bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–01–05
twenty-two papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.
  2. Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.
  3. Aspartate signalling drives lung metastasis via alternative translation.
  4. Parallel single-cell metabolic analysis and extracellular vesicle profiling reveal vulnerabilities with prognostic significance in acute myeloid leukemia.
  5. Identification of a selective pyruvate dehydrogenase kinase 1 (PDHK1) chemical probe by virtual screening.
  6. Aberrant activation of adenine nucleotide translocase 3 promotes progression and chemoresistance in multiple myeloma dependent on PINK1 transport.
  7. The human zinc-binding cysteine proteome.
  8. Metabolic plasticity in pancreatic cancer: The mitochondrial connection.
  9. A new peptide inhibitor of C1QBP exhibits potent anti-tumour activity against triple negative breast cancer by impairing mitochondrial function and suppressing homologous recombination repair.
  10. Proton Tunneling Allows a Proton-Coupled Electron Transfer Process in the Cancer Cell.
  11. D-loop mutations in mitochondrial DNA are a risk factor for chemotherapy resistance in esophageal cancer.
  12. Unsymmetric hydroxylamine and hydrazine BAM15 derivatives as potent mitochondrial uncouplers.
  13. Demethylzeylasteral inhibits oxidative phosphorylation complex biogenesis by targeting LRPPRC in lung cancer.
  14. Targeting chromosomally unstable tumors with a selective KIF18A inhibitor.
  15. Nucleotide metabolism-associated drug resistance gene NDUFA4L2 promotes colon cancer progression and 5-FU resistance.
  16. Flow-cytometry reveals mitochondrial DNA accumulation in Saccharomyces cerevisiae cells during cell cycle arrest.
  17. AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
  18. The Warburg Effect: Is it Always an Enemy?
  19. Paradoxical link between senescent cell state and liver cancer resolved.
  20. Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice.
  21. DNA replication initiation drives focal mutagenesis and rearrangements in human cancers.
  22. NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis.
  1. Exp Hematol Oncol. 2024 Dec 28. 13(1): 123
    AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.
    HyunJun Kang, Melissa Valerio, Jia Feng, Long Gu, Dinh Hoa Hoang, Amanda Blackmon, Shawn Sharkas, Khyatiben Pathak, Jennifer Jossart, Zhuo Li, Hongyu Zhang, Bin Zhang, Patrick Pirrotte, J Jefferson P Perry, Robert J Hickey, Linda Malkas, Guido Marcucci, Le Xuan Truong Nguyen.
      Cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed in acute myeloid leukemia (AML) cells, supporting oxidative metabolism and leukemia stem cell (LSC) growth. We report on AOH1996 (AOH), an oral compound targeting cancer-associated PCNA, which shows significant antileukemic activity. AOH inhibited growth in AML cell lines and primary CD34 + CD38 - blasts (LSC-enriched) in vitro while sparing normal hematopoietic stem cells (HSCs). In vivo, AOH-treated mice demonstrated prolonged survival compared to controls (50 vs. 35 days; p < 0.0001) with reduced LSC burden, as shown in secondary transplants (42 vs. 30 days, p < 0.0001). Mechanistically, AOH disrupted mitochondrial PCNA's binding to the OPA1 protein, enhancing OPA1's interaction with its E3 ligase, MARCH5, which led to OPA1 degradation. This process reduced mitochondrial length, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS), thereby inhibiting LSC expansion. The addition of venetoclax (VEN), an FDA-approved Bcl-2 inhibitor, further enhanced AOH's effects, reducing mitochondrial length, FAO, and OXPHOS while improving survival in AML models. While VEN is approved for AML, AOH is under clinical investigation for solid tumors, and our findings support its broader therapeutic potential.
    Keywords:  AML; AOH1996; Leukemic stem cells; Mitochondrial metabolism; PCNA inhibitor
    DOI:  https://doi.org/10.1186/s40164-024-00586-4
  2. Sci Adv. 2025 Jan 03. 11(1): eads8489
    Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.
    Xiujie Li-Harms, Jingjun Lu, Yu Fukuda, John Lynch, Aditya Sheth, Gautam Pareek, Marcin M Kaminski, Hailey S Ross, Christopher W Wright, Amber L Smith, Huiyun Wu, Yong-Dong Wang, Marc Valentine, Geoffrey Neale, Peter Vogel, Stanley Pounds, John D Schuetz, Min Ni, Mondira Kundu.
      The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on this process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.
    DOI:  https://doi.org/10.1126/sciadv.ads8489
  3. Nature. 2025 Jan 01.
    Aspartate signalling drives lung metastasis via alternative translation.
