bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–06–22
twenty-one papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Fumarate hits the brakes on mitophagy.
  2. The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells.
  3. Discovery and optimization of oxidative phosphorylation inhibitors from a phenotypic screen.
  4. Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
  5. Transcription arrest induces formation of RNA granules in mitochondria.
  6. Dysfunctional mitochondria trap proteins in the intermembrane space.
  7. Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
  8. Mitochondria-Targeted Microneedles Reverse Doxorubicin Resistance via Apoptosis-Ferroptosis Synergy.
  9. Rewriting cancer's code: A micropeptide's mitochondrial mission.
  10. Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis.
  11. Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies.
  12. Shaping the composition of the mitochondrial outer membrane.
  13. Loss of SLC25A20 in Pancreatic Adenocarcinoma Reversed the Tumor-Promoting Effects of a High-Fat Diet.
  14. NRF2 maintains redox balance via ME1 and NRF2 inhibitor synergizes with venetoclax in NPM1-mutated acute myeloid leukemia.
  15. Integrated spatial omics of metabolic reprogramming and the tumor microenvironment in pancreatic cancer.
  16. Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper.
  17. Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis.
  18. Loss of BAP1 defines a unique subtype of TP53-mutated de novo AML and confers sensitivity to BCL-xL inhibitors.
  19. The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
  20. Estimating physical conditions supporting gradients of ATP concentration in the eukaryotic cell.
  21. Pleiotropic Effects of Metformin on the Chemotherapy Response of HPV-Positive Cancer Cells.
  1. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00471-X. [Epub ahead of print]85(12): 2261-2263
    Fumarate hits the brakes on mitophagy.
    Ana Paula Magalhães Rebelo, Christian Frezza.
      In this issue of Molecular Cell, Ham et al.1 demonstrate that the metabolite fumarate, when accumulated in cells, can influence mitochondrial quality control by inhibiting Parkin translocation to mitochondria and blocking its E3 ligase activity via the fumarate-dependent post-translational modification called succination.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.032
  2. Haematologica. 2025 Jun 19.
    The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells.
    Kellen B Gil, Jamie Borg, Rosana Moreira Pereira, Anagha Inguva-Sheth, Geovana Araujo, Jeremy Rahkola, William Showers, Abby Grier, Angelo D'Alessandro, Clayton Smith, Christine McMahon, Daniel A Pollyea, Austin E Gillen, Maria L Amaya.
      Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for STAT3's mitochondrial functions. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also result in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML.
    DOI:  https://doi.org/10.3324/haematol.2025.287352
  3. Anticancer Drugs. 2025 Jun 20.
    Discovery and optimization of oxidative phosphorylation inhibitors from a phenotypic screen.
    Mahmoud El Shemerly, Florian Richalet, Dimitri Robay, Claude Nuoffer, Alexandra Kunz, Luc Bury, Claire Hisler, Norbert Hermann, Jochen Spickermann, Sven Weiler, Paul M J McSheehy, Laurenz Kellenberger, Heidi A Lane.
      Tumor metabolism and metabolic reprogramming in cancer cells represent a promising area in oncology research, offering new avenues for therapeutic intervention. While the 'Warburg effect' highlights the reliance of many tumors on aerobic glycolysis, emerging evidence indicates that some cancers also depend on mitochondrial oxidative phosphorylation (OXPHOS) for energy production, cancer cell survival, tumor progression, metastasis, and drug resistance. We conducted a high-throughput, differential, phenotypic screening followed by a focused medicinal chemistry campaign, leading to the identification of novel, potent OXPHOS inhibitors. These lead compounds selectively target complex I of the mitochondrial electron transport chain, thereby disrupting ATP production and oxygen consumption in cancer cells. In-vitro studies in breast cancer cell lines, along with published data, suggest that MCT4 expression may serve as a biomarker for drug sensitivity. Notably, low MCT4 expression correlated with higher potency in cell growth assays. The identified compounds exhibited favorable drug-like properties, including good pharmacokinetics and oral bioavailability in mice. Daily oral dosing significantly inhibited tumor growth in two in-vivo breast cancer models with low MCT4 expression levels. This efficacy, however, was accompanied by body weight loss, indicating the need to enhance the therapeutic index through optimization or rational combination therapy strategies. These findings highlight the therapeutic potential of targeting mitochondrial OXPHOS in cancers with defined metabolic dependencies, offering a novel approach for exploiting tumor-specific metabolic vulnerabilities for improved cancer treatment.
