bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–01–18
eighteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Daily briefing: Cancer cells stay hidden using stolen mitochondria.
  2. Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
  3. Mitochondrial fission during mitophagy requires both inner and outer mitofissins.
  4. Cancer might evade immune defences by stealing mitochondria.
  5. Mitochondrial transfer in cancer: mechanisms, immune evasion, and therapeutic opportunities.
  6. Evaluation of dual BCL-2/BCL-XL inhibition in AML preclinical models with and without prior venetoclax therapy.
  7. Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.
  8. Mitochondrial transfer from immune to tumor cells enables lymph node metastasis.
  9. Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
  10. Targeting mitochondrial complexes for cancer therapy.
  11. 6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
  12. Mitochondrial ligase MAPL drives pyroptotic cell death.
  13. Potassium ion homeostasis modulates mitochondrial function.
  14. PTMA safeguards mitochondrial integrity to sustain metabolic function and antitumor activity of CD8 T cells.
  15. mtDNApipe: A Pioneering Pipeline for High-Sensitivity Detection of Low-Frequency Mitochondrial DNA Mutations.
  16. Drivers of clinical resistance to venetoclax and hypomethylating agents in acute myeloid leukemia and strategies for improving efficacy.
  17. Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.
  18. New mitochondrial KV1.3 conjugates are potent and specific inducers of apoptosis in cancer models.
  1. Nature. 2026 Jan 15.
    Daily briefing: Cancer cells stay hidden using stolen mitochondria.
    Jacob Smith.
      
    DOI:  https://doi.org/10.1038/d41586-026-00181-z
  2. Nat Metab. 2026 Jan 16.
    Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
    Kimberly S Huggler, Kyle M Flickinger, Matthew H Forsberg, Carlos A Mellado Fritz, Gavin R Chang, Meghan F McGuire, Christian M Capitini, Jason R Cantor.
      Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis.
    DOI:  https://doi.org/10.1038/s42255-025-01428-1
  3. EMBO Rep. 2026 Jan 13.
    Mitochondrial fission during mitophagy requires both inner and outer mitofissins.
    Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Shun-Ichi Yamashita, Keiichi Inoue, Tomoyuki Fukuda, Nobuo N Noda, Tomotake Kanki.
      Mitophagy maintains mitochondrial homeostasis through the selective degradation of damaged or excess mitochondria. Recently, we identified mitofissin/Atg44, a mitochondrial intermembrane space-resident fission factor, which directly acts on lipid membranes and drives mitochondrial fission required for mitophagy in yeast. However, it remains unclear whether mitofissin is sufficient for mitophagy-associated mitochondrial fission and whether other factors act from outside mitochondria. Here, we identify a mitochondrial outer membrane-resident mitofissin-like microprotein required for mitophagy, and we name it mitofissin 2/Mfi2 based on the following results. Overexpression of an N-terminal Atg44-like region of Mfi2 induces mitochondrial fragmentation and partially restores mitophagy in atg44Δ cells. Mfi2 binds to lipid membranes and mediates membrane fission in a cardiolipin-dependent manner in vitro, demonstrating its intrinsic mitofissin activity. Coarse-grained molecular dynamics simulations further support the stable interaction of Mfi2 with cardiolipin-containing bilayers. Genetic analyses reveal that Mfi2 and the dynamin-related protein Dnm1 independently facilitate mitochondrial fission during mitophagy. Thus, Atg44 and Mfi2, two mitofissins with distinct localizations, are required for mitophagy-associated mitochondrial fission.
    Keywords:  Atg44; Mfi2; Mitochondrial Fission; Mitofissin; Mitophagy
    DOI:  https://doi.org/10.1038/s44319-025-00689-x
  4. Nature. 2026 Jan 14.
    Cancer might evade immune defences by stealing mitochondria.
    Laura Dattaro.
      
    Keywords:  Cancer; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-00123-9
  5. Genomics Inform. 2026 Jan 13.
    Mitochondrial transfer in cancer: mechanisms, immune evasion, and therapeutic opportunities.
    Hye In Ka, Hyun Goo Woo.
