bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–09–06
seventeen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
  2. Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
  3. Flow cytometry analysis of mitochondrial apoptotic priming with BH3 profiling on senescent cells.
  4. Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
  5. Horizontal mitochondrial transfer: an emerging field in cell biology.
  6. Direct binding of the C-terminal sequences of Bim and Bak contributes to efficient Bak activation.
  7. Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.
  8. Ionomycin suppresses cancer cell growth by disrupting mitochondrial transcription.
  9. Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
  10. Bone marrow stromal cells promote chemoresistance in acute myeloid leukaemia through P2RX7-mediated antioxidant defence.
  11. KDM6A loss enhances oxidative phosphorylation uncovering tissue-level convergent evolution.
  12. Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
  13. Non-genetic remodeling drives leukemia propagation and reveals actionable vulnerabilities in acute myeloid leukemia.
  14. Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity.
  15. XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia.
  16. MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
  17. A single-amino-acid cleavage controls global mitochondrial complex integrity.
  1. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2531151123
    Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
    Zhengyang Zhang, Liwei Zhang, Peng An, Xu Zhang, Yi Xia, Yunlu Kang, Xiaoxia Chen, Rongrong Hua, Yinhua Zhu, Yanling Hao, Yuan Huang, Yongting Luo, Junjie Luo, Guisheng Wang.
      Simultaneously profiling mitochondrial DNA (mtDNA) heteroplasmy and phenotypic variability at the single-cell level remains a challenge due to the absence of integrated methods that map mitochondrial genotypes alongside their functional states. We introduce human single-cell mitochondrial phenotype-coupled mtDNA sequencing (scMPCDS), a platform that quantifies mtDNA mutations and heteroplasmy together with mitochondrial membrane potential and reactive oxygen species within individual cells. Unlike bulk sequencing or separate single-omics techniques, scMPCDS directly correlates mitochondrial genomic instability with functional outcomes. Using this approach, we demonstrate that DdCBE-mediated mtDNA editing induces cell-specific off-target mutations in the mitochondrial genome, which coincide with diverse phenotypic changes. Applying scMPCDS to HeLa cells and clear cell renal cell carcinoma tissues, we identify single-cell subpopulations exhibiting distinct mtDNA mutation burdens and altered bioenergetic profiles, implicating potential mitochondrial heterogeneity-driven tumor evolution. Overall, scMPCDS serves as a versatile tool to unravel mitochondrial genotype-phenotype relationships at the single-cell level in both normal and disease states, thereby advancing precise mitochondrial diagnostics and therapeutics.
    Keywords:  cancer; mitochondrial phenotype; mtDNA editing; mtDNA heteroplasmy; single cell
    DOI:  https://doi.org/10.1073/pnas.2531151123
  2. 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
  3. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00179-2. [Epub ahead of print]210 1-16
    Flow cytometry analysis of mitochondrial apoptotic priming with BH3 profiling on senescent cells.
    Clara Alcon, Joan Montero.
      Cellular senescence is a stable form of cell cycle arrest triggered by diverse stressors such as telomere shortening, oncogene activation, DNA damage, and chemotherapy. While senescence acts as a tumor-suppressive mechanism, the long-term accumulation of senescent cells contributes to chronic inflammation, tissue dysfunction, and age-related diseases, largely through the senescence-associated secretory phenotype (SASP). Senescent cells are characterized by increased expression of p16INK4a and p21CIP1, enlarged morphology, and resistance to apoptosis. This apoptotic resistance is mainly driven by the upregulation of anti-apoptotic BCL-2 family of proteins, including BCL-2, BCL-xL, and MCL-1. Senolytics - drugs that selectively induce apoptosis in senescent cells - target these survival pathways to promote senescent cell clearance. BH3 profiling is a functional assay that assesses mitochondrial apoptotic priming by exposing permeabilized cells to BH3-domain peptides and measuring cytochrome c release. This technique allows the identification of anti-apoptotic dependencies in senescent cells and can be used in combination with senescence markers (p16 and p21) via flow cytometry to pinpoint populations with enhanced apoptotic resistance. Understanding the apoptotic landscape of senescent cells is critical for optimizing senolytic strategies and improving therapeutic outcomes, particularly in contexts such as cancer and therapy-induced senescence.