    Ginevra Doglioni, Juan Fernández-García, Sebastian Igelmann, Patricia Altea-Manzano, Arnaud Blomme, Rita La Rovere, Xiao-Zheng Liu, Yawen Liu, Tine Tricot, Max Nobis, Ning An, Marine Leclercq, Sarah El Kharraz, Panagiotis Karras, Yu-Heng Hsieh, Fiorella A Solari, Luiza Martins Nascentes Melo, Gabrielle Allies, Annalisa Scopelliti, Matteo Rossi, Ines Vermeire, Dorien Broekaert, Ana Margarida Ferreira Campos, Patrick Neven, Marion Maetens, Karen Van Baelen, H Furkan Alkan, Mélanie Planque, Giuseppe Floris, Albert Sickmann, Alpaslan Tasdogan, Jean-Christophe Marine, Colinda L G J Scheele, Christine Desmedt, Geert Bultynck, Pierre Close, Sarah-Maria Fendt.
      Lung metastases occur in up to 54% of patients with metastatic tumours1,2. Contributing factors to this high frequency include the physical properties of the pulmonary system and a less oxidative environment that may favour the survival of cancer cells3. Moreover, secreted factors from primary tumours alter immune cells and the extracellular matrix of the lung, creating a permissive pre-metastatic environment primed for the arriving cancer cells4,5. Nutrients are also primed during pre-metastatic niche formation6. Yet, whether and how nutrients available in organs in which tumours metastasize confer cancer cells with aggressive traits is mostly undefined. Here we found that pulmonary aspartate triggers a cellular signalling cascade in disseminated cancer cells, resulting in a translational programme that boosts aggressiveness of lung metastases. Specifically, we observe that patients and mice with breast cancer have high concentrations of aspartate in their lung interstitial fluid. This extracellular aspartate activates the ionotropic N-methyl-D-aspartate receptor in cancer cells, which promotes CREB-dependent expression of deoxyhypusine hydroxylase (DOHH). DOHH is essential for hypusination, a post-translational modification that is required for the activity of the non-classical translation initiation factor eIF5A. In turn, a translational programme with TGFβ signalling as a central hub promotes collagen synthesis in lung-disseminated breast cancer cells. We detected key proteins of this mechanism in lung metastases from patients with breast cancer. In summary, we found that aspartate, a classical biosynthesis metabolite, functions in the lung environment as an extracellular signalling molecule to promote aggressiveness of metastases.
    DOI:  https://doi.org/10.1038/s41586-024-08335-7
  4. Nat Commun. 2024 Dec 30. 15(1): 10878
    Parallel single-cell metabolic analysis and extracellular vesicle profiling reveal vulnerabilities with prognostic significance in acute myeloid leukemia.
    Dorian Forte, Roberto Maria Pellegrino, Paolo Falvo, Paulina Garcia-Gonzalez, Husam B R Alabed, Filippo Maltoni, Davide Lombardi, Samantha Bruno, Martina Barone, Federico Pasini, Francesco Fabbri, Ivan Vannini, Benedetta Donati, Gianluca Cristiano, Chiara Sartor, Simona Ronzoni, Alessia Ciarrocchi, Sandra Buratta, Lorena Urbanelli, Carla Emiliani, Simona Soverini, Lucia Catani, Francesco Bertolini, Rafael José Argüello, Michele Cavo, Antonio Curti.
      Acute myeloid leukemia (AML) is an aggressive disease with a high relapse rate. In this study, we map the metabolic profile of CD34+(CD38low/-) AML cells and the extracellular vesicle signatures in circulation from AML patients at diagnosis. CD34+ AML cells display high antioxidant glutathione levels and enhanced mitochondrial functionality, both associated with poor clinical outcomes. Although CD34+ AML cells are highly dependent on glucose oxidation and glycolysis for energy, those from intermediate- and adverse-risk patients reveal increased mitochondrial dependence. Extracellular vesicles from AML are mainly enriched in stem cell markers and express antioxidant GPX3, with their profiles showing potential prognostic value. Extracellular vesicles enhance mitochondrial functionality and dependence on CD34+ AML cells via the glutathione/GPX4 axis. Notably, extracellular vesicles from adverse-risk patients enhance leukemia cell engraftment in vivo. Here, we show a potential noninvasive approach based on liquid 'cell-extracellular vesicle' biopsy toward a redefined metabolic stratification in AML.
    DOI:  https://doi.org/10.1038/s41467-024-55231-9
  5. Eur J Med Chem. 2024 Dec 26. pii: S0223-5234(24)01092-4. [Epub ahead of print]284 117210
    Identification of a selective pyruvate dehydrogenase kinase 1 (PDHK1) chemical probe by virtual screening.
    Mason A Baber, Mya D Gough, Larisa Yeomans, Kyle Giesler, Kendall Muzzarelli, Chih-Jung Chen, Zahra Assar, Peter L Toogood.
