bims-mibica 2025-09-21 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–09–21
twenty-two papers selected by
Kelsey Fisher-Wellman, Wake Forest University

PLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer.
Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine.
Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer.
Intricate role of DRP1 and associated mitochondrial fission signaling in carcinogenesis and cancer progression.
Compartmentalized thymidine phosphorylation by mitochondrial nucleotide kinases TK2 and CMPK2.
Proton Transfer through a Charged Conduit in Respiratory Complex I: Long-Range Effects and Conformational Gating.
Covariation MS uncovers a protein that controls cysteine catabolism.
SREBP1a induced PINK1-Parkin mediated mitophagy facilitates ovarian cancer progression.
Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.
Clonal evolution and apoptosis resistance in myelodysplastic neoplasms and acute myeloid leukemia under treatment: insights from integrative longitudinal profiling.
Understanding the Functional Dependence and Inhibition of the Bcl‑2 Pro-Survival Proteins in a Wide Spectrum of Cancers toward Precision Medicine.
Anticancer Effect of the Triphenylphosphonium-Conjugated Quinolone Antibiotics Targeting Mitochondrial DNA Replication.
OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis.
Surgery-Induced Neutrophil Extracellular Traps Promote Tumor Metastasis by Reprogramming Cancer Cell Lipid Metabolism.
Development of novel analogs of the TRi-1 and TRi-2 selenoprotein thioredoxin reductase inhibitors with initial assessment of their cytotoxicity profiles.
The Nuclear-Encoded Cytochrome c Oxidase Subunit COX4-1 Enhances Hypoxia Tolerance in Glioblastoma Cells.
mtDNA base editing: Mind the gap.
Noninvasive in vivo discrimination between mitochondrial ROS and global ROS production in solid tumors using EPR spectroscopy.
Inhibition of anti-apoptotic BCL2 overcomes adaptive resistance to co-targeting of the protein kinase FAK and MEK in GNAQ-driven uveal melanoma.
BOGO: A Proteome-Wide Gene Overexpression Platform for Discovering Rational Cancer Combination Therapies.
Peroxisomal metabolism of branched fatty acids regulates energy homeostasis.
Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.

Oncogene. 2025 Sep 16.

PLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer.

Jia Peng, Qiongsi Zhang, Xiongjian Rao, Derek B Allison, Yifan Kong, Ruixin Wang, Jinghui Liu, Yanquan Zhang, Wendy Katz, Zhiguo Li, Xiaoqi Liu.

Although the involvement of polo-like kinase 1 (PLK1) in metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis has been previously described, the underlying molecular mechanism remains unclear. Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate into acetyl-CoA, the starting material for the tricarboxylic acid (TCA) cycle. In a companion study by Zhang et al., we demonstrated that PLK1 phosphorylation of PDHA1 at threonine 57 (PDHA1-T57) drives its protein degradation via mitophagy activation. Using a stable-isotope resolved metabolomics (SIRM) approach, we now show that PLK1 phosphorylation of PDHA1-T57 results in metabolic reprogramming from OXPHOS to glycolysis. Notably, cells mimicking PDHA1-T57 phosphorylation rely more on the aspartate-malate shuttle than on glucose-derived pyruvate to sustain the TCA cycle. This metabolic shift was also observed in mouse embryonic fibroblasts (MEFs) and transgenic mice conditionally expressing the PDHA1-T57D variant, highlighting the role of PLK1 in metabolic reprogramming in vivo. It is well-established that pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation of PDH leads to its inactivation and that dichloroacetic acid (DCA), a PDK inhibitor, has been investigated in preclinical and early clinical studies as a potential therapeutic agent for lung cancer. We demonstrated that DCA combined with Onvansertib, a PLK1 inhibitor, synergistically inhibits lung tumor growth by enhancing mitochondrial ROS, inhibiting glycolysis, and inducing apoptosis. This study aims to elucidate how PLK1-associated activity drives the metabolic reprogramming from OXPHOS to glycolysis during cellular transformation, thereby contributing to lung carcinogenesis. Our results provide support for a clinical trial to evaluate the efficacy of Onvansertib plus DCA in treating lung cancer.

DOI: https://doi.org/10.1038/s41388-025-03571-1
Mol Oncol. 2025 Sep 16.

Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine.

Shuangshuang Wu, Jianlei Zhao, Aaban Asfar Azmi, Avanti Gupte, Jenna Thibodeau, Shuang Liu, Jinli Yang, Guan Wang, Holly Edwards, Lisa A Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Julie Boerner, Maik Hüttemann, Jay Yang, Yue Wang, Jeffrey W Taub, Yubin Ge.

  Relapsed/refractory (R/R) disease is a major hurdle to long-term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)-based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC-resistant AML cell lines, primary AML patient samples, and patient-derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c-MYC and MCL-1, inducing AraC-resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two-drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10-fold reduction of VEN concentration. The roles of MCL-1 and c-MYC in the three-drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC-resistant AML by downregulating c-MYC and MCL-1 and to a lesser extent cellular respiration.

Keywords:  AZD4573; acute myeloid leukemia; azacitidine; venetoclax

DOI:  https://doi.org/10.1002/1878-0261.70124
bioRxiv. 2025 Sep 11. pii: 2025.09.10.675369. [Epub ahead of print]

Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer.

