 Sep 15. pii: e205218. [Epub ahead of print]

Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML.

Silvia Romero-Murillo, Irene Peris, Anna Maria Lucianò, Nerea Marcotegui, Carmen Vicente, Brian Tran, Kelsey Barrie, Caitlin M O'Connor, Andrea Torres-López, Maria C Mateos, Maria L Cayuela, Victoriano Mulero, Joaquín Fernández-Irigoyen, Enrique Santamaría, Maria D Odero, Goutham Narla.

  Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in acute myeloid leukemia (AML) patients. Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We recently demonstrated that the specific activation of the phosphatase PP2A-B56α enhances the pro-apoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics-based approaches and using both genetic and pharmacological tools, we define key roles for the tumor suppressor PP2A-B56α complex in OXPHOS regulation and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza-sensitive and -resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56α stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes.

Keywords:  Cell biology; Drug therapy; Hematology; Phosphoprotein phosphatases; Tumor suppressors

DOI:  https://doi.org/10.1172/jci.insight.205218
Nat Commun. 2026 Aug 14. pii: 9792. [Epub ahead of print]17(1):

DHODH inhibition drives albumin-mediated drug resistance through TERF2IP lactylation-activated macropinosome-mitochondria contact.

Junhu Yuan, Tan Wang, Yarui Ma, Guangyu Li, Chenxi Wang, Mei Liu, Zian Cai, Xiaoyue Wang, Xiaobing Wang, Hongying Wang, Yuchen Jiao.

Macropinocytosis enables cancer cells to scavenge extracellular nutrients and contributes to tumor progression, but its role in chemoresistance remains poorly characterized. Through CRISPR-Cas9 and small-molecule screens, we identify inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in pyrimidine synthesis, as an inducer of macropinocytosis. Mechanistically, DHODH inhibition triggers metabolic reprogramming toward glycolysis and lactate accumulation. This metabolic shift promotes lysine 208 lactylation of telomeric repeat-binding factor 2-interacting protein (TERF2IP), unveiling its moonlighting function in transcriptional activation of epiregulin, which activates EGFR signaling to promote macropinocytosis. Macropinosomes contact mitochondria, enabling albumin translocation into the mitochondrial intermembrane space where it interacts with DHODH, diminishing inhibitor binding and restoring DHODH activity. This adaptive response contributes to drug resistance in vitro and in vivo, and co-administration of DHODH inhibitors with macropinocytosis blockers or EGFR inhibitors enhances anti-tumor efficacy. Our findings reveal a previously unknown metabolic stress-induced macropinocytosis pathway and provide a rationale for combination therapy to enhance DHODH inhibitor efficacy in cancer treatment.

DOI: https://doi.org/10.1038/s41467-026-75872-2
Nat Commun. 2026 09 15. pii: 9788. [Epub ahead of print]17(1):

Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.

Ines Saenz-de-Santa-Maria, Anna Pepe, Jean-Yves Tinevez, Christel Brou, Yakov Vitrenko, Thomas Cokelaer, Elizabeth Cohen-Jonathan Moyal, Roberto Weigert, Chiara Zurzolo.

Tumor progression is driven by cancer cells' ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the functional consequences of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. Here we show bidirectional mitochondrial transfer between Glioblastoma (GBM) cells and non-tumoral astrocytes (AS). We report that transfer of damaged mitochondria from GBM cells to AS is associated with activation of mitophagy in recipient cells, while astrocyte-derived mitochondria to GBM cells correlates with changes in mitochondrial activity and metabolic readouts. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model allows the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings reveal a potential mechanism of tumor adaptation and highlight TNTs as promising therapeutic targets.

DOI: https://doi.org/10.1038/s41467-026-76619-9
Curr Mol Med. 2026 ;26(5): 516-528

Tamoxifen and Colchicine Alter Mitochondrial Respiration to Induce Cell Death in Low-metastatic Breast Cancer Cells.

Tashvinder Singh, Amitha Thankachan, Anjana Munshi, Sandeep Singh.