      PDHK1 is a non-canonical Ser/Thr kinase that negatively regulates the pyruvate dehydrogenase complex (PDC), restricting entry of acetyl-CoA into the tricarboxylic acid (TCA) cycle and downregulating oxidative phosphorylation. In many glycolytic tumors, PDHK1 is overexpressed to suppress activity of the PDC and cause a shift in metabolism toward an increased reliance on glycolysis (the Warburg effect). Genetic studies have shown that knockdown or knockout of PDHK1 reverts this phenotype and inhibits tumor growth in vitro and in vivo, but chemical tools to pharmacologically validate and build upon these data are lacking. We used AtomNet®, a deep convolutional neural network bioactivity predictor, to identify compound 7 as a potential inhibitor of PDHK1. During the process of hit validation, the active species was determined to be isomeric compound 10. Structure-activity studies based on 10 identified 17 as a low μM inhibitor of PDHK1 (IC50 = 1.5 ± 0.3 μM) that is selective against the other PDHK isoforms in both biochemical and cell-based assays. In A549 epithelial lung carcinoma cells, compound 17 inhibits phosphorylation of PDC E1α Ser232, a site that is specifically phosphorylated only by PDHK1, while minimally suppressing phosphorylation of Ser293, a site that is phosphorylated by all four PDHK isoforms. Altogether, these data identify 17 as a selective PDHK1 chemical probe useful for biochemical and cell-based studies.
    Keywords:  PDHK; Pyruvate metabolism; Virtual screening
    DOI:  https://doi.org/10.1016/j.ejmech.2024.117210
  6. Int J Biol Sci. 2025 ;21(1): 233-250
    Aberrant activation of adenine nucleotide translocase 3 promotes progression and chemoresistance in multiple myeloma dependent on PINK1 transport.
    Ke Hu, Yue Lai, Jinfeng Zhou, Chaolu Hu, Shushan Guo, Hui Zhang, Guanli Wang, Qikai Zhang, Xuejie Gao, Zhuning Wang, Yujie Liu, Qilin Feng, Hongfei Yi, Yu Peng, Yifei Zhang, Xiaosong Wu, Haiyan Cai, Jumei Shi.
      Chemoresistance is an important factor in multiple myeloma (MM) relapse and overall survival. However, the mechanism underlying resistance remains unclear. In this study, we identified adenine nucleotide translocase 3 (ANT3) as a novel biomarker and therapeutic target for MM progression and resistance to the proteasome inhibitor bortezomib (BTZ). The oncogenic functions of ANT3 in MM were verified using MM sensitive/drug-resistant cells, bone marrow tissues from patients with MM, orthotopic MM model, and subcutaneous tumor model. ANT3 knockdown impaired MM cell proliferation owing to a lack of cellular ATP levels, causing cell cycle arrest in the G0/G1 phase. Moreover, our study showed that ANT3 leads to BTZ resistance by promoting mitophagy. Notably, ANT3-mediated mitophagy is independent of its biological function as an ADP/ATP translocase. Mechanistically, ANT3 interacts with mitochondrial inner and outer membrane transporters, including Timm22 and Tomm20, thus restricting PINK1 import to the inner membrane of mitochondria. In this case, PINK1 is stabilized in the outer membrane of the mitochondria and recruits Parkin, resulting in mitophagy. Furthermore, targeted intervention with ANT3 combined with BTZ limited the growth of BTZ-resistant myeloma in vivo. This study identified ANT3 as a novel biomarker and therapeutic target for MM.
    Keywords:  Adenine nucleotide translocase 3; Bortezomib resistance; Mitophagy; Multiple myeloma
    DOI:  https://doi.org/10.7150/ijbs.101850
  7. Cell. 2024 Dec 26. pii: S0092-8674(24)01341-2. [Epub ahead of print]
    The human zinc-binding cysteine proteome.
    Nils Burger, Melanie J Mittenbühler, Haopeng Xiao, Sanghee Shin, Shelley M Wei, Erik K Henze, Sebastian Schindler, Sepideh Mehravar, David M Wood, Jonathan J Petrocelli, Yizhi Sun, Hans-Georg Sprenger, Pedro Latorre-Muro, Amanda L Smythers, Luiz H M Bozi, Narek Darabedian, Yingde Zhu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Jianwei Che, Edward T Chouchani.
      Zinc is an essential micronutrient that regulates a wide range of physiological processes, most often through zinc binding to protein cysteine residues. Despite being critical for modulation of protein function, the cysteine sites in the majority of the human proteome that are subject to zinc binding remain undefined. Here, we develop ZnCPT, a deep and quantitative mapping of the zinc-binding cysteine proteome. We define 6,173 zinc-binding cysteines, uncovering protein families across major domains of biology that are subject to constitutive or inducible zinc binding. ZnCPT enables systematic discovery of zinc-regulated structural, enzymatic, and allosteric functional domains. On this basis, we identify 52 cancer genetic dependencies subject to zinc binding and nominate malignancies sensitive to zinc-induced cytotoxicity. We discover a mechanism of zinc regulation over glutathione reductase (GSR), which drives cell death in GSR-dependent lung cancers. We provide ZnCPT as a resource for understanding mechanisms of zinc regulation of protein function.