Gokhan Unlu, Alon Millet, Khando Wangdu, Romain Donné, Ranya Erdal, Nicole L DelGaudio, Beste Uygur, Vyom Shah, Kevin Cho, Antonia Fecke, Feyza Cansiz, Zeynep Cagla Tarcan, Michael Isay-Del Viscio, Ece Kilic, Isabel Kurth, Henrik Molina, Albert Sickmann, Olca Basturk, Gary Patti, Semir Beyaz, Karl W Smith, Amaia Lujambio, Alpaslan Tasdogan, Sohail F Tavazoie, Kıvanç Birsoy.

Although oncogenic alterations influence tumor metabolism, how they impose distinct metabolic programs within a shared tissue context remains poorly defined. Here, we developed a rapid mitochondrial profiling platform to compare metabolites and proteins in genetic models of primary liver cancer (PLC). Analyses of six genetically distinct PLCs revealed that mitochondrial energy metabolism is largely dictated by oncogene identity. Kras -driven tumors required creatine metabolism to buffer energy demands during early tumorigenesis, whereas c-MYC -driven tumors relied on oxidative phosphorylation. Among c-MYC -driven PLCs, Pten -deficient tumors accumulated mitochondrial phosphoethanolamine, a precursor for phosphatidylethanolamine (PE) synthesis. Inhibition of PE synthesis selectively impaired the growth of Pten -deficient tumors and extended survival, in part through enhanced infiltration of CD8⁺ T cells and sensitization to TNFα-mediated cytotoxicity. Mechanistically, loss of PE elevated surface TNF receptor 2 (TNFR2), promoting TNFα signaling and pro-inflammatory response. These findings uncover genotype-specific mitochondrial metabolic liabilities and establish PE synthesis as a tumor-intrinsic mechanism of immune evasion in PLC.

DOI: https://doi.org/10.1101/2025.09.10.675369
Biochim Biophys Acta Rev Cancer. 2025 Sep 16. pii: S0304-419X(25)00195-7. [Epub ahead of print] 189453

Intricate role of DRP1 and associated mitochondrial fission signaling in carcinogenesis and cancer progression.

Soumya Ranjan Mishra, Priyadarshini Mishra, Prakash Kumar Senapati, Kewal Kumar Mahapatra, Sujit Kumar Bhutia.

  The process of mitochondrial fission is a major determinant of mitochondrial homeostasis. DRP1 is the chief architect of the mitochondrial fission process, and the DRP1 recruitment to the mitochondrial outer membrane is necessary for the mitochondrial division. DRP1 contributes to cancer progression by promoting cell proliferation, enhancing resistance to therapy, inhibiting mitochondrial-mediated apoptosis, suppressing immune responses, and sustaining cancer stem cell heterogeneity and self-renewal. Moreover, DRP1 drives metabolic reprogramming to support enhanced energy production and biosynthesis required for tumor growth and survival. In addition, DRP1-mediated mitochondrial fission also favours NLRP3 inflammasome activation within the tumor microenvironment, which regulates cancer progression. Interestingly, elevated levels of DRP1 expression have been identified as a significant prognostic marker, correlating with poor survival outcomes across multiple cancer types. Many DRP1 inhibitors have been developed for cancer treatment, but more specific and selective agents are needed to improve efficacy and reduce off-target effects. A comprehensive understanding of DRP1's role in cancer cells is essential for developing DRP1 inhibitors, which hold promise as novel anticancer therapies and may enhance the effectiveness of conventional treatments.

Keywords:  Cancer; Chemoresistance; DRP1; Metabolic reprograming; Mitochondrial fission; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.bbcan.2025.189453
J Biol Chem. 2025 Sep 16. pii: S0021-9258(25)02585-2. [Epub ahead of print] 110733

Compartmentalized thymidine phosphorylation by mitochondrial nucleotide kinases TK2 and CMPK2.

Avery S Ward, Vasudeva G Kamath, Chia-Heng Hsiung, Zachary J Lizenby, Alexander G Gillish, D Stave Kohtz, Edward E McKee.

  Deoxynucleotides (dNTPs) in post-mitotic tissues rely on deoxynucleoside salvage pathways in order to repair and replicate nuclear and mitochondrial DNA (mtDNA). Previous work from our laboratory showed in perfused rat heart and isolated mitochondria that the only substrate for TTP synthesis is thymidine. When thymidylate (TMP) is provided to bypass thymidine kinase 2 (TK2) the substrate is readily dephosphorylated to thymidine before salvage occurs suggesting compartmentalization within the heart mitochondrial matrix. The goal of this work extends these findings in the heart to mitochondria from other post-mitotic tissues, including rat liver, kidney, and brain. Using AZT to block mitochondrial thymidine kinase 2, we demonstrate that TMP cannot serve as a precursor for TTP synthesis in isolated mitochondria from any of these tissues unless it is de-phosphorylated to thymidine first. Broken mitochondria incubated with labeled TMP showed similar results as intact mitochondria, suggesting the findings are not related to TMP transport across the inner mitochondrial membrane. Further, using proximity labeling with immunofluorescence microscopy we provide evidence supporting the hypothesis that TMP compartmentation is accounted for by the interaction of TK2 and CMPK2 in the mitochondria. Differential fraction experiments provide additional evidence that association with TK2 allows CMPK2 to display TMPK2 activity. Together, the results indicate that a two-step phosphorylation of thymidine to TDP occurs because the proximity of TK2 and CMPK2 in the mitochondria prevents TMP from diffusing from the two enzymes.