      Intercellular mitochondrial transfer (MT) is emerging as a transformative communication axis in cancer biology. Intact mitochondria or mitochondrial components can be exchanged between tumor cells, stromal elements, and immune cells via tunneling nanotubes, extracellular vesicles, cell fusion, or phagocytic uptake. This organelle exchange enables metabolic adaptation by restoring OXPHOS (oxidative phosphorylation), increasing ATP production, and enhancing survival in hostile environments. Conversely, tumor cells also hijack mitochondria from cytotoxic lymphocytes thereby undermining immune function and contributing to immune escape and tumor progression. These converging metabolic exchanges fuel immune evasion, metastatic potential, and resistance to chemotherapy, radiation, and immunotherapy. Cutting-edge tracing tools, including mitochondrial reporter proteins and single-cell mitochondrial genome lineage mapping, have uncovered MT events both in vitro and in vivo. Therapeutic strategies designed to block mitochondrial trafficking, inhibit nanotube formation or vesicle uptake, or enhance immune cell mitochondrial resilience hold promise for tumor sensitization and restoration of antitumor immunity. A deeper understanding of MT provides novel insight into cancer metabolism and intercellular communication, offering a foundation for future therapeutic innovation and potential clinical application as both a biomarker and a therapeutic target.
    Keywords:  Cancer; Immune Evasion; Mitochondria; Mitochondrial Transfer
    DOI:  https://doi.org/10.1186/s44342-025-00064-1
  6. Exp Hematol. 2026 Jan 12. pii: S0301-472X(26)00012-3. [Epub ahead of print] 105379
    Evaluation of dual BCL-2/BCL-XL inhibition in AML preclinical models with and without prior venetoclax therapy.
    Reecha Shah, Nathan Kingston, Giulia Fabbri, Jamal Saeh, Courtney Andersen, Patricia Cheung.
      Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy that relies heavily on the anti-apoptotic protein B-cell lymphoma 2 (BCL-2) for survival.1 Venetoclax, a BCL-2 inhibitor, exploits this dependency and is currently approved for treatment of elderly AML patients. BCL-XL, another pro-survival protein in the BCL-2 family, has been identified as a key driver of both intrinsic and acquired resistance to venetoclax.2 Patients often develop resistance to BCL-2 inhibition through upregulation of BCL-XL.3 This study investigates the efficacy of a dual BCL-2/BCL-XL inhibitor and its combination with standard-of-care (SOC) agents. Dual BCL-2/BCL-XL inhibitor demonstrates robust activity in AML cell lines and patient-derived models, including activity in samples from patients who relapsed following venetoclax therapy. Its combination with SOC agents deepens the anti-leukemic activity both in vitro and in vivo. Among the combination regimens tested, cytarabine or hypomethylating agents (HMA) drive strong blast reduction in patient samples previously exposed to venetoclax and yield improved survival in AML patient-derived xenograft models with prior venetoclax/5-azacytidine treatment. These preclinical findings support the clinical evaluation of dual BCL-2/BCL-XL inhibition in AML patients, particularly, those who do not respond to venetoclax.
    Keywords:  AZD0466; Acute Myeloid Leukemia; Apoptosis; BCL-2/BCL-XL inhibitor; BH3 mimetic; Combination Treatment; Targeted therapy
    DOI:  https://doi.org/10.1016/j.exphem.2026.105379
  7. Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00501-4. [Epub ahead of print]90 103988
    Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.
    Viktor Antonsson Garellick, Nadia Gul, Parvin Horrieh, Dyar Mustafa, Angana A H Patel, Martin Dankis, Samantha W Alvarez, Johanna Berndtson, Saeed Mahdavi, Maria Schwarz, Andreas Persson, Fikret Zahirovic, Clotilde Wiel, Volkan I Sayin, Per Lindahl.
      Lung cancer cells are vulnerable to iron-dependent oxidation of phospholipids leading to ferroptosis, a process countered by glutathione peroxidase-4 that converts lipid hydroperoxides to lipid alcohols using glutathione as reducing agent. Since ferroptosis-inducing agents are in clinical development, identifying modifiers of ferroptosis susceptibility is warranted. Here, we investigate the impact of amino acids on susceptibility to buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that blocks biosynthesis of glutathione. We found that reduced amounts of amino acids other than cysteine increased the sensitivity to BSO and other ferroptosis-inducing agents, in a panel of mouse and human lung cancer cells, without affecting glutathione production. Activation of the amino acid sensor protein GCN2 and the integrated stress response lowered the threshold for lipid peroxidation by promoting ATF4-dependent mitochondrial respiration and reactive oxygen species leakage from the electron transport chain under glutathione depletion. The finding provides new insights into lung cancer metabolism and raises the possibility of using amino acid restricted diets in combination with ferroptosis-inducing agents as cancer therapies.