    Keywords:  electron transport chain; mitochondrial complex I; oxidative phosphorylation; tumor growth inhibition
    DOI:  https://doi.org/10.1097/CAD.0000000000001750
  4. Cancer Res. 2025 Jun 20.
    Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
    Natalia V Oleinik, Firdevs Cansu Atilgan, Mohamed Faisal Kassir, Han Gyul Lee, Alhaji H Janneh, Wyatt Wofford, Chase Walton, Zdzislaw M Szulc, Elizabeth G Hill, Alexander V Alekseyenko, Huseyin Cimen, Jessica H Hartman, Christina Voelkel-Johnson, Michael B Lilly, John J Lemasters, Norma Frizzell, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen.
      Bioactive ceramide induces cell death in part by promoting mitophagy. C18-ceramide levels are commonly reduced in head and neck squamous cell carcinoma (HNSCC), which correlates with poor prognosis, suggesting the potential of harnessing ceramide for cancer treatment. Here, we evaluated the ability of the ceramide analog LCL768 to induce mitophagy and metabolic stress in HNSCC. Mechanistically, LCL768 induced CerS1-mediated endogenous C18-ceramide accumulation in mitochondria to mediate mitophagy, which did not require the CerS1 transporter p17/PERMIT but was dependent on DRP1 activation via nitrosylation at C644. DRP1 facilitated anchoring of the endoplasmic reticulum (ER) and mitochondrial membranes by promoting the association between phosphatidylethanolamine in the ER and cardiolipin in mitochondrial membranes. Mutations of Drp1 that prevented its binding to ER and mitochondrial membranes blocked CerS1/C18-ceramide mitochondrial accumulation, inhibiting LCL768-mediated mitophagy. In addition, LCL768-driven mitophagy altered mitochondrial metabolism, resulting in fumarate depletion and leading to tumor suppression in vivo. Exogenous fumarate supplementation prevented LCL768-mediated mitophagy, mitochondrial trafficking of CerS1, ER-mitochondrial tethering, and tumor suppression in mice. Fumarate metabolism was associated with PARKIN succination at a catalytic cysteine (Cys431), inhibiting its association with PINK1 and ubiquitin and thereby preventing mitophagy. LCL768-induced fumarate depletion attenuated PARKIN succination to promote PARKIN activation and mitophagy, indicating a feed-forward mechanism that regulates mitophagy and fumarate metabolism through PARKIN succination. These data provide a mechanism whereby LCL768/CerS1-C18-ceramide-mediated mitophagy and tumor suppression are regulated by Drp1 nitrosylation, fumarate depletion, and PARKIN succination, providing a metabolic stress signature for lethal mitophagy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4042
  5. Life Sci Alliance. 2025 Sep;pii: e202403082. [Epub ahead of print]8(9):
    Transcription arrest induces formation of RNA granules in mitochondria.
    Katja G Hansen, Autum Baxter-Koenigs, Caroline Am Weiss, Erik McShane, L Stirling Churchman.
      Mitochondrial gene expression regulation is required for the biogenesis of oxidative phosphorylation (OXPHOS) complexes, yet the spatial organization of mitochondrial RNAs (mt-RNAs) remains unknown. Here, we investigated the spatial distribution of mt-RNAs during various cellular stresses using single-molecule RNA-FISH. We discovered that transcription inhibition leads to the formation of distinct RNA granules within mitochondria, which we term inhibition granules. These structures differ from canonical mitochondrial RNA granules and form in response to multiple transcription arrest conditions, including ethidium bromide treatment, specific inhibition or stalling of the mitochondrial RNA polymerase, and depletion of the SUV3 helicase. Inhibition granules appear to stabilize certain mt-mRNAs during prolonged transcription inhibition. This phenomenon coincides with an imbalance in OXPHOS complex expression, where mitochondrial-encoded transcripts decrease while nuclear-encoded subunits remain stable. We found that cells recover from transcription inhibition via resolving the granules, restarting transcription, and repopulating the mitochondrial network with mt-mRNAs within hours. We suggest that inhibition granules may act as a reservoir to help overcome OXPHOS imbalance during recovery from transcription arrest.
    DOI:  https://doi.org/10.26508/lsa.202403082
  6. EMBO J. 2025 Jun 16.
    Dysfunctional mitochondria trap proteins in the intermembrane space.