   BACKGROUND: Breast cancer cells exhibit mitochondrial respiration-mediated metabolic heterogeneity and tumour aggressiveness. Tamoxifen and Colchicine are known to interfere with oxidative stress in breast cancer cells. However, their role in regulating mitochondrial respiration remains poorly understood.
METHODS: MCF7 and MDA-MB-231 cells were used to analyse the metabolic modulatory effects of Tamoxifen and Colchicine. The roles of Tamoxifen and Colchicine in regulating ROS production, mitochondrial membrane potential, mitochondrial membrane integrity, and oxidative phosphorylation were assessed using ROS assay, JC-1 assay, and high-resolution respirometry, respectively. Their effects on mitochondrial biogenesis and mitochondria-dependent cytotoxicity were analysed using flow cytometry and confocal microscopy.
RESULTS: Tamoxifen and Colchicine exhibited cytotoxic effects by reducing ROS production, depolarising mitochondrial membrane potential, decreasing oxygen consumption, and inhibiting mitochondrial respiration. They specifically downregulated pyruvate-mediated mitochondrial respiration, preventing N-linked state mitochondrial respiration and reducing complex I activity. Colchicine demonstrated mitochondrialindependent cytotoxic effects, whereas Tamoxifen did not. Neither drug impacted mitochondrial membrane integrity. Tamoxifen and Colchicine decreased leak respiration, inhibited proton and electron transfer, and prevented non-phosphorylating electron transfer, potentially due to reduced complex I activity. Tamoxifen significantly inhibits mitochondrial biogenesis and induces a mitochondrial-dependent cell death pathway. In contrast, Colchicine had a low impact on mitochondrial biogenesis and induced a mitochondrial-independent cell death pathway.
DISCUSSION: Tamoxifen and colchicine suppress complex I-driven mitochondrial respiration in breast cancer cells, reducing oxidative phosphorylation-associated aggressiveness. Notably, only tamoxifen links this metabolic inhibition to impaired mitochondrial biogenesis and mitochondria-dependent cytotoxicity.
CONCLUSION: Tamoxifen and colchicine downregulate mitochondrial respiration and biogenesis, while only tamoxifen induces mitochondrial-dependent cytotoxicity.

Keywords:  Breast Cancer; Electron Transport Chain (ETC); MCF7; MDA-MB-231; Mitochondria; Oxidative Phosphorylation (OxPhos)

DOI:  https://doi.org/10.2174/0115665240344743251210121414
Curr Pharmacol Rep. 2026 ;12(1): 38

The Methionine-Mitochondria Axis in Cancer: Metabolic Cross-Talk and Therapeutic Vulnerabilities.

Md Salman Shakil, Matthew J McBride.

   Purpose of Review: This article describes the recent discoveries on how the amino acid methionine alters mitochondrial metabolism to support tumor function and growth. A detailed understanding of these mechanisms of cross-talk between the methionine cycle and mitochondria will empower the discovery and development of new metabolism-targeting cancer therapies.
Recent Findings: Methionine and metabolites of the methionine cycle are increasingly appreciated to have both direct and indirect roles in regulating mitochondrial metabolism, which are critical for survival, growth, and treatment-resistance in tumors. Recent work has discovered multiple mitochondrial transporters that directly connect tumor use of methionine-derived S-adenosylmethionine (SAM) to mitochondrial function. Carnitine is synthesized from SAM-mediated methylation of lysine and is critical for tumor energy generation by fatty acid oxidation. Tumors depend on mitochondrial transport of SAM to support methylation reactions and oxidative phosphorylation. Purine synthesis is supported by mitochondrial one-carbon units from the folate cycle in tumors, which requires remethylation of homocysteine to form methionine to prevent folate trapping. Preclinical and clinical studies investigating both pharmacological and nutritional interventions are uncovering the mechanisms by which mitochondrial function depends on methionine metabolism. Further exploration in this area will define both the targets and specific interventions with the greatest promise for the treatment of cancer patients.
Summary: Methionine metabolism influences many aspects of mitochondrial function, including energy generation, antioxidant defenses, and lipid composition. Understanding how tumors co-opt these processes and their dependence on the amino acid nutrient methionine provides an opportunity for new cancer therapies.

Keywords:  Cancer; Metabolism; Methionine; Methylation; Mitochondria; S-adenosylmethionine

DOI:  https://doi.org/10.1007/s40495-026-00481-y
Aging Cell. 2026 Sep;25(9): e70718

Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.

Renin Chang, Andy P Tsai, Boyang Wang, Kuan-Hao Tsui, Cheng-Yoong Pang, Chia-Jung Li.

