bims-mibica 2025-12-07 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–12–07
eleven papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.
Ditrioxzin synergizes with 2-deoxy-d-glucose to induce redox-dependent metabolic crisis in gastric cancer through dual targeting of peroxiredoxin 3 and glycolysis.
Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis.
Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.
CAV2-expressing nerves induce metabolic switch toward mitochondrial oxidative phosphorylation to promote cancer stemness.
Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax.
Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia.
Drink Responsibly: Cancer Cells also Like Sugary Drinks.
Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure.

Nat Metab. 2025 Dec 05.

Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.

Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, J Darren Stuart, Paul A Grimsrud, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene-gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.

DOI: https://doi.org/10.1038/s42255-025-01410-x
Nat Commun. 2025 Dec 03.

Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.

Geoffray Monteuuis, Ryan Awadhpersad, Daan van der Kolk, Sachin K Singh, Tuula A Nyman, Alina Malyutina, Nicola Zamboni, Kari Moisio, Juhana Juutila, Ville Hietakangas, Sara Seneca, Christopher J Carroll, Christopher B Jackson.

Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects - besides a compendium of known mitochondrial translation quality control factors - is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.

DOI: https://doi.org/10.1038/s41467-025-66656-1
Toxicol Appl Pharmacol. 2025 Dec 03. pii: S0041-008X(25)00442-9. [Epub ahead of print] 117666

Ditrioxzin synergizes with 2-deoxy-d-glucose to induce redox-dependent metabolic crisis in gastric cancer through dual targeting of peroxiredoxin 3 and glycolysis.

Nan Su, Lulu Pan, Xiaojing Shi, Ying Liu, Xiaxia Fan, Shilin Liu, Yong-Cheng Ma.

  Emerging evidence demonstrates that dual inhibition of glycolysis and mitochondrial function represents a potent anticancer strategy. Here, we report that Ditrioxzin (DTO), a synthetic ent-kaurane diterpenoid analog, selectively disrupts mitochondrial redox homeostasis by targeting peroxiredoxin 3 (Prx3) to induce hydrogen peroxide (H2O2) accumulation, thereby depolarizing mitochondrial membrane potential (MMP) and impairing oxidative phosphorylation (OXPHOS) in gastric cancer cells. DTO synergized with the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) to deplete ATP through dual metabolic blockade. In vitro studies revealed that DTO exerted selective cytotoxicity against gastric cancer cells (IC50 3.82-6.10 μM) but spared normal gastric epithelial cells (GES-1). Mechanistically, DTO directly bound Prx3, elevating H2O2 levels (>3-fold at 8 μM), oxidizing mitochondrial peroxiredoxins, and triggering redox-dependent mitochondrial dysfunction. Combined DTO/2-DG treatment promoted ATP depletion and apoptosis (69.6 % vs 24.1 % DTO alone) via ROS-dependent pathways, an effect abrogated by N-acetylcysteine. In vivo, DTO (10 mg/kg) and 2-DG (500 mg/kg) synergistically suppressed tumor growth (66 %, P < 0.001) in xenograft models without body weight loss or histopathological changes in kidney/heart. Our findings establish DTO as a novel Prx3-targeted agent that synergizes with 2-DG to induce metabolic crisis, providing a high-safety-profile therapeutic strategy for gastric cancer.

Keywords:  Cancer metabolism; Ent-Kaurane diterpenoid derivative; Glycolysis; Mitochondrial bioenergetics; Redox homeostasis

DOI:  https://doi.org/10.1016/j.taap.2025.117666
bioRxiv. 2025 Nov 17. pii: 2025.11.17.688927. [Epub ahead of print]

Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis.

Kelley R McCutcheon, Josh Wu, Yasemin Ceyhan Ozdemir, Brock J McKinney, Sharan Srinivasan, Ayaha Itokawa, Oliver J Newsom, Anna Vigil, Douglas B Fox, Lucas B Sullivan, James V Alvarez.