    Keywords:  BH3 profiling; Cell death; Flow cytometry; Senescence
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.011
  4. Redox Biol. 2026 Sep 02. pii: S2213-2317(26)00380-0. [Epub ahead of print]97 104381
    Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
    Tanvi Chaudhary, Sharath Mohan Bhat, Priyadarshika Pradhan, Manjunath B Joshi, Devanjan Sinha.
      Coordination of mitochondrial functional states with nuclear transcriptional programs remain critical for cellular adaptation. Here, we identify mitochondrial protein import capacity as a regulator of redox-dependent signalling in tumour cells. We show that the mitochondrial import motor component TIMM44, which is upregulated in angiogenesis-driven tumours, drives respiratory remodelling without increasing mitochondrial abundance. This mitochondrial reprogramming establishes a redox-competent state that activates ASK1-p38MAPK, resulting in SP1-dependent upregulation of VEGFA independently of HIF stabilization. Importantly, induction of mitochondrial biogenesis via PGC-1α fails to recapitulate this response despite increased active mitochondrial content, demonstrating that abundance of active mitochondria or generic metabolic activation is insufficient to drive this HIF-independent transcription. Collectively, our findings identify mitochondrial protein import process as an active signalling regulator rather than a passive housekeeping role, which links mitochondrial proteostasis to redox-sensitive kinase activation and transcriptional control. This work highlights a non-canonical mitochondrial signalling mechanism through which cells couple organelle remodelling to gene expression programs.
    DOI:  https://doi.org/10.1016/j.redox.2026.104381
  5. Trends Cell Biol. 2026 Sep 04. pii: S0962-8924(26)00168-6. [Epub ahead of print]
    Horizontal mitochondrial transfer: an emerging field in cell biology.
    Michael V Berridge, Zuzana Nahacka, Katerina Komrskova, Minghao Zheng, Jiri Neuzil.
      The field of horizontal mitochondrial transfer (HMT), also referred to as intercellular mitochondrial transfer, has recently gained momentum due to an increasing number of publications that go well beyond diseases such as cancer. From co-culture experiments to in vivo evidence in mouse cancer models, noncancerous diseases, and normal tissue and organ homeostasis and development, it is becoming increasingly clear that HMT is a fundamental physiological phenomenon broadly relevant to complex organisms. Recent methodological advances, epitomized by ultra-high-resolution microscopy and spatial and single-cell multiomics technologies, allow for research that strongly supports HMT as an emerging area of cell biology.
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.012
  6. Cell Death Differ. 2026 Sep 03.
    Direct binding of the C-terminal sequences of Bim and Bak contributes to efficient Bak activation.
    Dang Nguyen, Sabina Trebinjac, Tobias B Beigl, Frank Essmann, Kathryn M Murphy, David W Andrews.
      Apoptosis is regulated by Bcl-2 family of proteins through direct binding interactions at the mitochondrial outer membrane. Bak, a key cellular executioner protein in this family, differs from the other executioner proteins Bax and Bok in that it is constitutively localized at the mitochondrial outer membrane via its C-terminal sequence (CTS). Binding of the BH3-only protein Bim triggers conformational changes in Bak that lead to oligomerization and mitochondrial membrane permeabilization. However, the molecular mechanism by which Bim activates Bak remains incompletely understood. Here we demonstrate both in vitro and in cells, that efficient Bim-mediated activation of Bak requires not only the binding of the BH3-motif of Bim to the canonical BH3-binding groove of Bak, but also sequence specific, direct binding of the Bim-CTS to the Bak-CTS. These findings reveal an unexpected contribution of the Bak-CTS to the molecular control of Bak activation during apoptosis.
    DOI:  https://doi.org/10.1038/s41418-026-01848-w
  7. Cell Death Dis. 2026 Aug 07. pii: 766. [Epub ahead of print]17(1):
    Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.
    Na Li, Yanhong Ding, Bowen Yu, Yongqiang Wang, Tongbin Gao, Huiyong Yin, Zhenhua Li, Shuzhen Liu, Guohua Yu, Ningning Wang.