  The accumulation of somatic mitochondrial DNA (mtDNA) mutations across life is among the oldest and most debated proposed drivers of aging. A defining, counter-intuitive feature is that individual mutant molecules, although vanishingly rare when they arise, can come to dominate a cell's multi-copy mtDNA population through intracellular clonal expansion, producing a mosaic of respiratory-deficient cells across aging tissues. Here we synthesize current evidence to argue that clonal mosaicism of mtDNA heteroplasmy constitutes a quantifiable, tissue-specific molecular clock of aging. We trace foundational single-cell and multi-tissue observations of somatic mtDNA mutation, examine the causal evidence from mtDNA mutator mice, and dissect the debate between neutral genetic drift and cellular selection that governs clonal expansion. We then integrate recent single-cell and population-scale studies that have transformed the field: deep multi-tissue surveys revealing tissue-specific accumulation and a biphasic signature, biobank analyses linking heteroplasmy burden to mortality and organ-specific disease, and a two-step mechanism in which cryptic replication-error mutations become detectable through age-related clonal mosaicism. We discuss technologies such as single-cell mtDNA genotyping, duplex and long-read sequencing, and droplet digital PCR that now read the clock at single-molecule resolution, and we connect mutational accumulation to downstream aging phenotypes through mtDNA-driven innate immune signaling, cellular senescence and inflammaging. Finally, we position the mitochondrial clock alongside epigenetic and other aging clocks, highlighting concordance, complementarity, and what must be resolved before heteroplasmy can serve as a blood-based biomarker of biological age.

Keywords:  aging; clonal expansion; heteroplasmy; mitochondrial DNA; molecular clock; respiratory chain deficiency; somatic mutation

DOI:  https://doi.org/10.1111/acel.70718
Sci Rep. 2026 08 16. pii: 28708. [Epub ahead of print]16(1):

Specific targeting of cancer cell mitochondria with a malaria drug improves pancreatic cancer outcome.

Yan Ou, Adrian Lim, Ruoxiang Wang, Nora Mir, Vinicius F Calsavara, Qiang Wang, Yi Zhang, Stephen J Pandol, Mouad Edderkaoui.

  Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. In this paper, we present DZ-ART1, a first-in-class, dual-function therapeutic. This innovative agent is composed of a tumor-targeting heptamethine carbocyanine dye conjugated to artemisinin (ART). Near-infrared imaging demonstrated precise tumor localization of DZ-ART1 in mice. DZ-ART1 accumulated 5- to 10-fold more in cancer cells compared to normal cells. DZ-ART1 significantly decreased the survival of eight PDAC cell lines with little effect on normal cells. It increased the lethal effect of chemotherapies in vitro and in vivo. Functional assays confirmed DZ-ART1's ability to disrupt mitochondrial bioenergetics, deplete ATP, and induce reactive oxygen species production. Mitochondrial depletion of cancer cells decreased DZ-ART1 uptake and cytotoxicity, highlighting its mechanistically unique, mitochondria-dependent action. Transcriptomic profiling revealed DZ-ART1's broad reprogramming of PDAC pathways related to cell survival, cancer stemness, and metastasis. In three rigorously validated preclinical models - Krasþ/LSLG12D;Trp53þ/LSLR172H;Pdx-1-Cre (KPC) transgenic, syngeneic, and patient-derived xenografts (PDX) - DZ-ART1 markedly suppressed tumor growth and metastasis and prolonged survival, all without toxicity to normal tissues. DZ-ART1 represents a new class of anti-cancer therapeutics that uniquely combines diagnostic imaging and cancer cell organelle-specific targeting.

Keywords:  DZ-ART; Mitochondria; Pancreatic cancer

DOI:  https://doi.org/10.1038/s41598-026-66961-9
Cell. 2026 Sep 15. pii: S0092-8674(26)01010-X. [Epub ahead of print]

Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.

Kalil G Abdullah, Kenji Miki, Charles K Edgar, Shuangcheng Alivia Wu, Yi Xiao, Yuan-Tai Huang, Richard Drexler, Saritha Krishna, Vinesh T Puliyappadamba, Li Wei Rachel Tay, Fanen Yuan, Milan R Savani, Maged T Ghoche, Shawn E Kotermanski, Jeffrey I Traylor, Lei Guo, Kathryn Gunn, William H Hicks, Diana D Shi, Belgin Yalçın, Kim Kilian, Min Tang, Mitchell Moyer, Michael M Levitt, Mohamad El-Shami, Skyler Oken, Namya Manoj, Lauren C Gattie, Bailey C Smith, Pranita Kaphle, Tracey Shipman, Raymond E West, Chaoying Liang, Yasmina Eshac, Tzu-Yi Chia, Toral R Patel, Kimmo J Hatanpaa, Prithvi Raj, Jason M Miska, Denise M O Ramirez, Shang Ma, Thomas D Nolin, Bradley C Lega, Pascal O Zinn, Bianca J Kuhn, Natalie M Clark, C Williams, D R Mani, Michael A Gillette, Marco A Calzado, Lin Xu, Lauren G Zacharias, Feng Cai, Alexander Ksendzovsky, Thomas P Mathews, Julie-Aurore Losman, Benjamin Levi, Tara Barron, Jay R Gibson, Timothy E Richardson, Osaama H Khan, Sameer Agnihotri, Shawn L Hervey-Jumper, Simon Chamberland, Michelle Monje, Kimberly M Huber, Ralph J DeBerardinis, Samuel K McBrayer.