    Keywords:  GSR; cancer; cysteine proteomics; glutathione reductase; zinc; zinc-binding proteome
    DOI:  https://doi.org/10.1016/j.cell.2024.11.025
  8. Mol Metab. 2024 Dec 28. pii: S2212-8778(24)00220-5. [Epub ahead of print] 102089
    Metabolic plasticity in pancreatic cancer: The mitochondrial connection.
    Noemi Ghiglione, Damiano Abbo, Anastasia Bushunova, Andrea Costamagna, Paolo Ettore Porporato, Miriam Martini.
      Cellular metabolism plays a pivotal role in the development and progression of pancreatic ductal adenocarcinoma (PDAC), with dysregulated metabolic pathways contributing to tumorigenesis and therapeutic resistance. Distinct metabolic heterogeneity exists in pancreatic cancer, impacting patient prognosis, as variations in metabolic profiles influence tumor behavior and treatment responses. Here, we review the intricate interplay between mitochondrial dynamics, mitophagy, and cellular metabolism in PDAC. We highlight the significance of mitophagy dysregulation in PDAC pathogenesis, impacting treatment response and prognosis. Additionally, we examine the impact of mitochondrial dynamics alterations on PDAC progression, focusing on the role of fission and fusion processes in tumorigenesis. Ongoing trials have demonstrated the potential therapeutic value of targeting key regulators of mitochondrial dynamics and mitophagy. Despite challenges, targeting mitochondrial metabolism offers diverse strategies to enhance PDAC treatment efficacy, underscoring its potential in advancing cancer therapeutics.
    Keywords:  Metabolism; Mitochondria; Mitophagy; Oxidative phosphorylation; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.molmet.2024.102089
  9. Clin Transl Med. 2025 Jan;15(1): e70162
    A new peptide inhibitor of C1QBP exhibits potent anti-tumour activity against triple negative breast cancer by impairing mitochondrial function and suppressing homologous recombination repair.
    Xingxing Li, Yue Wu, Min Zhang, Fengliang Wang, Hong Yin, Yanrong Zhang, Shuli Zhao, Jiehua Ma, Mingming Lv, Cheng Lu.
      C1QBP exhibits heightened expression across a spectrum of tumours, thereby fostering their proliferation and metastasis, rendering it a pivotal therapeutic target. Nevertheless, to date, no pharmacological agents capable of directly targeting and inducing the degradation of C1QBP have been identified. In this study, we have unveiled a new peptide, PDBAG1, derived from the precursor protein GPD1, employing a peptidomics-based drug screening strategy. PDBAG1 has demonstrated substantial efficacy in suppressing triple-negative breast cancer (TNBC) both in vitro and in vivo. Its mechanism of action involves mitochondrial impairment and the inhibition of oxidative phosphorylation (OXPHOS), achieved through direct binding to C1QBP, thereby promoting its ubiquitin-dependent degradation. Concomitantly, due to metabolic adaptability, we have observed an up-regulation of glycolysis to compensate for OXPHOS inhibition. We observed an aberrant phenomenon wherein the hypoxia signalling pathway in tumour cells exhibited significant activation under normoxic conditions following PDBAG1 treatment. Through size-exclusion chromatography (SEC) and isothermal titration calorimetry (ITC) assays, we have validated that PDBAG1 is capable of binding C1QBP with a Kd value of 334 nM. Furthermore, PDBAG1 inhibits homologous recombination repair proteins and facilitates synergism with poly-ADP-ribose polymerase inhibitors in cancer therapy. This underscores that PDBAG1 ultimately induces insurmountable survival stress through multiple mechanisms while concurrently engendering therapeutic vulnerabilities specific to TNBC. KEY POINTS: The newly discovered peptide PDBAG1 is the first small molecule substance found to directly target and degrade C1QBP, demonstrating significant tumour inhibitory effects and therapeutic potential.
    Keywords:  C1QBP; anti‐tumour peptide; homologous recombination repair; mitochondrial function; targeted protein degradation
    DOI:  https://doi.org/10.1002/ctm2.70162
  10. JACS Au. 2024 Dec 23. 4(12): 4856-4865
    Proton Tunneling Allows a Proton-Coupled Electron Transfer Process in the Cancer Cell.
    Tong Zhang, Arindam Ghosh, Lisa Behringer-Pließ, Lata Chouhan, Ana V Cunha, Remco W A Havenith, Eugenia Butkevich, Lei Zhang, Olalla Vázquez, Elke Debroye, Jörg Enderlein, Shoubhik Das.