      Clear cell renal cell carcinoma (ccRCC) exhibits a paradoxical fructose metabolism signature characterized by upregulation of the fructose transporter GLUT5 alongside downregulation of the catabolic enzymes (ketohexokinase, aldolase B, and triokinase), a pattern associated with poor prognosis. Functionally, unlike the pro-survival effect of fructose under glucose deprivation, in the presence of glucose, fructose co-treatment suppresses ccRCC cell proliferation, and induces profound mitochondrial dysfunction, including impaired oxidative phosphorylation, loss of membrane potential, excessive mitochondrial superoxide production, reduced mtDNA copy number, and downregulation of mitochondria-encoded electron transport chain subunits (notably ND2 and ND4 of complex I). Mechanistically, co-treatment with glucose and fructose creates a metabolic trap resulting in fructose-1-phosphate accumulation and ATP depletion. This energy crisis drives profound depletion of purine and pyrimidine nucleotide pools, which selectively triggers the PERK-eIF2S1-ATF4-CHOP axis of the integrated stress response, thereby mediating mitochondrial impairment and ultimately sensitizing ccRCC cells to intrinsic apoptosis via BID cleavage and caspase-3 activation under nutrient stress. Pharmacological treatment with the chemical chaperone 4-phenylbutyric acid (4-PBA) or nucleoside supplementation reverses mitochondrial dysfunction and fructose-induced cytotoxicity. The tumor-suppressive effect of fructose is validated in patient-derived organoids and xenograft mouse models, where fructose administration significantly attenuates tumor growth via ER stress. These findings reveal fructose-driven nucleotide depletion and PERK-dependent ER stress leading to mitochondrial dysfunction, which underlies the tumor-suppressive toxicity of fructose and exposes a targetable metabolic vulnerability in ccRCC.
    DOI:  https://doi.org/10.1038/s41419-026-09157-3
  8. FEBS Open Bio. 2026 Sep 01.
    Ionomycin suppresses cancer cell growth by disrupting mitochondrial transcription.
    Lishen Wang, Mingqiang Deng, Dongmei He, Diqin Lai, Dongjun Liu, Dengyong Zhu, Zhenhua Zhang, Peng Tang, Chuanman Zhou, Menghui Yin, Xichen Bao.
      The Warburg effect has long suggested that oxidative phosphorylation (OXPHOS) is dispensable for tumor growth. However, recent studies have shown that the mitochondrial RNA polymerase inhibitors IMT1 and IMT1b, which impair OXPHOS, are potent anticancer agents. Here, we demonstrate that ionomycin, a selective ionophore known to modulate mitochondrial homeostasis, similarly inhibits mitochondrial gene expression across cancer cell lines. Specifically, gene expression and nascent RNA profiling revealed a global downregulation of mitochondrial gene transcription in Jurkat T, THP-1, HeLa, and NCI-H441 cells. Thus, we conclude that ionomycin suppressed mitochondrial gene transcription, impaired OXPHOS, and thereby inhibited cancer cell proliferation and growth, providing a novel insight into the function of ionomycin.
    Keywords:  OXPHOS; cell proliferation; ionomycin; mitochondrial gene transcription
    DOI:  https://doi.org/10.1002/2211-5463.70297
  9. Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00432-5. [Epub ahead of print] 103015
    Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
    Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H Rezaeian, Jennifer R Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G Hill, Lauren E Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S Najafabadi, John J Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin.
      High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.
    Keywords:  DHODH; LOX; MERCS; TNBC; ferroptosis; glucose metabolism; lysyl oxidase; mitochondria-ER contacts; mitophagy
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103015
  10. Exp Mol Med. 2026 Sep 03.
    Bone marrow stromal cells promote chemoresistance in acute myeloid leukaemia through P2RX7-mediated antioxidant defence.
    Ruolan You, Xiaoting Wang, Xiaoming Zheng, Wenqi Fang, Cen Jiang, Jingru Liu, Xiaolin Xu, Maoqing Tan, Danni Cai, Diyu Hou, Jing Zheng, Xinjian Lin, Huifang Huang.