Breast cancer recurrence remains a major clinical challenge, often associated with therapy resistance and altered metabolic states. To define metabolic vulnerabilities of recurrent disease, we performed a CRISPR knockout screen targeting 421 metabolic genes in paired primary and recurrent HER2-driven breast cancer cell lines. While both primary and recurrent tumors shared dependencies on core metabolic pathways, recurrent tumors exhibited selective essentiality for the de novo pyrimidine synthesis pathway, including Cad , Dhodh , and Ctps . Pharmacologic inhibition of the rate-limiting enzyme DHODH with BAY-2402234 selectively impaired the growth of recurrent tumor cells, while primary tumor cells were relatively resistant. BAY treatment robustly inhibited pyrimidine synthesis in all lines, but only recurrent cells underwent iron-dependent lipid peroxidation and ferroptotic cell death. Lipidomic profiling revealed enrichment of polyunsaturated ether phospholipids in recurrent cells, which may predispose them to ferroptosis. A sensitizer CRISPR screen in primary cells further identified nucleotide salvage and lipid metabolic pathways as modifiers of DHODH inhibitor sensitivity. Stable isotope tracing and nutrient depletion experiments showed that primary cells can compensate for DHODH inhibition through nucleotide salvage, whereas recurrent cells exhibit impaired salvage capacity, likely due to reduced expression of Slc28 / Slc29 nucleoside transporters. Together, these findings reveal that breast cancer recurrence is associated with increased dependence on de novo pyrimidine synthesis to suppress ferroptosis, highlighting a therapeutically actionable metabolic vulnerability in recurrent disease.

DOI: https://doi.org/10.1101/2025.11.17.688927
Nat Commun. 2025 Dec 04. 16(1): 10898

Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.

Tatiana N Tarasenko, Emily Warren, Bharati Singh, Amanda Fuchs, Jose Marin, Marten Szibor, Christopher King, Peter J McGuire.

T cell activation requires extensive metabolic reprogramming, but the specific requirement for mitochondrial respiration (MR) remains unresolved. While most studies have focused on aerobic glycolysis as the primary driver of proliferation and effector function, the role of MR has not been completely defined. To isolate MR from proton pumping by cytochrome c oxidase (COX), we expressed the non-proton-pumping alternative oxidase (AOX) in activated COX-deficient T cells. AOX restored electron flow, membrane potential, and mitochondrial ATP production, ultimately rescuing proliferation, effector and memory differentiation, and antiviral immunity. These improvements required upstream electron input, particularly from Complex I, with Complex II and DHODH contributing more modestly. Despite restored MR, glycolysis remained elevated, likely due to altered redox signaling. These findings demonstrate that MR, normally mediated by COX, is necessary and can be sufficient to support T cell activation and function, independent of proton translocation, provided upstream electron input is maintained.

DOI: https://doi.org/10.1038/s41467-025-65910-w
Cell Metab. 2025 Dec 02. pii: S1550-4131(25)00489-9. [Epub ahead of print]37(12): 2298-2300

Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.

Sébastien Ibanez, Olivier Feron.

Cancer cells experience multiple stresses within tumors, stemming from elevated metabolic activity, including nutrient shortage, waste buildup, hypoxia, and acidosis. According to Groessl et al.,1 acidosis is the dominant environmental factor offering metabolic flexibility to support tumor fitness and resilience to the other stresses by promoting mitochondria fusion and enhancing respiration capacity.

DOI: https://doi.org/10.1016/j.cmet.2025.11.005
Nat Commun. 2025 Dec 02.

CAV2-expressing nerves induce metabolic switch toward mitochondrial oxidative phosphorylation to promote cancer stemness.

Ze Zhang, Chunli Wang, Zhonghao Sun, Xiaotian Shi, Yanjie Shuai, Yafei Wang, Yun Wang, Hua Guo, Ruoyan Liu, Jingtao Luo.

Cancer cells and the nervous system engage in a dynamic interplay, significantly influencing initiation and progression in head and neck squamous cell carcinoma (HNSCC). Our findings highlight that cancer cells drive an increase in caveolin-2 (Cav2) expression within trigeminal ganglia and associated neural fibers in the tumor milieu, fostering a reciprocal attractant relationship between tumor cells and nerves. Notably, the knockout of Cav2, either globally or specifically in sensory neurons or glial cells, markedly attenuates the growth of orthotopically implanted tongue tumors. Moreover, Cav2-expressing nerves are implicated in shifting cancer cell metabolism towards mitochondrial oxidative phosphorylation, a process involved in maintenance of cancer stem cells (CSCs). Our results also demonstrate that Cav2-expressing nerves confer stemness properties to cancer cells. Disruption of Cav2 expression, both globally and in specific neural cell types, impedes tumorigenesis and progression in a 4-NQO-induced HNSCC mouse model. This interplay observed between cancer cells, neurons, and glial cells suggests a potential mechanism through which tumor-associated nerves might influence cancer stemness via metabolic reprogramming. This highlights a possible direction for anticancer therapy that warrants further investigation.

DOI: https://doi.org/10.1038/s41467-025-66914-2
Res Sq. 2025 Nov 19. pii: rs.3.rs-7682325. [Epub ahead of print]

Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax.