Keywords:  cytidine monophosphate kinase 2; mitochondrial disease; mitochondrial metabolism; nucleoside/nucleotide biosynthesis; nucleoside/nucleotide metabolism; thymidine kinase 2

DOI:  https://doi.org/10.1016/j.jbc.2025.110733
J Chem Inf Model. 2025 Sep 18.

Proton Transfer through a Charged Conduit in Respiratory Complex I: Long-Range Effects and Conformational Gating.

Luka Simsive, Oleksii Zdorevskyi, Vivek Sharma.

Energy coupling processes in respiratory complex I, a large redox-driven proton pump in the inner mitochondrial membrane, remain one of the most enigmatic problems in modern bioenergetics. Recent high-resolution cryo-EM structures of complex I revealed extensive hydration in the interior of the protein, including the buried E channel, which is an acidic charged conduit that bridges the quinone binding cavity with the extended membrane domain of the enzyme. Despite the general agreement that E channel participates in proton transfer, the absence of proton density in the cryo-EM maps poses a significant challenge to develop viable models of proton pumping. By adhering to the hypothesis that E channel catalyzes transfer of proton(s) from the quinone binding cavity to the membrane-bound proton pumping site(s), we performed hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations using the ∼2.4 Å cryo-EM structure of mitochondrial complex I fromMus musculus. By combining classical atomistic MD simulations with hybrid QM/MM free energy calculations, we identify several energetically favorable Grotthuss-competent proton transfer paths in the E channel region. As part of the long-range coupling in complex I, our calculations show that protonation of a single acidic amino acid residue in the distal MM surroundings can alter the dynamics of proton transfer in the E channel region. Additionally, we pinpoint the gating function of a highly conserved tyrosine residue in the E channel, which undergoes conformational flipping to establish an energetically favorable proton transfer path. In the context of the redox-coupled proton pumping mechanism of complex I, we propose a stepping-stone model of proton transfer through the E channel.

DOI: https://doi.org/10.1021/acs.jcim.5c01365
Nature. 2025 Sep 17.

Covariation MS uncovers a protein that controls cysteine catabolism.

Haopeng Xiao, Martha Ordonez, Emma C Fink, Taylor A Covington, Hilina B Woldemichael, Junyi Chen, Mika Sarkin Jain, Milan H Rohatgi, Shelley M Wei, Nils Burger, Muneeb A Sharif, Julius Jan, Yaoyu Wang, Jonathan J Petrocelli, Katherine Blackmore, Amanda L Smythers, Bingsen Zhang, Matthew Gilbert, Hakyung Cheong, Sumeet A Khetarpal, Arianne Smith, Dina Bogoslavski, Yu Lei, Laura Pontano Vaites, Fiona E McAllister, Nick Van Bruggen, Katherine A Donovan, Edward L Huttlin, Evanna L Mills, Eric S Fischer, Edward T Chouchani.

The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.

DOI: https://doi.org/10.1038/s41586-025-09535-5
Biochim Biophys Acta Mol Basis Dis. 2025 Sep 15. pii: S0925-4439(25)00391-6. [Epub ahead of print]1872(1): 168043

SREBP1a induced PINK1-Parkin mediated mitophagy facilitates ovarian cancer progression.

Sk Eashayan Tanbir, Sib Sankar Roy.

  Sterol regulatory element binding protein 1 (SREBP1) has emerged as a central regulator of lipid metabolism, playing a pivotal role in cancer progression. However, the oncogenic potential of SREBP1a is still underexplored. This study investigates the multifaceted contributions of SREBP1a on tumorigenesis, with a particular focus on ovarian cancer. Elevated expression of the SREBP1a isoform was found to enhance proliferation, migration, and invasion of ovarian cancer cells. Mechanistically, SREBP1a induces mitochondrial fission by upregulating DRP1 expression and promoting its activation through ser616 phosphorylation, resulting in a fragmented mitochondrial network that supports enhanced bioenergetic flexibility. In parallel, SREBP1a drives PINK1-Parkin-mediated mitophagy. This coupling of mitochondrial fission and mitophagy possibly ensures mitochondrial quality control, enhances cellular bioenergetics, and increases ATP production, supporting rapid cell proliferation and migration. Experimental evidences reveal that SREBP1 directly regulates DRP1 and PINK1 transcription, reinforcing its role in regulating mitochondrial dynamics. Furthermore, targeting SREBP1 using Fatostatin, a small-molecule inhibitor, effectively disrupts mitochondrial fission, impairs mitophagy, and attenuates tumor progression. These findings highlight the novel role of SREBP1a as a key regulator of mitochondrial dynamics, establishing it as a promising therapeutic target in ovarian cancer. Future studies should explore combinatorial strategies integrating SREBP1a inhibition with existing therapies to improve treatment outcomes.

Keywords:  DRP1; Fatostatin; Ovarian cancer; PINK1-Parkin mitophagy; SREBP1a

DOI:  https://doi.org/10.1016/j.bbadis.2025.168043
Sci Adv. 2025 Sep 19. 11(38): eadw9095

Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.

Anthony W Martinelli, Chun-Pei Wu, Tristan Vornbäumen, Hudson W Coates, Louise H Jordon, Niek Wit, Jia J Sia, Anneliese O Speak, James A Nathan.