    Keywords:  Amino acids; Ferroptosis; Glutathione; Integrated stress response; Lung cancer; Mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.redox.2025.103988
  8. Cell Metab. 2026 Jan 12. pii: S1550-4131(25)00545-5. [Epub ahead of print]
    Mitochondrial transfer from immune to tumor cells enables lymph node metastasis.
    Azusa Terasaki, Keshav Bhatnagar, Alexis T Weiner, Yuhao Tan, Viktoria Szeifert, Han-Li Huang, Lukas Wiggers, Viviana Rodrigues, Cara C Rada, Vishnu Shankar, Suguru Saito, Peter Ofori Ankomah, Theodore Roth, Bill Chiu, Robert West, Lingyin Li, Nathan Reticker-Flynn, Jeffrey D Axelrod, Jonathan R Brestoff, Bo Li, Edgar Engleman, Derick Okwan-Duodu.
      Although the immune system is a significant barrier to tumor growth and spread, established tumors evade immune attack and frequently colonize immune populated areas such as the lymph node. The mechanisms by which cancer cells subvert the tumor-immune microenvironment to favor spread to the lymph node remain incompletely understood. Here, we show that, as a common attribute, tumor cells hijack mitochondria from a wide array of immune cells. Mitochondria loss by immune cells decreases antigen-presentation and co-stimulatory machinery, as well as reducing the activation and cytotoxic capacity of natural killer (NK) and CD8 T cells. In cancer cells, the exogenous mitochondria fuse with endogenous mitochondria networks, leak mtDNA into the cytosol, and stimulate cGAS/STING, activating type I interferon-mediated immune evasion programs. Blocking mitochondrial transfer machinery-including cGAS, STING, or type I interferon-reduced cancer metastasis to the lymph node. These findings suggest that cancer cells leverage mitochondria hijacking to weaken anti-tumor immunosurveillance and use the acquired mitochondria to fuel the immunological requirements of lymph node colonization.
    Keywords:  MERCI; cGAS/STING; immune evasion; lymph node cancer metastasis; mitochondrial transfer
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.014
  9. Nat Commun. 2026 Jan 10.
    Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
    Minh Duc Nguyen, Ana Sierra-Magro, Vivek Singh, Anas Khawaja, Alba Timón-Gómez, Antoni Barrientos, Joanna Rorbach.
      The mitochondrial respiratory chain comprises four multimeric complexes (CI-CIV) that drive oxidative phosphorylation by transferring electrons to oxygen and generating the proton gradient required for ATP synthesis. These complexes can associate into supercomplexes (SCs), such as the CI + CIII₂ + CIV respirasome, but how SCs form, by joining preassembled complexes or by engaging partially assembled intermediates, remains unresolved. Here, we use cryo-electron microscopy to determine high-resolution structures of native human CI + CIII₂ + CIV late-assembly intermediates. Together with biochemical analyses, these structures show that respirasome biogenesis concludes with the final maturation of CIV while it is associated with fully assembled CI and CIII₂. We identify HIGD2A as a placeholder factor within isolated and supercomplexed CIV that is replaced by subunit NDUFA4 during the last step of CIV and respirasome assembly. This mechanism suggests that placeholders such as HIGD2A act as molecular timers, preventing premature incorporation of NDUFA4 or its isoforms and ensuring the orderly progression of pre-SC particles into functional respirasomes. Since defects in CIV assembly, including NDUFA4 deficiencies, cause severe encephalomyopathies and neurodegenerative disorders, understanding the molecular architecture and assembly pathways of isolated and supercomplexed CIV offers insight into the pathogenic mechanisms underlying these conditions.
    DOI:  https://doi.org/10.1038/s41467-025-68274-3
  10. Biochem Pharmacol. 2026 Jan 10. pii: S0006-2952(26)00026-2. [Epub ahead of print] 117695
    Targeting mitochondrial complexes for cancer therapy.
    Alaa M A Osman, Alya A Arabi.