Lee Graves, Sabrina Daglish, Owen Canterbury, Paul Graves, Sarah Carter, Sydney Beese, Maggie Hynek, Brandon Mouery, Andrei Mistreanu, Aadra Bhatt, Nestor Tellez, Mitchell Butler, Lucas Aponte-Collazo, Emily Fennell, Laura Herring, Scott Lyons, C Mills, Hani Ashamalla, Edwin Iwanowicz, John Morris Iv, James Bear, Yoshimi Greer, Stanley Lipkowitz.

ONC201 is a first-in-class, FDA approved small molecule activator of the mitochondrial ATP-dependent caseinolytic peptidase P (ClpP). This and other related small molecules referred to as ClpP agonists, exert antiproliferative effects in several cancer cell types. We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines. Senescence was determined by increased β-galactosidase activity, downregulation of phosphorylated Rb, c-Myc (Myc), and lamin B1, upregulation of senescent-associated secretory phenotype (SASP), and extended cell proliferation assays. These responses were not observed in ClpP knockout cell lines, demonstrating ClpP-dependence. Proteomics analyses identified multiple events related to the development of senescence including cell cycle arrest and mitochondrial dysfunction. Flow cytometry confirmed an S-phase arrest; DNA damage was detected by Comet assay, 53BP1, phospho-S*Q, and γH2A.X immunostaining. In parallel with this, activation of the ATM pathway and phosphorylation of Chk2 was observed. We determined that ClpP agonist-induced senescence was irreversible in both in vitro and in vivo studies. Following TR-57 treatment and drug washout, cells remained growth arrested which coincided with the loss of Myc protein. By contrast, cells treated with the cell cycle inhibitor and senescence inducer, abemaciclib rapidly regained p-Rb and Myc expression and cell proliferation following washout. This response was reproduced in vivo wherein senescent 4T1-Luc cells did not develop tumors following injection into mice. Finally, the combination of a ClpP agonist with a known senolytic (venetoclax), synergistically increased the amount of cell death observed. Combining a ClpP agonist with a PARP inhibitor (olaparib) produced an additive effect. In summary, we show that ClpP activators stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells.

DOI: https://doi.org/10.21203/rs.3.rs-7682325/v1
Cell Commun Signal. 2025 Dec 02.

Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia.

Piotr Chroscicki, Nikodem Kasak, Dorota Dymkowska, Laura Turos-Korgul, Dominik Cysewski, Vira Chumak, Dawid Stepnik, Monika Kusio-Kobialka, Agata Kominek, Magdalena Lebiedzinska-Arciszewska, Alicja Krop, Joanna Szczepanowska, Mariusz Wieckowski, Tomasz Stoklosa, Krzysztof Zablocki, Katarzyna Piwocka.

   BACKGROUND: Alterations in cancer cell metabolism have recently gained considerable attention as a possible cause of adaptation and resistance to therapy. However, the underlying molecular mechanisms, particularly in leukemia resistance occurring in the bone marrow microenvironment, remain unclear. Here, we explore the role of direct stroma-leukemia interactions and transfer of membrane vesicles along with proteins as a mechanism of stroma-driven protection.
METHODS: K562 CML leukemia cells and primary CD34 + CML blasts were cultured alone or co-cultured with HS-5 stromal cells to mimic the bone marrow microenvironment conditions. Imatinib treatment was used experimentally as it is a standard first-line treatment in CML. Assessment of vesicles transfer, metabolic parameters, mitochondrial function phenotyping, Trans-SILAC proteomics and metabolomics, together with apoptosis assessment, verified the influence of stroma on metabolic plasticity, protein transfer and adaptation to imatinib in leukemic cells. Trans-system evaluated necessity of direct cell-cell contact. Data from single-cell atlas of diagnostic CML bone marrow were used to correlate gene expression profiles with clinical outcome. Telaglenastat was used to validate the clinical potential of our findings.
RESULTS: Stromal cells enhanced metabolic plasticity and oxidative capacity in leukemia, thereby protecting against metabolic decline and oxidative stress caused by imatinib. Direct stroma-leukemia contact was necessary for vesicles transfer, metabolic rearrangement and protection from imatinib-induced apoptosis. This was accompanied with shift towards OXPHOS activity, associated with increased utilization of non-glucose substrates. We found the presence of stromal TCA-related proteins in leukemic cells, associated with higher TCA cycle dynamics and activity, increased glutamine and reduced oxidative stress. The gene expression profiles correlated with clinical resistance to TKIs. Targeting the glutamine-TCA axis by telaglenastat in combination with imatinib reversed the stroma-driven protection, leading to increased apoptosis.
CONCLUSION: This study describes a novel mechanism of direct bone marrow-mediated protection of leukemic cells from imatinib/TKI, related to transfer of metabolic proteins leading to higher activity of TCA cycle, metabolic plasticity and adaptation. Targeting the stroma-driven TCA cycle-related metabolism combined with imatinib presents a promising strategy to achieve therapeutic efficacy to overcome bone marrow microenvironment-mediated protection in CML.