Cellular iron levels must be tightly regulated to ensure sufficient iron for essential enzymatic functions while avoiding the harmful generation of toxic species. Here, to better understand how iron levels are controlled, we carry out genome-wide mutagenesis screens in human cells. Alongside mapping known components of iron sensing, we determine the relative contributions of iron uptake, iron recycling, ferritin breakdown, and mitochondrial flux in controlling the labile iron pool. We also identify SETD2, a histone methyltransferase, as a chromatin modifying enzyme that controls intracellular iron availability through ferritin breakdown. Functionally, we show that SETD2 inhibition or cancer-associated SETD2 mutations render cells iron deficient, thereby driving resistance to ferroptosis and potentially explaining how some tumors evade antitumoral immunity.

DOI: https://doi.org/10.1126/sciadv.adw9095
Leukemia. 2025 Sep 19.

Clonal evolution and apoptosis resistance in myelodysplastic neoplasms and acute myeloid leukemia under treatment: insights from integrative longitudinal profiling.

Paolo Mazzeo, Sarah Mae Penir, Evgenii Shumilov, Sebastian Wolf, Björn Häupl, Katharina Markus, Katayoon Shirneshan, Katharina Rittscher, Elzbieta Brzuszkiewicz, Enver Aydilek, Hannes Treiber, Thomas Oellerich, Christina Ganster, Detlef Haase, Raphael Koch.

Treatment of high-risk Myelodysplastic Neoplasms (hr-MDS) and (secondary) Acute Myeloid Leukemia (AML) remains a clinical challenge. The combination of azacitidine and venetoclax (aza/ven) may improve treatment outcomes, but still fails in a significant fraction of patients. We established a single-center collection of longitudinal samples from patients with MDS and AML/sAML and performed comprehensive genetic, proteomic and functional apoptosis profiling to identify biomarkers and targetable escape mechanisms to aza/ven. Baseline genetic characterization (n = 55) identified high-risk genetic alterations, while longitudinal analyses (n = 268, mean 8.7 [3-20] timepoints) revealed distinct genetic profiles of clonal evolution. Functional BH3-profiling at treatment initiation identified heterogeneous dependencies on BCL-2 family members. Notably, high BCL-2 dependence correlated with genetic response to aza/ven and improved overall survival, whereas increased BCL-xL dependence was associated with resistance. We further identified patterns of acquired resistance, with loss of apoptotic priming and shifts in anti-apoptotic dependencies contributing to treatment failure. BH3 profiling revealed functional shifts toward MCL-1 and/or BCL-xL in individual cases, suggesting potential therapeutic targets to overcome resistance. In vitro, BCL-xL inhibition effectively counteracted resistance in increased BCL-xL dependence cases. In summary, we characterized treatment-associated clonal evolution in MDS and AML, providing insights into clinical response, disease progression and potential individualized therapeutic strategies.

DOI: https://doi.org/10.1038/s41375-025-02756-7
ACS Pharmacol Transl Sci. 2025 Sep 12. 8(9): 2922-2935

Understanding the Functional Dependence and Inhibition of the Bcl‑2 Pro-Survival Proteins in a Wide Spectrum of Cancers toward Precision Medicine.

Karson J Kump, Ejaz Ahmad, Charles Foucar, Rita A Avelar, Carlos Murga-Zamalloa, Matthew Lieberman, Malathi Kandarpa, Ahmed S A Mady, Analisa DiFeo, Lin Zhang, Sami Malek, Tycel Phillips, Ryan Wilcox, Dale Bixby, Moshe Talpaz, Zaneta Nikolovska-Coleska.

  Introducing and integrating functional assays into clinical cancer care can further enhance the effectiveness of precision cancer medicine. Bcl-2 pro-survival proteins have emerged as promising targets across various cancers, with Venetoclax, a highly selective Bcl-2 inhibitor, being the first approved drug of this category. This study aims to explore BH3 profiling as a functional diagnostic to distinguish pro-survival dependence in a variety of human cancers to identify antiapoptotic Bcl-2 family protein dependencies and sensitivity to BH3 mimetics. The obtained results demonstrate that, in general, hematological cancer cell lines are sensitive to Bcl-2 or Mcl-1 inhibitors. Notably, certain lymphoma subtypes of B-cell and T-cell origin show preferential dependence on Bcl-2 and Mcl-1, respectively. These conclusions were supported and enhanced by follow-up studies of primary patient-derived samples. Immunohistochemistry of patient specimens supported the identified overexpression and functional involvement of Bfl-1 in T-cell lymphomas, highlighting a new potential precision therapy opportunity. Functional profiling of various solid tumor cell lines, including ovarian cancer PDX models, revealed that most solid tumors have a dependence on a combination of Bcl-2 family antiapoptotic proteins. Treatment with a combination of Bcl-xL and Mcl-1 inhibitors induced significant apoptosis in a majority of the tested solid tumor cell lines. The results of this study reveal a functional dependence on Bcl-2 antiapoptotic proteins in various cancers and offer more tailored strategies for utilizing BH3 mimetics in precision cancer therapy.

Keywords:  BH3 profiling; Bcl-2 pro-survival proteins; apoptosis; hematological cancers; precision medicine; solid tumors

DOI:  https://doi.org/10.1021/acsptsci.5c00088
Cancer Sci. 2025 Sep 16.