    Tamara Flohr, Markus Räschle, Johannes M Herrmann.
      The accumulation of mitochondrial precursor proteins in the cytosol due to mitochondrial dysfunction compromises cellular proteostasis and is a hallmark of diseases. Why non-imported precursors are toxic and how eukaryotic cells prevent their accumulation in the cytosol is still poorly understood. Using a proximity labeling-based assay to globally monitor the intramitochondrial location of proteins, we show that, upon mitochondrial dysfunction, many mitochondrial matrix proteins are sequestered in the intermembrane space (IMS); something we refer to as "mitochondrial triage of precursor proteins" (MitoTraP). MitoTraP is not simply the result of a general translocation block at the level of the inner membrane, but specifically directs a subgroup of matrix proteins into the IMS, many of which are constituents of the mitochondrial ribosome. Using the mitoribosomal protein Mrp17 (bS6m) as a model, we found that IMS sequestration prevents its mistargeting to the nucleus, potentially averting interference with assembly of cytosolic ribosomes. Thus, MitoTraP represents a novel, so far unknown mechanism of the eukaryotic quality control system that protects the cellular proteome against the toxic effects of non-imported mitochondrial precursor proteins.
    Keywords:  Intermembrane Space; Mitochondria; Nucleolus; Protein Targeting; Ribosome
    DOI:  https://doi.org/10.1038/s44318-025-00486-1
  7. Nat Commun. 2025 Jun 17. 16(1): 5328
    Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
    Prince Saforo Amponsah, Jan-Eric Bökenkamp, Olha Kurpa, Svenja Lenhard, Anna Myronova, Daniel Osmar Vega Velazquez, Celina Hirschelmann, Christian Behrends, Johannes M Herrmann, Markus Räschle, Zuzana Storchová.
      Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-60857-4
  8. ACS Nano. 2025 Jun 18.
    Mitochondria-Targeted Microneedles Reverse Doxorubicin Resistance via Apoptosis-Ferroptosis Synergy.
    Tianshu Hao, Hanze Guo, Chenyuan Wang, Shisuo Jing, Wen Zhang, Yongnian Zeng, Jinxuan Hou, Zhiyin Song, Wei Li.
      Mitochondrial hyperfunction in doxorubicin (DOX)-resistant breast cancer cells mitigates oxidative stress, contributing to chemoresistance. Here, we present a precise mitochondria-targeted microneedle (MN) delivery strategy incorporating hollow DOX-TPP@ZIF-67 nanoparticles to overcome chemotherapy resistance. This platform was synthesized by loading mitochondria-targeted DOX-TPP into ZIF-67 structures and embedded into fast-dissolving MN patches for localized, organelle-specific drug delivery. Mitochondrial accumulation of DOX-TPP induces ROS overproduction, triggering apoptosis, disrupting cystine-cysteine conversion, depleting glutathione (GSH), and inactivating GPX4. The resulting oxidative imbalance promotes lipid peroxidation and ferroptosis. Additionally, the hydrogen peroxide generated during metabolic reprogramming drives further ferroptosis via the Fenton-like reaction. This approach effectively suppresses the growth of chemoresistant tumors and prolongs survival in DOX-resistant animal models. Our results demonstrate that mitochondria-targeted MN delivery provides a precise strategy to overcome chemoresistance and uncover a mechanism by which enhanced anthracycline efficacy drives the synergistic activation of mitochondrial dysfunction, apoptosis, and ferroptosis.
    Keywords:  ROS; drug-resistant breast cancer; microneedle; organelle-specific drug delivery; targeting mitochondria
    DOI:  https://doi.org/10.1021/acsnano.5c06302
  9. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00473-3. [Epub ahead of print]85(12): 2263-2264
    Rewriting cancer's code: A micropeptide's mitochondrial mission.
    George A Calin, Tanvi H Visal.
      In this issue of Molecular Cell, Zhu et al.1 uncover a lncRNA-derived micropeptide that disrupts mitochondrial RNA processing, revealing a new layer of metabolic vulnerability in hepatocellular carcinoma (HCC).
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.034
  10. Cancer Metab. 2025 Jun 16. 13(1): 28
    Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis.
    Ann-Kathrin Daum, Lisa Schlicker, Marc A Schneider, Thomas Muley, Ursula Klingmüller, Almut Schulze, Michael Thomas, Petros Christopoulos, Holger Sültmann.