Keywords:  Bone marrow stroma; Glutamine; Imatinib; Leukemia microenvironment; Metabolic plasticity; Mitochondria; Proteome; Resistance; TCA; TNTs

DOI:  https://doi.org/10.1186/s12964-025-02564-7
Cancer Res. 2025 Dec 02.

Drink Responsibly: Cancer Cells also Like Sugary Drinks.

Fabio Zani, Julianna Blagih.

Sugar-sweetened beverages (SSBs), which contain both glucose and fructose, have been linked to an increased incidence of colorectal cancer (CRC). Their effects on CRC progression, however, are unclear. In their recent work, Feng and colleagues investigated how exposure to SSBs affects CRC metastasis. They discovered that several CRC cell lines showed enhanced migration when exposed to glucose and fructose together, compared to cells exposed to glucose or fructose alone. Similarly, in mouse models of CRC liver metastasis, mice fed with both glucose and fructose developed more liver metastases, suggesting that SSBs promote CRC spread. Leveraging on metabolomic analyses, they discovered that in the presence of both glucose and fructose, the enzyme SORD converts fructose to sorbitol, regenerating NAD⁺ from NADH. Deleting SORD reduced the NAD+/NADH ratio and CRC cell migration and metastasis. Restoring the NAD⁺/NADH ratio rescued migration, suggesting that SORD-driven NAD⁺ regeneration promotes metastatic behaviour. Furthermore, they demonstrated that increased NAD⁺/NADH levels have a profound effect on cell metabolism, supporting glycolysis, the TCA cycle, and the mevalonate pathway. Interestingly, pharmacologic inhibition of the mevalonate pathway with statins reduced cell migration and liver metastasis in mice consuming SSBs. Together, these findings demonstrate that SSBs enhance CRC metastasis through SORD-dependent metabolic reprogramming. By regenerating NAD⁺ and glycolysis and the mevalonate pathway, SORD links SSB consumption to increased tumor cell migration and metastatic potential.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5296
Blood Adv. 2025 Dec 06. pii: bloodadvances.2025018178. [Epub ahead of print]

Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure.

Kuo-Kai Chin, Brian J Ball, Yasmin Abaza, Jessica K Altman, Rahul K Thakur, Moiez Ali, Andriy Derkach, Mark B Geyer, Aaron D Goldberg, Tamanna Haque, Meghan C Thompson, Jae H Park, Martin S Tallman, Sheng F Cai, Eunice S Wang, Ibrahim Aldoss, Eytan M Stein.

Menin inhibitors (MENINi) show promise for relapsed or refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangements (KMT2Ar) and NPM1 mutations (NPM1c). Outcomes after MENINi failure are poorly understood. To characterize the mutational landscape and subsequent outcomes, we conducted a multicenter retrospective study of adults from 4 U.S. centers with R/R AML after MENINi failure (relapse after response or primary refractory). The 84 patients (63% KMT2Ar, n=53; 23% NPM1c, n=19) who received MENINi were heavily pre-treated: 86% (n=72) had prior intensive chemotherapy (IC), 77% venetoclax (VEN, n=67), and 38% (n=32) allogeneic stem cell transplantation. After MENINi failure, 40% of patients (n=34) received supportive care. Of the 60% (n=50) that were treated, common regimens were hypomethylating agent (HMA)/VEN (26%, n=13), clinical trial (26%, n=13), and gilteritinib-based therapy (18%, n=9). The CR/CRi rate for non-trial therapies was 19% (n=7); ORR was 32% (n=12). All CR/CRi occurred with HMA/VEN (n=2, 15%), IC+VEN (n=4, 67%), or MENINi switching (bleximenib to revumenib, n=1, 50%). No FLT3-mutant patients responded to gilteritinib (0/6 gilteritinib-naïve). Median overall survival (mOS) from start of next therapy was 4.4 months; patients who achieved CR/CRi had mOS of 15.4 vs 3.4 months for non-responders (p=0.048). Outcomes after MENINi failure are poor, but responses occur with VEN-based regimens or MENINi switching. FLT3-ITD, WT1, and MEN1 mutations are associated with resistance.

DOI: https://doi.org/10.1182/bloodadvances.2025018178