      Proton-coupled electron transfer (PCET) is a fundamental redox process and has clear advantages in selectively activating challenging C-H bonds in many biological processes. Intrigued by this activation process, we aimed to develop a facile PCET process in cancer cells by modulating proton tunneling. This approach should lead to the design of an alternative photodynamic therapy (PDT) that depletes the mitochondrial electron transport chain (ETC), the key redox regulator in cancer cells under hypoxia. To observe this depletion process in the cancer cell, we monitored the oxidative-stress-induced depolarization of mitochondrial inner membrane potential (MMP) using fluorescence lifetime imaging microscopy (FLIM). Typically, increasing metabolic stress of cancer cells is reflected in a nontrivial change in the fluorophore's fluorescence lifetime. After 30 min of irradiation, we observed a shift in the mean lifetime value and a drastic drop in overall fluorescence signal. In addition, our PCET strategy resulted in drastic reorganization of mitochondrial morphology from tubular to vesicle-like and causing an overall depletion of intact mitochondria in the hypodermis of C. elegans. These observations confirmed that PCET promoted ROS-induced oxidative stress. Finally, we gained a clear understanding of the proton tunneling effect in the PCET process through photoluminescence experiments and DFT calculations.
    DOI:  https://doi.org/10.1021/jacsau.4c00815
  11. Sci Rep. 2024 Dec 30. 14(1): 31653
    D-loop mutations in mitochondrial DNA are a risk factor for chemotherapy resistance in esophageal cancer.
    Takashi Harino, Koji Tanaka, Daisuke Motooka, Yasunori Masuike, Tsuyoshi Takahashi, Kotaro Yamashita, Takuro Saito, Kazuyoshi Yamamoto, Tomoki Makino, Yukinori Kurokawa, Kiyokazu Nakajima, Hidetoshi Eguchi, Yuichiro Doki.
      Esophageal cancer is a highly aggressive disease, and acquired resistance to chemotherapy remains a significant hurdle in its treatment. mtDNA, crucial for cellular energy production, is prone to mutations at a higher rate than nuclear DNA. These mutations can accumulate and disrupt cellular function; however, mtDNA mutations induced by chemotherapy in esophageal cancer remain unexplored. We aimed to identify such mutations in esophageal cancer, pre- and post-chemotherapy, and explore the relationship between them and clinicopathological factors associated with chemotherapy resistance. We investigated mtDNA mutations in Human esophageal squamous cell carcinoma (ESCC) cancer cell lines (TE8 and TE11) and patient samples (27 pre- and post-chemotherapy, and 96 post-chemotherapy) using next-generation sequencing. Our analysis revealed a rise in mtDNA mutations following chemotherapy, particularly within the D-loop region. Moreover, mutations in a specific D-loop segment (hypervariable segment 1; HVS1) were associated with lower mtDNA copy number, poorer response to chemotherapy, and decreased five-year survival rates. These findings suggest that HVS1 mutations in mtDNA acquired after chemotherapy may contribute to treatment resistance and poorer clinical outcomes in patients with esophageal cancer. This study sheds light on the mechanisms of chemotherapy resistance and provides valuable insights for future research to overcome this challenge.
    Keywords:  Chemotherapy; D-loop; Esophageal cancer; Mitochondrial DNA; MtDNA copy number; Mutation
    DOI:  https://doi.org/10.1038/s41598-024-80226-3
  12. Bioorg Med Chem. 2024 Dec 18. pii: S0968-0896(24)00459-0. [Epub ahead of print]118 118045
    Unsymmetric hydroxylamine and hydrazine BAM15 derivatives as potent mitochondrial uncouplers.
    Joseph E Quinlan, Joseph M Salamoun, Christopher J Garcia, Stefan Hargett, Martina Beretta, Riya Shrestha, Catherine Li, Kyle L Hoehn, Webster L Santos.
      Chemical mitochondrial uncouplers are protonophoric, lipophilic small molecules that transport protons from the mitochondrial intermembrane space into the matrix independent of ATP synthase, thus uncoupling nutrient oxidation from ATP production. Our previous work identified BAM15 (IC50 0.27 μM) as a potent and efficacious mitochondrial uncoupler with potential for obesity treatment. In this paper, we investigate in vitro and in vivo properties of hydroxylamine and hydrazine BAM15 derivatives and reveal the high uncoupling nature of these compounds. Our structure-activity relationship studies revealed that the hydroxylamine BAM15 analogs are more potent than hydrazine ones. For example, the most potent of the hydrazine series was 5a with an EC50 value of 4.6 μM and 103 % activity of BAM15 while compound 4e was the best among the hydroxylamine series with EC50 value of 340 nM and 118 % BAM15 mitochondrial uncoupling activity in rat L6 myoblasts. Pharmacokinetic profiling of 5a and 4e revealed low exposure (2-220 nM) and short half-life (15-27 min) in mice.
    Keywords:  Aniline; BAM15; Hydrazine; Hydroxylamine; Mitochondrial uncouplers; Protonophore; Pyrazines; Structure–activity relationship
    DOI:  https://doi.org/10.1016/j.bmc.2024.118045
  13. J Cancer. 2025 ;16(1): 227-240
    Demethylzeylasteral inhibits oxidative phosphorylation complex biogenesis by targeting LRPPRC in lung cancer.