      Mitochondrial Complexes I-IV in the electron transport chain (ETC) are strategic targets for cancer treatment since they provide the energy and biosynthetic demands of cancer cells. This review covers in silico, in vitro, and in vivo findings related to the inhibition of ETC complexes in order to block cancer cell survival. It covers details about bioenergetic disruption as well as innovative therapeutic strategies such as photodynamic therapy (PDT). This review, thus, serves as a guide for the development of novel small molecules and repurposed drugs for cancer treatment that target the ETC. In addition, this review shows how deep learning and AI-based nanotechnologies are being applied to predict the oxidative phosphorylation (OXPHOS) activity, identify ETC dependencies in cancer cells, and accelerate the discovery of mitochondrial complex-targeted anticancer drugs. It further explains how targeting ETC complexes can be implemented in precision medicine strategies.
    Keywords:  Artificial Intelligence; Cancer; Drug discovery; Electron transport chain; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.bcp.2026.117695
  11. Nat Commun. 2026 Jan 14. 17(1): 229
    6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
    Saeed Daneshmandi, Qi Yan, Eduardo Cortes Gomez, Jee Eun Choi, Eriko Katsuta, Ehsan Gharib, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa W-M Fan, Jianmin Wang, Elizabeth A Repasky, Philip L McCarthy, Hemn Mohammadpour.
      The mechanisms underlying the metabolic adaptation of myeloid cells within the tumor microenvironment remain incompletely understood. Here, we identify 6-phosphogluconate dehydrogenase (6PGD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), as an important regulator of monocytic-myeloid derived suppressor cell (M-MDSC) function. Our findings reveal that tumor M-MDSCs upregulate 6PGD expression via IL-6/STAT3 signaling. Blocking 6PGD, using either genetic or pharmacological approaches, impairs the immunosuppressive function of M-MDSCs and suppresses tumor growth. Mechanistically, 6PGD inhibition leads to the accumulation of its substrate, 6-phosphogluconate (6PG), within M-MDSCs, activates the JNK1-IRS1 and PI3K-AKT-pDRP1 signaling pathways, leading to mitochondrial fragmentation and elevated mitochondrial reactive oxygen species (ROS). This metabolic shift drives M-MDSCs toward an M1-like proinflammatory phenotype. Furthermore, 6PGD blockade synergizes with anti-PD-1 immunotherapy in a preclinical tumor model, substantially improving therapeutic outcomes. Our data reveals 6PGD as a possible therapeutic target to disrupt M-MDSC function and improve cancer immunotherapy outcomes.
    DOI:  https://doi.org/10.1038/s41467-025-68102-8
  12. Nat Struct Mol Biol. 2026 Jan 15.
    Mitochondrial ligase MAPL drives pyroptotic cell death.
    Yue Feng.
      
    DOI:  https://doi.org/10.1038/s41594-025-01735-x
  13. J Cell Biol. 2026 Apr 06. pii: e202505110. [Epub ahead of print]225(4):
    Potassium ion homeostasis modulates mitochondrial function.
    Adam James Waite, Beiduo Rao, Elizabeth Schinski, Nathaniel H Thayer, Manuel Hotz, Austin E Y T Lefebvre, Celeste Sandoval, Daniel E Gottschling.
      Age-associated decline in mitochondrial membrane potential (MMP) is a ubiquitous aspect of eukaryotic organisms and is associated with many aging-related diseases. However, it is not clear whether this decline is a cause or consequence of aging, and therefore whether interventions to reduce MMP decline are a viable strategy to promote healthier aging and longer lifespans. We developed a screening platform in Saccharomyces cerevisiae to identify mutations that slowed or abrogated the age-associated decline in MMP. Characterization of the longest-lived mutant revealed that reduced internal potassium increased MMP and extended lifespan. Distinct interventions improved cellular MMP and lifespan: deleting a potassium transporter; altering the balance between kinases and phosphatases that control potassium transporter activity; and reducing available potassium in the environment. Similarly, in isolated mitochondria, reducing the concentration of potassium was sufficient to increase MMP. These data indicate that the most abundant monovalent cation in eukaryotic cells plays a critical role in tuning mitochondrial function, consequently impacting lifespan.
    DOI:  https://doi.org/10.1083/jcb.202505110
  14. Sci Immunol. 2026 Jan 23. 11(115): eadz7275
    PTMA safeguards mitochondrial integrity to sustain metabolic function and antitumor activity of CD8 T cells.
    Keling Huang, Xiaoxue Li, Wenhua Liang, Shuyao Wu, Youqiong Ye, Yan Lu, Junke Zheng, Weifang Wang, Qifan Zheng, Guo Fu, Song Gao, Feng Wang.
      Immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often limited by the progressive exhaustion of tumor-reactive CD8 T cells. By analyzing transcriptomes of CD8 T cells from patients treated with ICB across cancer types, we found that prothymosin alpha (PTMA) is highly expressed in progenitor exhausted T (TPEX) cells and is associated with treatment response. PTMA expression was directly controlled by T cell factor 1 (TCF1), a central regulator of TPEX cell maintenance in the tumor microenvironment. In mice, genetic deletion of Ptma from T cells compromised CD8 T cell persistence in tumors and abolished the therapeutic effect of programmed cell death protein 1 (PD-1) blockade. PTMA preserved mitochondrial DNA integrity through interaction with mitochondrial transcription factor A (TFAM), sustaining T cell oxidative phosphorylation under metabolic stress. Our findings identify the TCF1-PTMA axis as a molecular link between mitochondrial fitness and durable T cell-mediated antitumor immunity, offering insights and potential directions for future therapeutic strategies to boost immunotherapy efficacy.
    DOI:  https://doi.org/10.1126/sciimmunol.adz7275
  15. Anal Chem. 2026 Jan 15.
    mtDNApipe: A Pioneering Pipeline for High-Sensitivity Detection of Low-Frequency Mitochondrial DNA Mutations.
    Wenjie Guo, Shengjing Li, Tianlei Sun, Zhangwen Lei, Kaixiang Zhou, Lei Zhang, Xu Guo, Feng Zhou, Yang Liu, Jinliang Xing.
      Accurate detection of low-frequency mitochondrial DNA (mtDNA) mutations is essential for advancing molecular profiling, yet it is often confounded by sequencing artifacts, nuclear mitochondrial DNA (NUMTs), and oxidative damage-induced errors. Although unique molecular identifier (UMI)-based duplex sequencing can reduce such errors, its high cost and limited efficiency restrict its widespread use. Here, we present mtDNApipe, a bioinformatics pipeline tailored for capture-based mtDNA sequencing that integrates multiple layers of error suppression. The workflow combines stringent prealignment filtering to remove low-quality reads, overlap-based correction exploiting paired-end redundancy, and exclusion of soft-clipped reads to minimize NUMT interference. Additionally, an endogenous UMI (eUMI)-guided deduplication strategy corrects strand-specific damage, while terminal mutation filtering mitigates end-repair artifacts. When applied to technical replicates of peripheral blood mononuclear cells with low mtDNA copy numbers and paired fresh tumor tissues with high copy numbers, mtDNApipe reduced false positives by more than 80% in the low-frequency range while maintaining sensitivity. Notably, it achieved accuracy comparable to that of conventional UMI-based methods but without their cost and complexity. Compared with existing tools, mtDNApipe demonstrated superior robustness for detecting low-frequency heteroplasmy, offering a reliable and cost-effective solution for high-fidelity mtDNA mutation analysis with broad applications in biomarker discovery, molecular diagnostics, and analytical genomics.
    DOI:  https://doi.org/10.1021/acs.analchem.5c05068
  16. Hemasphere. 2026 Jan;10(1): e70282
    Drivers of clinical resistance to venetoclax and hypomethylating agents in acute myeloid leukemia and strategies for improving efficacy.
    Ida Vänttinen, Joseph Saad, Tanja Ruokoranta, Sari Kytölä, Guangrong Qin, Bahar Tercan, Pia Ettala, Anu Partanen, Marja Pyörälä, Johanna Rimpiläinen, Timo Siitonen, Mikko Manninen, Peter J M Valk, Gerwin Huls, Vésteinn Thorsson, Caroline A Heckman, Mika Kontro, Heikki Kuusanmäki.
      The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with hypomethylating agents (HMAs) has improved treatment outcomes for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy and is increasingly used in the relapsed/refractory setting. However, primary resistance remains a significant challenge, affecting 20%-35% of treatment-naïve and around 50% of previously treated AML patients. To investigate the mechanisms driving primary resistance to VEN-HMA therapy, we analyzed genetic, transcriptomic, BCL-2 family protein expression, and ex vivo drug sensitivity data from 101 AML patients and correlated these profiles with clinical outcomes to VEN-HMA. Our study found that blasts from refractory patients exhibit an elevated BCL-XL/BCL-2 protein expression ratio, an immature CD34+CD38- phenotype, and frequent TP53 mutations. Consistent with the high ratio of BCL-XL/BCL-2, resistant samples showed increased ex vivo sensitivity to the dual BCL-2/BCL-XL inhibitor navitoclax. In addition, SMAC mimetics were effective in refractory blasts, which correlated with high TNF gene expression in these cells. Ex vivo treatment with the combination of navitoclax and SMAC mimetics further enhanced the eradication of VEN-HMA refractory blasts, although toxicity was also observed in healthy CD34+ cells. In conclusion, our integrative analysis identifies molecular signatures associated with primary VEN-HMA resistance and highlights BCL-2/BCL-XL inhibition and SMAC mimetics as therapeutic strategies to target resistance.