      Acute myeloid leukaemia (AML) remains a therapeutically challenging malignancy owing to its high relapse rates and chemoresistance, often linked to elevated antioxidant defences. Here, we demonstrate that bone marrow stromal cells (BMSCs) confer chemoresistance in AML by upregulating the purinergic receptor P2RX7. Blocking P2RX7 restored chemosensitivity of AML cells. Mechanistically, BMSC-mediated P2RX7 overexpression induces calcium influx and mitochondrial calcium overload, triggering mitochondrial stress and a compensatory antioxidant response. This process involves mitochondrial phosphoglycerate mutase 5 (PGAM5) transducing reactive oxygen species signals, interfering with Keap1-Nrf2 complex formation and leading to Nrf2 stabilization, thereby enhancing cellular antioxidant defences. These findings identify a vital role of P2RX7 in the BMSC-driven redox adaptation programme that underlies AML chemoresistance and highlight P2RX7 signalling as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s12276-026-01839-4
  11. EMBO J. 2026 Sep 04.
    KDM6A loss enhances oxidative phosphorylation uncovering tissue-level convergent evolution.
    Antonino Alex Cartalemi, Dalia Rosano, Camilla Ferrari, Gemma Crupi, Laura Cassina, Guido Gatti, Federica Corigliano, Simona Punzi, Ilaria Villanti, Daphné Dupéré-Richer, Chiara D'Ercole, Veronica Ruggieri, Annarita Miluzio, Tiziana Bruno, Jose Manuel Garcia Manteiga, Valentina Giansanti, Richard L Bennett, Davide Cittaro, Luca Madaro, Alessandra Boletta, Telmo Pievani, Stefano Biffo, Maurizio Fanciulli, Michele Ciboddo, Jonathan Licht, Giovanni Tonon.
      The tumor suppressor KDM6A/UTX, a histone demethylase and a 2-oxoglutarate-dependent dioxygenase, is frequently lost in many cancer types. We show that KDM6A loss pervasively activates oxidative phosphorylation in several solid tumors, generating a pseudo-hyperoxic environment, opposite from the pseudo-hypoxia observed in VHL-mutated renal carcinomas. Mechanistically, KDM6A sustains the expression of the coil-coil domain gene CCDC3, which inhibits CREB1-driven transcription of the mitochondrial regulator PPARGC1A. In the hematological cancer multiple myeloma where KDM6A is frequently deleted, its loss similarly promotes oxidative phosphorylation, but via an alternative mechanism: the increased transfer of mitochondria from stromal to myeloma cells via tunneling nanotubes, triggered by the loss of the mTORC1 inhibitor TRAF3IP3. Beyond cancer, KDM6A regulates oxidative phosphorylation also during development and in adult tissues, engaging either the CCDC3-CREB1 or the TRAF3IP3-mTORC1 pathways. These mutually exclusive associations suggest a tissue-level convergent evolution, positioning KDM6A as a central modulator of mitochondrial activity through context-specific partners.
    DOI:  https://doi.org/10.1038/s44318-026-00891-0
  12. Nat Genet. 2026 Sep 02.
    Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
    Matthew G Jones, Dawei Sun, Kyung Hoi Joseph Min, William N Colgan, Haoyu Wang, Tivadar Török, Juliano Ribeiro, Jessie Xue, Erik C Cardoso, Yao Rong, Luyi Tian, Jackson A Weir, Victor Z Chen, Luke W Koblan, Kathryn E Yost, Nicolas Mathey-Andrews, Edridge D'Souza, Andrew J C Russell, Robert R Stickels, Karol S Balderrama, William M Rideout, Min Dai, Giovanni Marrero, Vipin Kumar, Anjali Saqi, Benjamin Herzberg, Benjamin Izar, Howard Y Chang, Joo-Hyeon Lee, Tyler Jacks, Fei Chen, Jonathan S Weissman, Nir Yosef, Dian Yang.