    Lina Wang, Wei Zhou, Wenxi Wang, Yuxin Liang, Qiqi Xue, Zhen Zhang, Jinghe Yuan, Xiaohong Fang.
      Targeted inhibition of mitochondrial oxidative phosphorylation (OXPHOS) complex generation is an emerging and promising cancer treatment strategy, but limited targets and specific inhibitors have been reported. Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is an atypical RNA-binding protein that regulates the stability of all 13 mitochondrial DNA-encoded mRNA (mt-mRNA) and thus participates in the synthesis of the OXPHOS complex. LRPPRC is also a prospective therapeutic target for lung adenocarcinoma, serving as a promising target for OXPHOS inhibition. In this study, we identified Demethylzeylasteral (T-96), a small molecule extracted from the Chinese herb Tripterygium wilfordii Hook. f., as a novel inhibitor of LRPPRC. T-96 directly bound to the RNA-binding domain of LRPPRC, inhibiting its interaction with mt-mRNA. This led to instability in both mt-mRNA and LRPPRC protein. Treatment with T-96 significantly reduced the mRNA and protein levels of the OXPHOS complex. As a consequence of LRPPRC inhibition, T-96 treatment induced a defect in the synthesis of the OXPHOS complex, inhibiting mitochondrial aerobic respiration and ATP synthesis. Moreover, T-96 exhibited potent antitumor activity for lung adenocarcinoma in vitro and in vivo, and the antitumor effect of T-96 was dependent on LRPPRC expression. In conclusion, this study not only identified the first traditional Chinese medicine monomer inhibitor against OXPHOS complex biosynthesis as well as a novel target of Demethylzeylasteral, but also shed light on the unique antitumor mechanism of bioactive compounds derived from traditional Chinese medicine.
    Keywords:  Demethylzeylasteral (T-96); LRPPRC; OXPHOS; Traditional Chinese Medicine (TCM); lung cancer
    DOI:  https://doi.org/10.7150/jca.92797
  14. Nat Commun. 2025 Jan 02. 16(1): 307
    Targeting chromosomally unstable tumors with a selective KIF18A inhibitor.
    Aaron F Phillips, Rumin Zhang, Mia Jaffe, Ryan Schulz, Marysol Chu Carty, Akanksha Verma, Tamar Y Feinberg, Michael D Arensman, Alan Chiu, Reka Letso, Nazario Bosco, Katelyn A Queen, Allison R Racela, Jason Stumpff, Celia Andreu-Agullo, Sarah E Bettigole, Rafael S Depetris, Scott Drutman, Shinsan M Su, Derek A Cogan, Christina H Eng.
      Chromosome instability is a prevalent vulnerability of cancer cells that has yet to be fully exploited therapeutically. To identify genes uniquely essential to chromosomally unstable cells, we mined the Cancer Dependency Map for genes essential in tumor cells with high levels of copy number aberrations. We identify and validate KIF18A, a mitotic kinesin, as a vulnerability of chromosomally unstable cancer cells. Knockdown of KIF18A leads to mitotic defects and reduction of tumor growth. Screening of a chemical library for inhibitors of KIF18A enzymatic activity identified a hit that was optimized to yield VLS-1272, which is orally bioavailable, potent, ATP non-competitive, microtubule-dependent, and highly selective for KIF18A versus other kinesins. Inhibition of KIF18A's ATPase activity prevents KIF18A translocation across the mitotic spindle, resulting in chromosome congression defects, mitotic cell accumulation, and cell death. Profiling VLS-1272 across >100 cancer cell lines demonstrates that the specificity towards cancer cells with chromosome instability differentiates KIF18A inhibition from other clinically tested anti-mitotic drugs. Treatment of tumor xenografts with VLS-1272 results in mitotic defects leading to substantial, dose-dependent inhibition of tumor growth. The strong biological rationale, robust preclinical data, and optimized compound properties enable the clinical development of a KIF18A inhibitor in cancers with high chromosomal instability.
    DOI:  https://doi.org/10.1038/s41467-024-55300-z
  15. Sci Rep. 2025 Jan 02. 15(1): 570
    Nucleotide metabolism-associated drug resistance gene NDUFA4L2 promotes colon cancer progression and 5-FU resistance.
    Hongxin He, Shiyao Zheng, Shangkun Jin, Weijie Huang, Enhao Wei, Shen Guan, Chunkang Yang.