Anticancer Effect of the Triphenylphosphonium-Conjugated Quinolone Antibiotics Targeting Mitochondrial DNA Replication.

Yuming Qiao, Yuki Kida, Xiaoyi Lai, Nobuko Koshikawa, Rie Igarashi, Atsushi Takatori, Keizo Takenaga.

  Antibacterial quinolones are widely used to treat bacterial infections in humans. They inhibit bacterial DNA gyrase and topoisomerase IV, whose analogous enzymes are present in mammalian mitochondria. Quinolones inhibit mitochondrial topoisomerases, thereby leading to mitochondrial DNA (mtDNA) replication suppression and cancer cell death. Meanwhile, high concentrations of quinolones are required to induce cancer cell death, possibly owing to poor delivery to the mitochondria. In this study, we synthesized nalidixic acid (NA) and ciprofloxacin (CFX) conjugated with the mitochondria-targeting moiety triphenylphosphonium (TPP), NX-TPP and CFX-TPP, to enhance mitochondrial delivery and examined their anticancer efficacy. NX-TPP and CFX-TPP markedly reduced the antibacterial activity, although CFX-TPP was more active than NX-TPP. However, both NX-TPP and CFX-TPP significantly induced cell death in colon HT-29, pancreatic MIAPaCa-2, and other cancer cells but not in non-cancerous cells including normal dermal fibroblasts and human vascular endothelial cells at a comparative level. NX-TPP induced necrosis-like cell death characterized by cell membrane ballooning and rupture. Mechanistically, NX-TPP was efficiently incorporated into the mitochondria, leading to increased mitochondrial reaction oxygen species (mtROS) generation and mitophagy, and decreased mtDNA copy number and mitochondrial respiration. NX-TPP inhibited tumor growth in HT-29 and MIAPaCa-2 xenograft mouse models without any apparent adverse effects. These results suggest that mtDNA replication-targeting quinolone derivatives, termed MitoQNs, that exhibit reduced antibacterial activity, thereby decreasing antibiotic resistance induction, and enhanced anticancer efficacy, are candidate drugs for cancer therapy.

Keywords:  TPP; antibiotic resistance; mitochondria; mtDNA replication; quinolones

DOI:  https://doi.org/10.1111/cas.70199
Cell Metab. 2025 Sep 16. pii: S1550-4131(25)00381-X. [Epub ahead of print]

OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis.

Christina Mayerhofer, Dan Li, Trine Kristiansen, Ernst Mayerhofer, Azeem Sharda, Giulia Schiroli, Karin Gustafsson, Lingli He, Michael Mazzola, Sam Keyes, Anna Kiem, Eve Crompton, Yanxin Xu, Sovannarith Korm, Zhixun Dou, Charles Vidoudez, Peter G Miller, Nick van Gastel, Timothy A Graubert, David T Scadden.

  Acute myeloid leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDXs) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting BCAAs further reduced chemoresistant AML cells, but relapse still occurred. Among the persisting cells, we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate- and iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA. We found that OGFOD1 upregulates protein synthesis in AML, driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML while sparing normal hematopoiesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation. Targeting OGFOD1 may offer a distinctive, translation-modifying means of reducing the chemopersisting cells that drive relapse.

Keywords:  BCAA; OGFOD1; Ribo-seq; acute myeloid leukemia; chemoresistance; metabolism; protein biosynthesis; ribosome pausing; translation accuracy

DOI:  https://doi.org/10.1016/j.cmet.2025.08.008
Cancer Res. 2025 Sep 18.

Surgery-Induced Neutrophil Extracellular Traps Promote Tumor Metastasis by Reprogramming Cancer Cell Lipid Metabolism.

Tony Haykal, Ruiqi Yang, Celine Tohme, Zhengyi He, Silvia Liu, David A Geller, Christof Kaltenmeier, Stacy L Gelhaus, Richard L Simmons, Hamza O Yazdani, Samer Tohme.

Cancer surgery is a double-edged sword, as it can induce an inflammatory response that promotes tumor recurrence and progression. In this study, we explored the effects of surgery-induced neutrophil extracellular traps (NETs) in reprogramming cancer metabolism to foster metastatic tumor growth. To model the effect of surgery on tumor progression, mice bearing subcutaneous tumors underwent a midline laparotomy with mesenteric exploration for 30 mins. Mice subjected to surgery showed accelerated primary subcutaneous and lung metastatic tumor growth. Perioperative inhibition of NET formation utilizing DNAse, GSK484, or PAD4 knockout mice prevented surgically induced tumor growth, whereas pre-treating cancer cells with NETs in vitro before inoculation increased tumor burden. Cancer cells exposed to surgical stress in vivo or treated with NETs in vitro showed activation of the MYC oncogenic pathway and fatty acid oxidation (FAO). NETs also stimulated uptake of long-chain fatty acids (LCFA) and upregulation of CD36, the main LCFA transporter. Blocking FAO with etomoxir, a CPT1α inhibitor, prevented metastatic tumor growth induced by surgical NETs. FA metabolism was crucial for cancer cells under anoikis stress, allowing survival of circulating cancer cells exposed to NETs. Analysis of patient data substantiated the correlation between NET abundance and lipid metabolism, and plasma from post-operative patients upregulated CD36 expression and promoted the proliferation of colorectal cancer cells. Together, these findings show that the systemic NETosis response triggered by surgery promotes tumor progression by activating the MYC transcriptional program and reprogramming FAO metabolism in cancer cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3393
Free Radic Biol Med. 2025 Sep 16. pii: S0891-5849(25)00985-2. [Epub ahead of print]

Development of novel analogs of the TRi-1 and TRi-2 selenoprotein thioredoxin reductase inhibitors with initial assessment of their cytotoxicity profiles.