      Tumor progression is driven by dynamic interactions between cancer cells and their surrounding microenvironment. Here we integrate high-resolution spatial transcriptomics and evolving lineage-tracing technologies to elucidate how tumor expansion, plasticity and metastasis co-evolve with microenvironmental remodeling in a Kras;Trp53-driven mouse model of lung adenocarcinoma. We find that subclonal expansion contributes to a hypoxic, immunosuppressive and fibrotic microenvironment that is associated with the emergence of prometastatic cancer cell states. We use tumor phylogeography to delineate intercellular interactions that are rewired in the expanding tumor niche and use co-culture systems to dissect how intercellular interactions and hypoxia influence cancer cell state. Furthermore, we find that metastases arise from spatially confined primary tumor subclones and remodel the distant metastatic niche into a fibrotic, collagen-rich microenvironment. Together, we present a comprehensive dataset integrating spatial assays and lineage tracing to elucidate how sequential changes in cancer cell state and microenvironmental structures cooperate to promote tumor progression.
    DOI:  https://doi.org/10.1038/s41588-026-02739-z
  13. Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00434-9. [Epub ahead of print] 103017
    Non-genetic remodeling drives leukemia propagation and reveals actionable vulnerabilities in acute myeloid leukemia.
    Clement Larrue, Paolo Angelino, Sarah Mouche, Alexa S Green, Emeline Boet, Ismael Boussaid, Claudia Perez-Carretero, Rudy Birsen, Maxime Sajot, Thomas A Mckee, Ambrine Sahal, Nicolas Chapuis, François Vergez, Christian Recher, Véronique Mansat-De Mas, Olivier Kosmider, Pierre Sujobert, Frederic Catez, Jean-Jacques Diaz, Jean-Emmanuel Sarry, Petros Tsantoulis, Jerome Tamburini.
      Acute myeloid leukemia (AML) persistence and relapse are sustained by leukemia-propagating cells, yet the molecular programs supporting their expansion during disease evolution remain incompletely understood. Using serial patient-derived xenotransplantation, we establish a longitudinal model in which leukemia-initiating capacity progressively increases. Integrated single-cell transcriptomics and multi-omics profiling reveal a predominantly non-genetic trajectory that follows a conserved pattern across models and is associated with coordinated changes across epigenetic, transcriptional, and proteomic layers. Ribosome profiling and rRNA 2'-O-methylation analyses further support a stage-specific increase in translational activity with ribosome remodeling in advanced xenografts. A pharmacological screen of 3,247 compounds uncovers a limited set of vulnerabilities that consistently emerge during disease progression, including CRBN-dependent degradation of GSPT1 (CC-885) and IAP antagonism (AZD5582). In vivo validation shows that both agents markedly reduce leukemic burden, impair leukemia propagation, and enhance cytarabine activity in patient-derived xenograft (PDX) models. Together, these findings show that leukemic propagation is driven by a non-genetic remodeling program, providing a framework to prioritize and test stage-specific therapeutic strategies in AML.
    Keywords:  DNA methylation; acute myeloid leukemia; drug screening; leukemic stem cells; patient-derived xenografts; ribosome profiling; serial xenotransplantation; translational regulation
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103017
  14. Nat Commun. 2026 Sep 04. pii: 9151. [Epub ahead of print]17(1):
    Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity.
    Diego Gilioli, Simona Fusco, Teresa Tavella, Tatiana Volpari, Antonella Santoro, Martin Schönlein, Kety Giannetti, Edoardo Carsana, Nicolò Gualandi, Roberta Noberini, Chiara Brombin, Salvatore Russo, Sara Feola, Yvonne Giannoula, Rui M M Branca, Janne Lehtiö, Tiina M Sikanen, Markus Haapala, Laura Passerini, Angela Andrisani, Giacomo Farina, Alessia Zangari, Anastasia Conti, Lucrezia Della Volpe, Matteo Barcella, Stefano Beretta, Federico Mario Aletti, Matteo Giovanni Carrabba, Silvia Gregori, Chiara Bonini, Ivan Merelli, Fabio Ciceri, Vincenzo Cerullo, Tiziana Bonaldi, Luca Vago, Clemens A Schmitt, Raffaella Di Micco.