       BACKGROUND: Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating evidence suggests that cancer-associated fibroblasts (CAFs) within the tumor microenvironment contribute to therapy resistance. This study aimed to investigate CAF-driven molecular networks that shape the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells.
    METHODS: Three-dimensional (3D) spheroid co-cultures comprising ALK-rearranged lung adenocarcinoma cells and CAFs were utilized to model the tumor microenvironment. Single-cell RNA sequencing was performed to uncover transcriptional differences between TKI-treated homotypic and heterotypic spheroids. Functional assays assessed the effects of CAF-conditioned medium and CAF-secreted factors on tumor cell survival, proliferation, lipid metabolism, and downstream AKT signaling. The therapeutic potential of targeting metabolic vulnerabilities was evaluated using pharmacological inhibition of lipid metabolism and by ferroptosis induction.
    RESULTS: CAFs significantly diminished the apoptotic response of lung tumor cells to ALK inhibitors while simultaneously enhancing their proliferative capacity. Single-cell RNA sequencing identified lipogenesis-associated genes as a key transcriptional difference between TKI-treated homotypic and heterotypic lung tumor spheroids. CAF-conditioned medium and the CAF-secreted factors HGF and NRG1 activated AKT signaling in 3D-cultured ALK-rearranged lung tumor cells, leading to increased de novo lipogenesis and suppression of lipid peroxidation. These metabolic adaptations were critical for promoting tumor cell survival and fostering therapy resistance. Notably, both dual inhibition of ALK and the lipid-regulatory factor SREBP-1, as well as co-treatment with ferroptosis inducers such as erastin or RSL3, effectively disrupted the CAF-driven metabolic-supportive niche and restored sensitivity of resistant lung tumor spheroids to ALK inhibition.
    CONCLUSIONS: This study highlights a critical role for CAFs in mediating resistance to ALK-TKIs by reprogramming lipid metabolism in ALK-rearranged lung cancer cells. It suggests that targeting these metabolic vulnerabilities, particularly through inhibition of lipid metabolism or induction of ferroptosis, could provide a novel therapeutic approach to overcome resistance and improve patient outcomes.
    Keywords:  3D cell culture; Cancer-associated fibroblasts; EML4-ALK; Lipid metabolism; Lung adenocarcinoma; Therapy resistance
    DOI:  https://doi.org/10.1186/s40170-025-00400-7
  11. Haematologica. 2025 Jun 19.
    Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies.
    Binu Kandathilparambil Sasi, Chiara Tarantelli, Stephen Martindale, Elisa Civanelli, Eleonora Cannas, Giulio Sartori, Alberto J Arribas, Stacey M Fernandes, Samantha J Shupe, John-Hanson Machado, Svitlana Tyekucheva, Yue Ren, Michael Lahn, Lars Van der Veen, Giusy Di Conza, Francesco Bertoni, Jennifer R Brown.
      The phosphoinositide 3-kinase (PI3K) pathway remains a potent drug target in hematological malignancies despite the challenges that have affected clinical drug development, particularly unpredictable toxicity, and inherent/acquired drug resistance. Herein, we tested the activity of a novel PI3Kδ selective, non-ATP competitive inhibitor, roginolisib (IOA-244), in hematological malignancies including diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). To identify rational actionable combination partners that can be tested in hematologic malignancies, an unbiased pharmacological screening of 474 compounds was carried out in two lymphoma cell lines. We identified BCL2 blockade with venetoclax as synergistically active with roginolisib, a finding confirmed in a broad panel of lymphoma cell lines, DLBCL cell lines and primary CLL samples. We further demonstrate that the sensitizing effects of roginolisib to venetoclax correlate with suppression of downstream PI3K/AKT pathways and alterations in the expression of the apoptotic proteins BIM, mediated through FOXO1 transactivation, and MCL1, with ubiquitination and degradation mediated through GSK3α/β activation. These findings support proof of concept for roginolisib development in hematological malignancies as a single agent or in combination with venetoclax. A clinical trial of roginolisib with venetoclax and an anti-CD20 antibody is initiating in CLL.
    DOI:  https://doi.org/10.3324/haematol.2024.287180
  12. Nat Cell Biol. 2025 Jun;27(6): 890-901
    Shaping the composition of the mitochondrial outer membrane.
    Gayathri Muthukumar, Jonathan S Weissman.