      Chemotherapy is an effective way to improve the prognosis of colorectal cancer patients, but patient resistance to chemotherapeutic agents is becoming a major obstacle to treatment. Nucleotide metabolism correlates with the progression of colorectal cancer and chemotherapy resistance, but the mechanisms involved need to be further investigated. We calculated the half-maximal inhibitory concentrations (IC50) of 5-Fluorouracil (5-FU) in colorectal cancer patients using the "oncopredict" package, screened nucleotide metabolism-related drug resistance genes, and constructed a risk score model. According to the Kaplan-Meier(KM) analysis, the overall survival (OS) and disease-free survival (PFS) of the high-risk group were significantly lower than those of the low-risk group. In addition, the nomogram we constructed had good performance in predicting OS in colon adenocarcinoma (COAD) patients. We validated NDUFA4L2 by cellular functionality experiments, animal tumorigenesis experiments and drug resistance experiments. It was demonstrated that NDUFA4L2 promoted the proliferation and migration of colon cancer cells, while the abnormal regulation of NDUFA4L2 affected the 5-FU resistance of colon cancer cells. In conclusion, we found that NDUFA4L2 promotes the progression and metastasis of colon cancer, as well as resistance to 5-FU chemotherapy.
    Keywords:  5-fluorouracil resistance; Colon cancer; NDUFA4L2; Nucleotide metabolism; Prognosis
    DOI:  https://doi.org/10.1038/s41598-024-84353-9
  16. Front Cell Dev Biol. 2024 ;12 1497652
    Flow-cytometry reveals mitochondrial DNA accumulation in Saccharomyces cerevisiae cells during cell cycle arrest.
    Elena Yu Potapenko, Nataliia D Kashko, Dmitry A Knorre.
      Mitochondria are semi-autonomous organelles containing their own DNA (mtDNA), which is replicated independently of nuclear DNA (nDNA). While cell cycle arrest halts nDNA replication, mtDNA replication continues. In Saccharomyces cerevisiae, flow cytometry enables semi-quantitative estimation of mtDNA levels by measuring the difference in signals between cells lacking mtDNA and those containing mtDNA. In this study, we used flow cytometry to investigate mtDNA accumulation in yeast cells under G1 and G2 phase cell cycle arrest conditions utilising thermosensitive mutants cdc4-3 and cdc15-2. In line with the previous studies, cell cycle arrest induced a several-fold accumulation of mtDNA in both mutants. The total DNA levels in arrested cells correlated with cell forward scattering, suggesting a relationship between individual cell mtDNA quantity and size. In cell cycle-arrested cells, we observed no correlation between cell size and intercellular mtDNA copy number variability. This implies that as cell size increases during arrest, the mtDNA content remains within a specific limited range for each size class. This observation suggests that mtDNA quantity control mechanisms can function in cell cycle-arrested cells.
    Keywords:  cell cycle arrest; cell cycle defect; mtDNA; mtDNA copy number; mtDNA copy number control; yeast
    DOI:  https://doi.org/10.3389/fcell.2024.1497652
  17. Nat Cell Biol. 2025 Jan 02.
    AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
    Xuewei Zhai, Ronghui Yang, Qiaoyun Chu, Zihao Guo, Pengjiao Hou, Xuexue Li, Changsen Bai, Ziwen Lu, Luxin Qiao, Yanxia Fu, Jing Niu, Binghui Li.
      Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment.
    DOI:  https://doi.org/10.1038/s41556-024-01549-x
  18. Front Biosci (Landmark Ed). 2024 Nov 27. 29(12): 402
    The Warburg Effect: Is it Always an Enemy?
    Christos Papaneophytou.
      The Warburg effect, also known as 'aerobic' glycolysis, describes the preference of cancer cells to favor glycolysis over oxidative phosphorylation for energy (adenosine triphosphate-ATP) production, despite having high amounts of oxygen and fully active mitochondria, a phenomenon first identified by Otto Warburg. This metabolic pathway is traditionally viewed as a hallmark of cancer, supporting rapid growth and proliferation by supplying energy and biosynthetic precursors. However, emerging research indicates that the Warburg effect is not just a strategy for cancer cells to proliferate at higher rates compared to normal cells; thus, it should not be considered an 'enemy' since it also plays complex roles in normal cellular functions and/or under stress conditions, prompting a reconsideration of its purely detrimental characterization. Moreover, this review highlights that distinguishing glycolysis as 'aerobic' and 'anaerobic' should not exist, as lactate is likely the final product of glycolysis, regardless of the presence of oxygen. Finally, this review explores the nuanced contributions of the Warburg effect beyond oncology, including its regulatory roles in various cellular environments and the potential effects on systemic physiological processes. By expanding our understanding of these mechanisms, we can uncover novel therapeutic strategies that target metabolic reprogramming, offering new avenues for treating cancer and other diseases characterized by metabolic dysregulation. This comprehensive reevaluation not only challenges traditional views but also enhances our understanding of cellular metabolism's adaptability and its implications in health and disease.
    Keywords:  Warburg effect; cancer metabolism; cellular metabolism; glycolysis; metabolic reprogramming
    DOI:  https://doi.org/10.31083/j.fbl2912402
  19. Nature. 2025 Jan 01.
    Paradoxical link between senescent cell state and liver cancer resolved.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-04137-z
  20. Mol Metab. 2024 Dec 31. pii: S2212-8778(24)00223-0. [Epub ahead of print] 102092
    Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice.