Miloš Jović, Radosveta Gencheva, Karoline C Scholzen, Qing Cheng, Života Selaković, Elias S J Arnér, Igor M Opsenica.

  The human selenoprotein thioredoxin reductases are encoded and expressed as separate cytosolic (TXNRD1) and mitochondrial (TXNRD2) isoforms, with both having been suggested as potential anticancer drug targets. The TRi-1 compound was recently shown to preferentially inhibit TXNRD1 in cells, while the TRi-2 compound seems to target both isoforms in a cellular context, albeit to different extent. Attempting to evaluate whether TXNRD1 or TXNRD2 inhibition most closely correlates with cytotoxicity we here synthesized several analogs of both TRi-1 and TRi-2, including triphenyl phosphonium derivatives designed to accumulate in mitochondria. We evaluated 11 compounds in comparison with TRi-1 and TRi-2 with regards to inhibition of TXNRD1 and TXNRD2 in pure enzyme assays, and their cytotoxicity profiles towards human lung adenocarcinoma A549 cells, with constitutively high NRF2 activity and thus potent antioxidant defense. Human squamous cell carcinoma FaDu cells with lower NRF2 and lower TXNRD1 activity were much more sensitive to the compounds. The results strengthen the notion that compound-derived inhibition of either TXNRD1 or TXNRD2 can yield cytotoxicity in human cancer cells. Comparing two pairs of matched inhibitor scaffolds for the effects of adding a triphenyl phosphonium group, we found that this moiety ensured minimal inhibition of cellular cytosolic TXNRD1 activity, as assessed using the specific RX1 activity probe, while maintaining cytotoxicity, which was thus likely involving targeting of TXNRD2 in the mitochondria. Our results represent a blueprint for initial evaluations of novel small molecule inhibitors of TXNRD1 and TXNRD2, correlating such inhibition of pure enzymes as well as in cells in relation to their cytotoxicity.

Keywords:  SecTRAPs; adenocarcinoma; click chemistry; mitochondria; redox homeostasis; triphenylphosphonium

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.028
J Oncol Res Ther. 2025 ;pii: 10299. [Epub ahead of print]10(3):

The Nuclear-Encoded Cytochrome c Oxidase Subunit COX4-1 Enhances Hypoxia Tolerance in Glioblastoma Cells.

Claudia R Oliva, Susanne Flor, Md Yousuf Ali, Corinne E Griguer.

  Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. While chemo- and radiotherapy are often effective in treating newly diagnosed GBM, increasing evidence suggests that treatment-induced metabolic alterations promote tumor recurrence and further resistance. In addition, GBM tumors are typically hypoxic, which further contributes to treatment resistance. Recent studies have shown that changes in glioma cell metabolism driven by a shift in the isoform expression of mitochondrial cytochrome c oxidase (CcO) subunit 4 (COX4), a key regulatory subunit of mammalian CcO, may underlie the treatment-induced metabolic alterations in GBM cells. However, the impact of hypoxia on GBM energetics is not fully understood. Using isogenic GBM cell lines expressing either COX4-1 or the alternative COX4 isoform, COX4-2, we found that COX4-1 expressing cells maintained a more oxidative metabolism under hypoxia, characterized by increased CcO activity and ATP production, enhanced assembly of CcO-containing mitochondrial supercomplexes, and reduced superoxide production. Furthermore, COX4-1 expression was sufficient to increase radioresistance under hypoxic conditions. Untargeted metabolomic analysis revealed that the most significantly upregulated pathways in COX4-1-expressing cells under hypoxia were purine and methionine metabolism. In contrast, COX4-2-expressing cells showed increased activation of glycolysis and the Warburg effect. Our study provides new insights into how CcO regulatory subunits influence cellular metabolic networks and radioresistance in GBM under hypoxia, identifying potential therapeutic targets for improved treatment strategies.

Keywords:  COX4–1; Cytochrome c oxidase; Glioma; Hypoxia; Mitochondrial supercomplexes; Radioresistance

DOI:  https://doi.org/10.29011/2574-710x.10299
Mol Cell. 2025 Sep 18. pii: S1097-2765(25)00713-0. [Epub ahead of print]85(18): 3351-3352

mtDNA base editing: Mind the gap.

Jose Domingo Barrera-Paez, Carlos T Moraes.

In this issue of Molecular Cell, Xiang et al.1 provided insights into the mechanism and structure-guided engineering of DdCBE for mitochondrial DNA base editing. More precise editing was achieved by better defining the editing window.

DOI: https://doi.org/10.1016/j.molcel.2025.08.028
Redox Biol. 2025 Sep 15. pii: S2213-2317(25)00384-2. [Epub ahead of print]87 103871

Noninvasive in vivo discrimination between mitochondrial ROS and global ROS production in solid tumors using EPR spectroscopy.

Barbara Mathieu, Justin D Rondeau, Lionel Mignion, Pierre Sonveaux, Bernard Gallez.