      Mitochondria are critical double-membraned organelles that act as biosynthetic and bioenergetic cellular factories, with the outer membrane providing an interface with the rest of the cell. Mitochondrial outer membrane proteins regulate a variety of processes, including metabolism, innate immunity and apoptosis. Although the biophysical and functional diversity of these proteins is highly documented, the mechanisms of their biogenesis and the integration of that into cellular homeostasis are just starting to take shape. Here, focusing on α-helical outer membrane proteins, we review recent insights into the mechanisms of synthesis and cytosolic chaperoning, insertion and assembly in the lipid bilayer, and quality control of unassembled or mislocalized transmembrane domains. We further discuss the role convergent evolution played in this process, comparing key biogenesis players from lower eukaryotes, including yeast and trypanosomes, with multicellular metazoan systems, and draw comparisons with the endoplasmic reticulum biogenesis system, in which membrane proteins face similar challenges.
    DOI:  https://doi.org/10.1038/s41556-025-01683-0
  13. Theranostics. 2025 ;15(13): 6516-6533
    Loss of SLC25A20 in Pancreatic Adenocarcinoma Reversed the Tumor-Promoting Effects of a High-Fat Diet.
    Sang Myung Woo, Ho Lee, Joon Hee Kang, Mingyu Kang, Wonyoung Choi, Sung Hoon Sim, Jung Won Chun, Nayoung Han, Kyung-Hee Kim, Woojin Ham, Woosol Hong, Chaeyoung Kim, Jeong Hwan Park, Dawool Han, Jong In Yook, Woo Jin Lee, Soo-Youl Kim.
      Rationale: Although it is known that High-fat diet (HFD) promotes the development of pancreatic ductal adenocarcinoma (PDAC), no direct link between HFD and cancer has been identified. Previously, we showed that ATP production by cancer cells depends on fatty acid oxidation (FAO); therefore, we hypothesized that blocking FAO may prevent HFD-induced promotion of PDAC growth. Methods: To determine whether FAO is increased in PDAC patients, we analyzed a tissue microarray by immunohistochemical staining to detect carnitine palmitoyl transferase I. To block FAO, SLC25A20 (carnitine-acylcarnitine carrier) was knocked down in cancer cells, which was implanted for xenograft in mice and treated with a high-fat diet (HFD, 60% fat). To compare cancer development including survival rates, and histopathological differences were analyzed by crossbreeding of KPC mice (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) with KPC/Slc25a20+/- mice. Results: SLC25A20 knockdown in cancer cells reduced ATP production and inhibited cell growth. Proteome analysis revealed that SLC25A20 knockdown reduced cancer cell growth significantly due to inactivation of mTOR via decreased ATP production, ultimately leading to cell death. The median survival time of KPC/Slc25a20+/- tumor-bearing mice was 3.1 weeks longer than that of KPC tumor-bearing mice. In mice fed an HFD, the growth of xenografts derived from SLC25A20 knockdown PDAC cells was 65-95% lower than that of xenografts derived from control cells. Conclusion: Blocking FAO by SLC25A20 knockdown reversed HFD-induced promotion of PDAC growth.
    Keywords:  Fatty acid oxidation; High-fat diet; PDAC; Pancreatic cancer; SLC25A20
    DOI:  https://doi.org/10.7150/thno.114912
  14. Cancer Metab. 2025 Jun 18. 13(1): 32
    NRF2 maintains redox balance via ME1 and NRF2 inhibitor synergizes with venetoclax in NPM1-mutated acute myeloid leukemia.
    Jiayuan Hu, Zihao Yuan, Yan Shu, Jun Ren, Jing Yang, Lisha Tang, Xingyu Wei, Yongcan Liu, Fangfang Jin, Qiaoling Xiao, Xinyi Chen, Nan Wu, Wen Zhao, Ziwei Li, Ling Zhang.
       BACKGROUND: Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations represents a distinct subtype of leukemia. Emerging evidence suggests that regulation of redox metabolism contributes to tumorigenesis and reveals a metabolic vulnerability in anti-tumor therapies. However, the role of redox homeostasis between reactive oxygen species (ROS) and antioxidant systems plays in NPM1-mutated AML has not been fully elucidated.