  The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an alternative function. GAA accumulates in GAA N-methyltransferase (GAMT) deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABAA receptors and causing depolarizing currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

Keywords:  GABA; GAMT deficiency; cancer metabolism; cancer neuroscience; creatine; glioma; guanidinoacetate; inborn error of metabolism; metabolite signaling

DOI:  https://doi.org/10.1016/j.cell.2026.08.037
Nat Commun. 2026 Aug 15. pii: 9829. [Epub ahead of print]17(1):

Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.

Hyunmin Cho, Ruhi Sayana, Abhishek Koladiya, Pasqualina Colella, Sangkyun Cho, James W S Jahng, Juan Jose Vasquez, Jessica Arozqueta Basurto, Joseph C Wu, Natalia Gomez-Ospina.

Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.

DOI: https://doi.org/10.1038/s41467-026-76775-y
Cancer Drug Resist. 2026 ;9 30

Divergent transcriptional programs and constrained metabolic states reveal selective metabolic dependencies in chemoresistant luminal breast cancer.

Melis Poyraz, Buse Sari, Jérôme Ambroise, Melanie Spears, Martin Michaelis, Jindrich Cinatl, Romain Boidot, Kristian Serafimov, Olivier Feron, François P Duhoux, Manon Desgres, Cyril Corbet.

  Aim: Resistance to neoadjuvant chemotherapy remains a major challenge in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC). Although anthracyclines and taxanes constitute the standard sequential regimen, the metabolic adaptations accompanying resistance to these agents remain poorly defined. We investigated whether chemoresistance is associated with shared or drug-specific metabolic alterations. Methods: Parental MCF-7 and ZR-75-1 cells and their anthracycline-, and taxane-resistant derivatives, were characterized through multi-omics, Seahorse-based metabolic flux, and pharmacological inhibition analyses, alongside validation in patient transcriptomic datasets. Results: Chemoresistant cells displayed reduced drug sensitivity and improved recovery following treatment withdrawal. Transcriptomic profiling revealed extensive yet largely distinct gene expression changes among resistant models, whereas metabolomics showed limited divergence. Functional studies demonstrated concurrent reductions in mitochondrial respiration and glycolytic capacity, indicating a low-bioenergetic phenotype without compensatory metabolic rewiring. Lipidomic changes were heterogeneous and model-dependent. Despite this overall metabolic constraint, spermidine and spermine levels were increased across all resistant models, whereas upregulation of the polyamine-related genes ATP13A4 and SAT1 was specific to anthracycline-resistant cells. Chemoresistant phenotypes conferred reduced sensitivity to mitochondrial inhibitors. In contrast, sensitivity to polyamine pathway inhibition varied across models. Clinical datasets corroborated key experimental features, showing increased ATP binding cassette subfamily B member 1 (ABCB1) expression and significant post-treatment suppression of oxidative phosphorylation and glycolysis signatures. Polyamine pathway enrichment trends were less uniform, reflecting clinical heterogeneity. Conclusion: Chemoresistance in HR+/HER2- BC is characterized by heterogeneous transcriptional remodeling but relative metabolic constraint. Clinical dataset validation confirms post-chemotherapy bioenergetic suppression, while polyamine alterations represent context-dependent adaptations rather than universal vulnerabilities.

Keywords:  Breast cancer; HR+/HER2- disease; anthracycline; chemoresistance; metabolic plasticity; neoadjuvant chemotherapy; polyamine metabolism; taxane

DOI:  https://doi.org/10.20517/cdr.2026.57
Blood. 2026 Sep 17. 148(12): 1521-1522

RAS seals fate in AML besieged by FLT3 and BCL2 inhibitors.

Andrew H Wei.

DOI: https://doi.org/10.1182/blood.2026034877