  Because the precise site of ROS production plays a key role in cellular redox signaling and its (patho)physiological consequences, it is crucial to develop tools that enable site-specific detection of ROS in complex systems, including in vivo. Here, we propose the use of Electron Paramagnetic Resonance (EPR) and dual nitroxide sensors composed of mitoTEMPO and carbamoyl-proxyl (3CP) to probe ROS production in the mitochondrial and intracellular/extracellular compartments, respectively. For the proof-of-concept, the decay rates of the nitroxides were measured in 4T1 breast tumor models, both in vitro and in vivo, using 9 GHz and 1 GHz spectrometers, respectively. To modulate the level of ROS either in the cytosol or in the mitochondria, cells and mice were treated with either the glutathione synthesis inhibitor l-Buthionine Sulfoximine (L-BSO) or Antimycin A, an inhibitor of the complex III of the mitochondrial electron transport chain, or their appropriate controls. In mice, an increase in relative decay rate was observed for 3CP, but not for mitoTEMPO, 1 and 2 days after starting L-BSO treatment, while the opposite result was obtained after Antimycin A treatment. These observations were consistent with results obtained on cells in vitro. Ex-vivo analyses of tumors, with or without ferricyanide that converts hydroxylamines back to nitroxides, revealed non-significant changes in the total amount of nitroxide + hydroxylamine, suggesting that the blood wash-out did not play a role in the decay of the nitroxide signal. In addition, the use of genetically engineered 4T1 cells that overexpress the mitochondrial isoform superoxide dismutase 2 (SOD2) allowed the assessment of the contribution of superoxide production to EPR signal decay. Overall, this study identifies a new protocol to noninvasively discriminate the site of ROS production in vivo.

Keywords:  3-Carbamoyl-proxyl; Cancer; EPR; ESR; Mitochondria; Nitroxide; ROS; mitoTEMPO

DOI:  https://doi.org/10.1016/j.redox.2025.103871
J Biol Chem. 2025 Sep 11. pii: S0021-9258(25)02564-5. [Epub ahead of print] 110712

Inhibition of anti-apoptotic BCL2 overcomes adaptive resistance to co-targeting of the protein kinase FAK and MEK in GNAQ-driven uveal melanoma.

Simone Lubrano, Rodolfo Daniel Cervantes-Villagrana, Nadia Arang, Adam Officer, Sendi Rafael Adame-Garcia, Gabriela Cuesta-Margolles, Andrew E Aplin, J Silvio Gutkind.

  Uveal melanoma (UVM) is the most common eye cancer in adults, with 50% of patients developing overt metastasis that often proves fatal. The majority of UVM harbor mutations in GNAQ or GNA11, encoding constitutively active Gαq proteins. Combined inhibition of MEK and FAK downstream of Gαq has shown promising effects in UVM cells by inducing apoptotic cell death, but resistance to this strategy can occur in the clinic. Here, we aimed to identify new targets to overcome resistance to MEK + FAK inhibition (FAKi+MEKi). Reverse-phase protein array (RPPA) analysis in UVM cells treated with FAKi+MEKi showed increased levels of pro-apoptotic proteins such as PUMA and BIM, which promoted cell death. However, we observed an adaptive increase in anti-apoptotic proteins, including BCL2, upon FAK+MEK blockade. We generated UVM cells resistant to FAKi+MEKi by prolonged exposure. Whole-exome sequencing did not reveal relevant acquired mutations; instead, resistant cells exhibit increased BCL2 levels. Moreover, expression of a stable BCL2 mutant confers resistance to both FAKi+MEKi and FAKi+"RAF-MEK clamp" (avutometinib) treatment. Of direct translational relevance, we found that an approved BCL2 inhibitor (venetoclax) displays synergistic efficacy with FAK+MEK blockade and overcomes acquired resistance, including when combined with darovasertib, a dual PKC/PKN inhibitor limiting MEK and FAK signaling that is under clinical evaluation. Our findings suggest that resistance to FAKi+MEKi in UVM cells can be driven by an adaptive upregulation of the anti-apoptotic protein BCL2, and that, in turn, BCL2 inhibitors represent a promising precision-targeted strategy to overcome FAKi+MEKi treatment resistance and improve therapeutic outcomes.

Keywords:  BCL2; FAK; MEK; Resistance; avutometinib; darovasertib; uveal melanoma; venetoclax

DOI:  https://doi.org/10.1016/j.jbc.2025.110712
bioRxiv. 2025 Sep 07. pii: 2025.09.02.673780. [Epub ahead of print]

BOGO: A Proteome-Wide Gene Overexpression Platform for Discovering Rational Cancer Combination Therapies.

Kyeong Beom Jo, Mohammed M Alruwaili, Da-Eun Kim, Yongjun Koh, Hyeyeon Kim, Kwontae You, Ji-Sun Kim, Saba Sane, Yanqi Guo, Jacob P Wright, Hyobin Julianne Lim, Maricris N Naranjo, Atina G Coté, Frederick P Roth, David E Hill, Jung-Hyun Choi, Hunsang Lee, Kenneth A Matreyek, Kyle K-H Farh, Jong-Eun Park, Hyunkyung Kim, Andrei V Bakin, Dae-Kyum Kim.