    METHODS: First, ROS-related metabolic pathways in NPM1-mutated AML were analyzed using RNA-sequencing data. Intracellular and mitochondrial ROS levels in leukemia cells were detected using flow cytometry (FCM). The expression of nuclear factor (erythroid-derived 2)-like 2 (NRF2) was analyzed in public databases and further validated in AML primary blasts and cell lines by quantitative real-time PCR (qRT-PCR), western blotting, and immunofluorescence. Next, the mechanism underlying NRF2 expression was investigated through the RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP) and rescue experiments. Additionally, the downstream target gene of NRF2 was identified by bioinformatics analysis and chromatin immunoprecipitation (ChIP) assays. Furthermore, RNA interference and the NRF2 inhibitor ML385 were applied to explore the role of NRF2 in leukemia. Finally, the anti-leukemic effects of ML385 alone or in combination with the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax on AML cells were investigated using FCM analysis and western blotting, and further explored in cell line-derived xenograft (CDX) mouse models.
    RESULTS: In this study, we identified significant ROS accumulation in leukemia cells with NPM1 mutations. Meanwhile, elevated NRF2 expression and its nuclear localization were observed in NPM1-mutated AML cells. The high NRF2 expression levels were at least partially induced by fat mass and obesity-associated protein (FTO) via m6A modification. Functionally, NRF2 exerts its antioxidant effects by transcriptionally upregulating malic enzyme 1 (ME1) expression and enhancing its activity. Targeting NRF2/ME1 axis reduced NADPH/NADP+ ratio, increased ROS levels, impaired leukemia cell viability, and promoted apoptosis. More importantly, NRF2 inhibitor ML385 in combination with venetoclax showed synergistic anti-leukemic activity in vitro and in vivo.
    CONCLUSION: Overall, our findings provide new insight into the therapeutic potential of targeting NRF2 and guide the development of innovative combination therapies in NPM1-mutated AML.
    Keywords:  Acute myeloid leukemia; ME1; NRF2; Nucleophosmin 1; Redox homeostasis; Venetoclax
    DOI:  https://doi.org/10.1186/s40170-025-00401-6
  15. iScience. 2025 Jun 20. 28(6): 112681
    Integrated spatial omics of metabolic reprogramming and the tumor microenvironment in pancreatic cancer.
    Hao Wu, Qiyao Zhang, Zhen Cao, Hongtao Cao, Mengwei Wu, Mengdi Fu, Tingping Huang, Xianlin Han, Xiaoyan Chang, Ziwen Liu.
      Metabolic reprogramming is a defining feature of pancreatic cancer, influencing tumor progression and the tumor microenvironment. By integrating single-cell transcriptomics, spatial transcriptomics, and spatial metabolomics, this study visualized the spatial co-localization of metabolites and gene expression within tumor samples, uncovering metabolic heterogeneity and intercellular interactions. Spatial transcriptomics identified distinct pathological regions, which were further characterized using single-cell transcriptomic data and pathologist annotations. Pseudotime trajectory analysis revealed metabolic shifts along the malignant progression, while single-cell Metabolism (scMetabolism) delineated metabolic differences between pathological regions, classifying them as hypermetabolic or hypometabolic. Notably, aberrant cell communication between cancer cells, macrophages, and fibroblasts was observed, with key receptor-ligand pairs significantly co-expressed in malignant regions and correlated with poor prognosis. Spatial metabolomics imaging identified signature metabolites, highlighting metabolic alterations in amino acid metabolism, polyamine metabolism, fatty acid synthesis, and phospholipid metabolism. This integrated analysis provides critical insights into pancreatic cancer metabolism, offering potential avenues for targeted therapeutic interventions.
    Keywords:  Cancer; Metabolomics; Microenvironment; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.112681
  16. Commun Biol. 2025 Jun 17. 8(1): 936
    Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper.
    Elodie Lafargue, Jean-Pierre Duneau, Nicolas Buzhinsky, Pamela Ornelas, Alexandre Ortega, Varun Ravishankar, James Sturgis, Ignacio Casuso, Lucie Bergdoll.
      VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid-protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.
    DOI:  https://doi.org/10.1038/s42003-025-08311-5
  17. Nat Cell Biol. 2025 Jun;27(6): 902-917
    Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis.
    Maria Livia Sassano, Yulia Y Tyurina, Antigoni Diometzidou, Ellen Vervoort, Vladimir A Tyurin, Sanket More, Rita La Rovere, Francesca Giordano, Geert Bultynck, Benjamin Pavie, Johan V Swinnen, Hülya Bayir, Valerian E Kagan, Luca Scorrano, Patrizia Agostinis.