      Chemotherapy resistance and disease relapse are major determinants of treatment failure in acute myeloid leukemia (AML). Therapy-induced senescence (TIS) is one outcome of chemotherapy, but its immunological consequences in AML remain unclear. Here we show that ex vivo chemotherapy induces senescence in a subset of therapy-naïve AML samples. TIS is marked by elevated interferon signaling, upregulation of human leukocyte antigen (HLA) class I and II molecules, and increased presentation of leukemia- and senescence-associated peptides, conferring AML cells antigen-presenting cell-like features. These changes enhance autologous CD4+ and CD8+ T cell responses against AML, both ex vivo and in patient-derived xenograft models. TIS also restores AML sensitivity to immune checkpoint blockade therapy. Mechanistically, we identify reduced Polycomb Repressive Complex 2 (PRC2) activity as central to TIS induction and its immunogenicity. PRC2 inhibition reactivates senescence-related genes and HLA expression in non-senescent AML cells, enabling T cell activation. These findings uncover a senescence-driven immune mechanism with potential to improve therapy outcomes in AML.
    DOI:  https://doi.org/10.1038/s41467-026-76853-1
  15. J Clin Invest. 2026 Sep 01. pii: e204701. [Epub ahead of print]
    XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia.
    Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang.
      Activating mutations in FMS-like tyrosine kinase 3 (FLT3) drive aggressive acute myeloid leukemia (AML) and confer poor prognosis. Although FLT3 inhibitors have improved outcomes, their efficacy is frequently limited by microenvironment-mediated signaling and treatment-emergent resistance. XY0206 is a structurally optimized derivative of sunitinib, an inhibitor approved for multiple solid tumors. Biochemical, multi-omics, and functional analyses showed that XY0206 directly engages FLT3 and suppresses downstream STAT5, AKT, and ERK signaling, resulting in apoptosis in FLT3-ITD AML cells. Across models of FLT3-dependent resistance, XY0206 retained antileukemic activity, including in FLT3-ITD cells harboring the F691L gatekeeper mutation, a recurrent alteration conferring resistance to approved FLT3 inhibitors. In primary AML blasts and xenograft models, XY0206 exhibited enhanced antileukemic activity with favorable tolerability relative to gilteritinib. In a phase I/II trial (NCT04471064) of XY0206 monotherapy in patients with relapsed or refractory (R/R) AML, XY0206 achieved a composite complete remission rate (CRc) of 45.7% overall, with a notable 60.0% CRc rate among patients with FLT3-ITD mutations. Three of eight patients with prior FLT3 inhibitor-exposed R/R AML also achieved CRc. Together, these findings support further clinical evaluation of XY0206 as a FLT3-directed therapeutic in AML, particularly in disease settings with reduced sensitivity to existing FLT3 inhibitors.
    Keywords:  Cell biology; Clinical Research; Clinical trials; Drug therapy; Hematology; Leukemias
    DOI:  https://doi.org/10.1172/JCI204701
  16. Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930
    MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
    Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.
      Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.
    Keywords:  CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage
    DOI:  https://doi.org/10.1016/j.celrep.2026.117930
  17. Nat Struct Mol Biol. 2026 Aug 31.
    A single-amino-acid cleavage controls global mitochondrial complex integrity.
    Cansu Kücükköse, Marcin Luzarowski, Fabian Stockert, Annette Flotho, Miguel Cosenza-Contreras, Fatih Demir, Max Gilbert, Jörn Dengjel, Friedel Drepper, Mandy Jeske, Hans-Georg Koch, Pitter F Huesgen, F-Nora Vögtle.
      Mitochondrial proteostasis depends on precise N-terminal processing of imported precursor proteins. Defects in this maturation step are implicated in disease, yet the functional impact in humans remains unclear. Here we show that the intermediate cleaving peptidase ICP55, which removes a single amino acid, acts as a key stabilizer of multimeric mitochondrial protein complexes. Using proteomics and complexome profiling, we identify over 100 human ICP55 substrates and demonstrate that loss of ICP55 triggers widespread destabilization of protein assemblies, with a global shift toward smaller subcomplexes. Thus, we uncover a conserved, post-translational mechanism that safeguards mitochondrial proteostasis by regulating complex integrity through a single amino-acid cleavage, and we reveal N-terminal proteoform control as an unexpected layer of organellar homeostasis.
    DOI:  https://doi.org/10.1038/s41594-026-01876-7
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