Cancer drug resistance remains a major barrier to durable treatment success, often leading to relapse despite advances in precision oncology. While combination therapies are being increasingly investigated, such as chemotherapy with small molecule inhibitors, predicting drug response and identifying rational drug combinations based on resistance mechanisms remain major challenges. Therefore, a proteome-wide, single-gene overexpression screening platform is essential for guiding rational therapy selection. Here, we present BOGO (Bxb1-landing pad human ORFeome-integrated system for a proteome-wide Gene Overexpression), a robust, scalable, and reproducible screening platform that enables single-copy, site-specific integration and overexpression of ~19,000 human ORFs across cancer cell models. Using BOGO, we identified drug-specific response drivers for 16 chemotherapeutic agents and integrated clinical datasets to uncover proliferation and resistance-associated genes with prognostic potential. Drug response similarity networks revealed both shared and unique mechanisms, highlighting key pathways such as autophagy, apoptosis, and Wnt signaling, and notable resistance-associated genes including BCL2, POLD2, and TRADD. In particular, we proposed a synergistic combination of the BCL2 family inhibitor ABT-263 (Navitoclax®) and the DNA analog TAS-102 (Lonsurf®), which revealed that lysosomal modulation is a key mechanism driving DNA analog resistance. This combination therapy selectively enhanced cytotoxicity in colorectal and pancreatic cancer cells in vitro, and demonstrated therapeutic benefit in vivo in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Together, these findings establish BOGO as a powerful gene overexpression perturbation platform for systematically identifying chemoresistance and chemosensitization drivers, and for discovering rational combination therapies. Its scalability and reproducibility position BOGO as a broadly applicable tool for functional genomics and therapeutic discovery beyond cancer resistance.

DOI: https://doi.org/10.1101/2025.09.02.673780
Nature. 2025 Sep 17.

Peroxisomal metabolism of branched fatty acids regulates energy homeostasis.

Xuejing Liu, Anyuan He, Dongliang Lu, Donghua Hu, Min Tan, Abenezer Abere, Parniyan Goodarzi, Bilal Ahmad, Brian Kleiboeker, Brian N Finck, Mohamed Zayed, Katsuhiko Funai, Jonathan R Brestoff, Ali Javaheri, Patricia Weisensee, Bettina Mittendorfer, Fong-Fu Hsu, Paul P Van Veldhoven, Babak Razani, Clay F Semenkovich, Irfan J Lodhi.

Brown and beige adipocytes express uncoupling protein 1 (UCP1), a mitochondrial protein that dissociates respiration from ATP synthesis and promotes heat production and energy expenditure. However, UCP1-/- mice are not obese1-5, consistent with the existence of alternative mechanisms of thermogenesis6-8. Here we describe a UCP1-independent mechanism of thermogenesis involving ATP-consuming metabolism of monomethyl branched-chain fatty acids (mmBCFA) in peroxisomes. These fatty acids are synthesized by fatty acid synthase using precursors derived from catabolism of branched-chain amino acids9 and our results indicate that β-oxidation of mmBCFAs is mediated by the peroxisomal protein acyl-CoA oxidase 2 (ACOX2). Notably, cold exposure upregulated proteins involved in both biosynthesis and β-oxidation of mmBCFA in thermogenic fat. Acute thermogenic stimuli promoted translocation of fatty acid synthase to peroxisomes. Brown-adipose-tissue-specific fatty acid synthase knockout decreased cold tolerance. Adipose-specific ACOX2 knockout also impaired cold tolerance and promoted diet-induced obesity and insulin resistance. Conversely, ACOX2 overexpression in adipose tissue enhanced thermogenesis independently of UCP1 and improved metabolic homeostasis. Using a peroxisome-localized temperature sensor named Pexo-TEMP, we found that ACOX2-mediated fatty acid β-oxidation raised intracellular temperature in brown adipocytes. These results identify a previously unrecognized role for peroxisomes in adipose tissue thermogenesis characterized by an mmBCFA synthesis and catabolism cycle.

DOI: https://doi.org/10.1038/s41586-025-09517-7
Trends Cancer. 2025 Sep 16. pii: S2405-8033(25)00204-3. [Epub ahead of print]

Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.

Huiyu Li, Wenyi Jin, Junhong Liu, Yundong Zhou, Xiaoli Shan, Yubiao Zhang, Yongliang Kou, Chunyan Deng, Cheng Jin, Junjie Kuang, Yui-Leung Lau, João Conde, Baozhen Huang, Queran Lin.

  The tumor microenvironment (TME) imposes profound metabolic and functional constraints on immune cells, with mitochondrial dysfunction emerging as a pivotal driver of immunosuppression. While mitochondrial metabolism is well recognized for its role in energy production and cellular homeostasis, its dynamic regulation of immune cell activation, differentiation, and exhaustion within the TME remains underexplored. In this review we summarize insights into how TME stressors such as hypoxia, nutrient competition, and metabolic byproducts subvert mitochondrial dynamics, redox balance, and mitochondrial DNA (mtDNA) signaling in T cells, natural killer (NK) cells, and macrophages, thereby directly impairing their antitumor efficacy. We emphasize that the restoration of mitochondrial fitness in immune cells, achieved by targeting metabolites in the TME and mitochondrial quality control, represents a pivotal axis for adoptive cell therapies (ACTs) and TME reprogramming.

Keywords:  ROS; chimeric antigen receptor (CAR); metabolism; mitochondria; tumor immunotherapy

DOI:  https://doi.org/10.1016/j.trecan.2025.08.006