    Brecht Attema, Montserrat A de la Rosa Rodriguez, Evert M van Schothorst, Sander Grefte, Guido Jej Hooiveld, Sander Kersten.
      The peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. Previously, the mitochondrial transporter SLC25A47 was suggested to play a role in energy metabolism and liver-specific uncoupling, but further research is lacking. Here, we identify SLC25A47 as a PPARα-regulated and fasting-induced gene in human and mouse hepatocytes. We explored the potential role of SLC25A47 using mice overexpressing and lacking SLC25A47. Adenoviral-mediated overexpression of SLC25A47 minimally impacted metabolic parameters during fasting and high-fat feeding. During high-fat feeding, SLC25A47 ablation also did not influence any metabolic parameters, apart from a minor improvement in glucose tolerance. In fasted mice, SLC25A47 ablation was associated with modest, reproducible, and likely indirect reductions in plasma triglycerides and glycerol. SLC25A47 ablation did not influence energy expenditure. Depending on the nutritional status, metabolomics showed modest alterations in plasma, liver, and hepatic mitochondrial levels of various metabolites related to amino acid metabolism, TCA cycle, and fatty acid metabolism. No major and consistent alterations in levels of specific metabolites were found that establish the substrate for and function of SLC25A47. Collectively, our results hint at a role of SLC25A47 in amino acid and fatty acid metabolism, yet suggest that SLC25A47 is dispensable for hepatic lipid homeostasis during fasting and high-fat feeding.
    DOI:  https://doi.org/10.1016/j.molmet.2024.102092
  21. Nat Commun. 2024 Dec 30. 15(1): 10850
    DNA replication initiation drives focal mutagenesis and rearrangements in human cancers.
    Pierre Murat, Guillaume Guilbaud, Julian E Sale.
      The rate and pattern of mutagenesis in cancer genomes is significantly influenced by DNA accessibility and active biological processes. Here we show that efficient sites of replication initiation drive and modulate specific mutational processes in cancer. Sites of replication initiation impede nucleotide excision repair in melanoma and are off-targets for activation-induced deaminase (AICDA) activity in lymphomas. Using ductal pancreatic adenocarcinoma as a cancer model, we demonstrate that the initiation of DNA synthesis is error-prone at G-quadruplex-forming sequences in tumours displaying markers of replication stress, resulting in a previously recognised but uncharacterised mutational signature. Finally, we demonstrate that replication origins serve as hotspots for genomic rearrangements, including structural and copy number variations. These findings reveal replication origins as functional determinants of tumour biology and demonstrate that replication initiation both passively and actively drives focal mutagenesis in cancer genomes.
    DOI:  https://doi.org/10.1038/s41467-024-55148-3
  22. Redox Biol. 2024 Dec 19. pii: S2213-2317(24)00457-9. [Epub ahead of print]79 103479
    NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis.
    Kaifeng Niu, Zixiang Chen, Mengge Li, Guannan Ma, Yuchun Deng, Ji Zhang, Di Wei, Jiaqi Wang, Yongliang Zhao.
      Lactate-mediated lactylation on target proteins is recently identified as the novel posttranslational modification with profound biological functions. RNA 5-methylcytosine (m5C) modification possesses dynamic and reversible nature, suggesting that activity of its methyltransferase NSUN2 is actively regulated. However, how NSUN2 activity is response to acidic condition in tumor microenvironment and then regulates cancer cell survival remain to be clarified. Here, we demonstrate that NSUN2 activity is enhanced by lactate-mediated lactylation at lysine 508, which then targets glutamate-cysteine ligase catalytic subunit (GCLC) mRNA to facilitates GCLC m5C formation and mRNA stabilization. The activated GCLC induces higher level of intracellular GSH accompanied by decreased lipid peroxidation and resistant phenotype to ferroptosis induction by doxorubicin (Dox) in gastric cancer cells. Specifically, the effect of NSUN2 lactylation-GCLC-GSH pathway is nearly lost when NSUN2 K508R or GCLC C-A mutant (five cytosine sites) was introduced into the cancer cells. We further identify the catalytic subunit N-α-acetyltransferase 10 (NAA10) as the lactytransferase of NSUN2, and lactate treatment substantially enhances their association and consequent NSUN2 activation. Taken together, our findings convincingly elucidate the signaling axis of NAA10-NSUN2-GCLC that potently antagonizes the ferroptosis under acidic condition, and therefore, targeting NSUN2 lactylation might be an effective strategy in improving the prognosis of cancer patients.
    Keywords:  Ferroptosis; GCLC; Glutathione synthesis; Lactylation; NSUN2; RNA 5-methylcytosine
    DOI:  https://doi.org/10.1016/j.redox.2024.103479
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