      The peroxidation of membrane phospholipids (PLs) is a hallmark of ferroptosis. The endoplasmic reticulum and mitochondria have been implicated in ferroptosis, but whether intracellular PL peroxidation ensues at their contact sites (endoplasmic reticulum-mitochondria contact sites, EMCSs) is unknown. Using super-resolution live imaging, we charted the spatiotemporal events triggered by ferroptosis at the interorganelle level. Here we show that EMCSs expand minutes after localized PL peroxides are formed and secondarily spread to mitochondria, promoting mitochondrial reactive oxygen species and fission. Oxidative lipidomics unravels that EMCSs host distinct proferroptotic polyunsaturated-PLs, including doubly proferroptotic polyunsaturated-acylated PLs, demonstrating their high propensity to undergo PL peroxidation. Endoplasmic reticulum-mitochondria untethering blunts PL peroxidation and ferroptosis, while EMCS stabilization enhances them. Consistently, distancing EMCSs protects the ferroptosis-susceptible triple-negative breast cancer subtype, harbouring high EMCS-related gene expression and basal PL peroxide levels. Conversely, in insensitive triple-negative breast cancer subtypes, bolstering EMCSs sensitizes them to ferroptosis. Our data unveil endoplasmic reticulum-mitochondria appositions as initial hubs of PL peroxide formation and posit that empowering EMCSs endorses ferroptosis in cancer cells.
    DOI:  https://doi.org/10.1038/s41556-025-01668-z
  18. Blood. 2025 Jun 20. pii: blood.2024026417. [Epub ahead of print]
    Loss of BAP1 defines a unique subtype of TP53-mutated de novo AML and confers sensitivity to BCL-xL inhibitors.
    Jaclyn Andricovich, Coen Johannes Lap, Alexandros Tzatsos.
      Mutations in TP53 are mutually exclusive with other known drivers of myeloid transformation and define a distinct molecular subtype within de novo Acute Myeloid Leukemia (AML) that is associated with a complex karyotype, resistance to chemotherapy, and poor prognosis. Although TP53 defects are rare in de novo AML, biallelic mutations are a defining molecular feature of erythroleukemia. The genetic alterations that cooperate with defective TP53 to transform erythroid progenitors remain unknown. We found that loss of BAP1 (BRCA1 Associated Protein-1) co-occurs in one-third of patients with TP53-mutated AML, is associated with an erythroid-primed gene expression signature, and confers an additional adverse effect on overall survival. BAP1 is a tumor suppressor involved in the DNA damage response as well as epigenetic regulation through histone H2AK119 de-ubiquitination. While Bap1KO mice develop myelodysplasia with prominent dyserythropoiesis, combined deletion of Bap1 and Trp53 caused transplantable erythroleukemia, and occasionally mixed AML, mirroring the heterogeneity of human disease. Bulk and single-cell RNA-seq coupled to ChIP-seq in hematopoietic progenitors revealed that Bap1 loss triggers a proinflammatory response and cooperates with Trp53 deficiency to transform erythroid-primed multipotent progenitors. Mechanistically, genomic instability led to the development of erythroleukemia, while epigenetic deregulation caused myelomonocytic skewing suggesting a dichotomous and context dependent role for BAP1. We also demonstrate that BAP1 deficient erythroleukemia is dependent on BCL2L1 expression and is sensitive to BCL-xL inhibitors in vivo.
    DOI:  https://doi.org/10.1182/blood.2024026417
  19. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00266-9. [Epub ahead of print]
    The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
    Jesse S S Novak, Lisa Polak, Sanjeethan C Baksh, Douglas W Barrows, Marina Schernthanner, Benjamin T Jackson, Elizabeth A N Thompson, Anita Gola, M Deniz Abdusselamoglu, Alain R Bonny, Kevin A U Gonzales, Julia S Brunner, Anna E Bridgeman, Katie S Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H Amalia Pasolli, Thomas S Carroll, Lydia W S Finley, Elaine Fuchs.