    DOI:  https://doi.org/10.1002/hem3.70282
  17. bioRxiv. 2026 Jan 06. pii: 2026.01.05.697775. [Epub ahead of print]
    Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.
    Melvin Li, Bradley Priem, Luke V Loftus, Michael J Betenbaugh, Kenneth J Pienta, Sarah R Amend.
      Therapy resistance is the leading cause of cancer-related deaths. Drug-tolerant persister cells (DTPs) represent a major barrier to cancer cure, mediating resistance through adaptive cell state transitions and driving tumor progression. Here, we investigate metabolic differences between DTPs and drug-sensitive cancer cells using integrated fluxomics. Proteomic profiling and extracellular flux analyses revealed that DTPs upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that DTPs utilize glucose to fuel the pentose phosphate pathway (PPP) to generate NADPH and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that DTPs sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. These findings reveal a systems-level shift in DTP metabolism that maintains antioxidant activity for cell survival, highlighting potential new targets and treatment paradigms to overcome therapy resistance.
    DOI:  https://doi.org/10.64898/2026.01.05.697775
  18. Biomed Pharmacother. 2026 Jan 14. pii: S0753-3322(26)00028-4. [Epub ahead of print]195 118996
    New mitochondrial KV1.3 conjugates are potent and specific inducers of apoptosis in cancer models.
    Špela Gubič, Marzia Fois, Xiaoyi Shi, Ivan Džajić, Daniela Secci, Katja Kološa, Alja Štern, Joshua A Nasburg, Hai M Nguyen, Veronica Carpanese, Gayathri Viswanathan, Vanessa Checchetto, Maša Omerzel, Tim Božič, Boštjan Markelc, Tanja Jesenko, Maja Čemažar, Ildiko Szabo, Heike Wulff, Bojana Žegura, Tina Kosjek, Andrej Emanuel Cotman, Tihomir Tomašič, Luis A Pardo, Lucija Peterlin Mašič.
      Mitochondrial KV1.3 channels (mitoKV1.3) have emerged as promising targets for cancer therapy due to their role in regulating apoptosis, independent of upstream signalling pathways and Bcl-2 family protein levels. Here, we present a new non-psoralene Kv1.3 mitochondria-targeted conjugates. These conjugates, particularly cis-8 and cis-9, exhibit nanomolar affinity and high selectivity for KV1.3 while effectively inducing apoptosis in tumor cells. Unlike their parent KV1.3 inhibitors, which lack cytotoxicity, the mitoKV1.3 conjugates induce rapid mitochondrial depolarization, and caspase-3/7 activation, culminating in dose-dependent tumor cell death in both 2D and 3D models. Mechanistically, cis-8 and cis-9 disrupt mitochondrial membrane potential and selectively target cancer cells, sparing normal cells at lower concentrations. Notably, KV1.3 knockout models confirmed the dependence of cytotoxicity on mitoKV1.3 inhibition. The conjugates demonstrated robust antitumor activity in murine pancreatic intraepithelial neoplasia (PanIN)-derived organoids, with preferential action over normal pancreatic organoids, highlighting their tumor selectivity. Importantly, safety assessments showed no significant DNA damage or chromosomal aberrations at non-cytotoxic doses. This study introduces a new structural class of mitochondria-targeted KV1.3 inhibitors with enhanced solubility compared to psoralen-based analogues. The unique mechanism of action, characterized by rapid depolarization and moderate ROS dependence, underscores their potential as selective anticancer agents. These findings warrant further investigation into in vivo efficacy and potential synergy with existing therapies.
    Keywords:  Apoptosis; Cancer; Mitochondrial KV1.3; Mitochondrial targeting
    DOI:  https://doi.org/10.1016/j.biopha.2026.118996
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