      Epidermal stem cells produce the skin's barrier that excludes pathogens and prevents dehydration. Hair follicle stem cells (HFSCs) are dedicated to bursts of hair regeneration, but upon injury, they can also reconstruct, and thereafter maintain, the overlying epidermis. How HFSCs balance these fate choices to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover serine as an unconventional, non-essential amino acid that impacts this process. When dietary serine dips, endogenous biosynthesis in HFSCs fails to meet demands (and vice versa), slowing hair cycle entry. Serine deprivation also alters wound repair, further delaying hair regeneration while accelerating re-epithelialization kinetics. Mechanistically, we show that HFSCs sense each fitness challenge by triggering the integrated stress response, which acts as a rheostat of epidermal-HF identity. As stress levels rise, skin barrier restoration kinetics accelerate while hair growth is delayed. Our findings offer potential for dietary and pharmacological intervention to accelerate wound healing.
    Keywords:  dietary intervention; epidermal stem cells; fate selection; hair follicle stem cells; hair regrowth; integrated stress response; serine metabolism; tissue regeneration; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.010
  20. Biophys J. 2025 Jun 16. pii: S0006-3495(25)00376-5. [Epub ahead of print]
    Estimating physical conditions supporting gradients of ATP concentration in the eukaryotic cell.
    Rajneesh Kumar, Iain G Johnston.
      The ATP molecule serves as an energy currency in eukaryotes (and all life), providing the energy needed for many essential cellular processes. But the extent to which substantial spatial differences exist in ATP concentration in the cell remains incompletely known. It is variously argued that ATP diffuses too quickly for large gradients to be established, or that the high rates of ATP production and use (sources and sinks) can support large gradients even with rapid diffusion - and microscopic models and detailed experiments in different specific cases support both pictures. Here we attempt a mesoscopic investigation, using reaction-diffusion modelling in a simple biophysical picture of the cell to attempt to ask, generally, which conditions cause substantial ATP gradients to emerge within eukaryotic cells. If ATP sources (like mitochondria) or sinks (like the nucleus) are spatially clustered, large fold changes in concentration can exist across the cell; if sources and sinks are more spread then rapid diffusion indeed prevents large gradients being established. This dependence holds in model cells of different sizes, suggesting its generality across cell types. Our theoretical work will complement developing intracellular approaches exploring ATP concentration inside eukaryotic cells.
    DOI:  https://doi.org/10.1016/j.bpj.2025.06.016
  21. J Med Virol. 2025 Jun;97(6): e70434
    Pleiotropic Effects of Metformin on the Chemotherapy Response of HPV-Positive Cancer Cells.
    Alicia Avenhaus, Bianca J Kuhn, Milica Velimirović, Tobias D Strobel, Julia Bulkescher, Claudia Lohrey, Jeroen Krijgsveld, Felix Hoppe-Seyler, Karin Hoppe-Seyler.
      Improved treatment strategies for HPV-positive cancers are urgently required. The viral E6/E7 oncoproteins are essential for the proliferation of HPV-positive cancer cells and considered attractive therapeutic targets. Metformin is proposed to be repurposed for cancer therapy, but this is under controversial debate. We previously demonstrated that E6/E7 expression and the proliferation of HPV-positive cancer cells are repressed by Metformin. Here, we explore the effects of Metformin on the phenotype of HPV-positive cancer cells in detail, either applied as monotreatment or in combination with chemotherapeutic agents. We provide evidence that the downregulation of E6/E7 is not the primary mechanism underlying Metformin's growth-inhibitory effect in HPV-positive cancer cells. Specifically, compared to targeted E6/E7 repression by RNA interference (RNAi), Metformin treatment differently altered the expression of growth regulatory proteins, exerted different effects on the cell cycle, and was able to suppress growth even in the presence of E6/E7. Furthermore, we found that cancer cells pre-treated with Metformin become resistant to senescence induction by the pro-senescent chemotherapeutic agent Etoposide, likely as a secondary effect of Metformin-induced growth inhibition. Finally, depending on experimental conditions, we uncover divergent, even opposing, effects on the proliferation of HPV-positive cancer cells when Metformin is combined with Cisplatin, with p53 playing a key role in these processes. Collectively, our results show that Metformin exerts complex effects on the phenotype of HPV-positive cancer cells, which are critically influenced by experimental conditions. Our findings may also explain the discrepant results in the literature, reporting agonistic or antagonistic effects upon combining Metformin with Cisplatin.
    Keywords:  Metformin; cervical cancer; chemotherapy; human papillomavirus (HPV); oncogenesis; oncoproteins
    DOI:  https://doi.org/10.1002/jmv.70434
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