bims-mibica 2025-11-30 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–11–30
twenty-two papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Pitavastatin counteracts venetoclax resistance mechanisms in acute myeloid leukemia by depleting geranylgeranyl pyrophosphate.
Inhibition of oligomeric BAX by an anti-apoptotic dimer.
Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.
Mitochondrial NAD+ drives liver regeneration.
The proton motive force maintains mtDNA euploidy by balancing mtDNA replication with cell proliferation.
SNAP23 deficiency triggers Trim21 mitochondrial translocation to suppress TFAM-mediated oxidative metabolism and drive chemoresistance in colorectal cancer.
Mitochondrial metabolic rewiring sensitizes mTORC1 inhibitor persister cells to cuproptosis.
Spectrum and Impact of Mitochondrial DNA Mutations in Ovarian Cancer.
Multiomics analyses of human colorectal cancer reveal changes in mitochondrial metabolism associated with chemotherapy resistance.
Age distinguishes selection from causation in cancer genomes.
N-terminal α-amino SUMOylation promotes phosphorylation-independent cofilin-1 translocation to the mitochondrial matrix and induces apoptosis.
Macropinocytosis enables metabolic recycling of extracellular DNA in cancer cells.
ASAH1-mediated sphingolipid metabolic reprogramming in venetoclax resistance of AML: beyond the monocytic phenotypes.
Chemiosmotic vs Conformational Models of Oxidative Phosphorylation: Theory and Mechanistic Insights.
Na+/H+ Exchanger 1 Inhibition Overcomes Venetoclax Resistance in Acute Myeloid Leukemia.
Therapeutic potential of metformin-based combination therapy in acute myeloid leukemia.
Intrinsic errors in mitochondrial translation trigger a decline in cell fitness.
Very long-chain fatty acids drive 1-deoxySphingolipid toxicity.
Glycolytic ATP production enables rapid mammalian cell growth.
Dynamic BH3 profiling predicts clinical outcomes in acute myeloid leukemia.
Targeting METTL3 Induces a Metabolic Vulnerability in ER+ Breast Carcinoma Cells.
A triple-action PROTAC for wild-type p53 cancer therapy.

bioRxiv. 2025 Nov 05. pii: 2025.10.27.684888. [Epub ahead of print]

Pitavastatin counteracts venetoclax resistance mechanisms in acute myeloid leukemia by depleting geranylgeranyl pyrophosphate.

Roberta Buono, Dennis Juarez, Madhuri Paul, Sarah J Skuli, Ian B Wong, Ishita Tarnekar, Zhili Ying, Izabelle Le, Gerald Wertheim, A'ishah Bakayoko, Marisa Kruidenier, Said M Sebti, Marina Konopleva, Angela G Fleischman, Cholsoon Jang, Martin Carroll, David A Fruman.

The BCL2 inhibitor venetoclax has therapeutic activity in several hematological malignancies. In acute myeloid leukemia (AML), venetoclax combined with hypomethylating agents is the standard of care for patients unfit for intensive chemotherapy, but intrinsic and acquired resistance are common. Loss of p53 function is strongly associated with venetoclax resistance, and adding venetoclax to 5-azacitidine provides no overall survival benefit in TP53 -mutant AML. Other frequent mechanisms of venetoclax resistance in AML include FLT3 mutations, MCL-1 upregulation, and altered mitochondrial metabolism. Unfortunately, it has been challenging to develop agents that target these mechanisms directly and combinatorially. Here we report that pitavastatin, an inhibitor of HMG-CoA-reductase, promotes apoptosis and overcomes several venetoclax resistance mechanisms in human AML cells. At clinically achievable concentrations, pitavastatin treatment has potent cytotoxic activity in cells with mutations in TP53 or FLT3 . The apoptotic mechanism involves p53-independent PUMA upregulation and reduced MCL-1 expression. Pitavastatin also suppresses mitochondrial gene expression and oxidative metabolism. The pro-apoptotic actions of pitavastatin depend on depletion of geranylgeranyl pyrophosphate (GGPP) and can be recapitulated by inhibiting GGPP synthase or geranylgeranyltransferase-1 enzymes. These results provide a mechanistic rationale for adding pitavastatin to AML regimens to prevent or overcome venetoclax resistance.

DOI: https://doi.org/10.1101/2025.10.27.684888
Cell. 2025 Nov 21. pii: S0092-8674(25)01242-5. [Epub ahead of print]

Inhibition of oligomeric BAX by an anti-apoptotic dimer.

Catherine E Newman, Micah A Gygi, Haleh Alimohamadi, Thomas M DeAngelo, Christina M Camara, Julian Mintseris, Ezra Yu, Edward P Harvey, Zachary J Hauseman, Lixin Fan, Yun-Xing Wang, Elizabeth W-C Luo, Marina Godes, Jacob Gehtman, Ann M Cathcart, Steven P Gygi, John R Engen, Gregory H Bird, Gerard C L Wong, Thomas E Wales, Loren D Walensky.

  BAX is a pro-apoptotic BCL-2 protein that resides in the cytosol as a monomer until triggered by cellular stress to form an oligomer that permeabilizes mitochondria and induces apoptosis. The paradigm for apoptotic blockade involves heterodimeric interactions between pro- and anti-apoptotic monomers. Here, we find that full-length BCL-w forms a distinctive, symmetric dimer (BCL-wD) that dissociates oligomeric BAX (BAXO), inhibits mitochondrial translocation, promotes retrotranslocation, blocks membrane-porating activity, and influences apoptosis induction of cells. Structure-function analyses revealed discrete conformational changes upon BCL-w dimerization and reciprocal structural impacts upon BCL-wD and BAXO interaction. Small-angle X-ray scattering (SAXS) analysis demonstrated that BAXO disrupts membranes by inducing negative Gaussian curvature, which is reversed by positive Gaussian curvature exerted by BCL-wD. Systematic truncation and mutagenesis dissected the core features of BCL-wD activity-dimerization, BAXO engagement, and membrane interaction. Our studies reveal a downstream layer of apoptotic control mediated by protein and membrane interactions of higher-order BCL-2 family multimers.

Keywords:  BAX; BCL-2 family proteins; BCL-w; anti-apoptotic; apoptosis; cell death; chemical crosslinking mass spectrometry; dimer; hydrogen deuterium exchange mass spectrometry; membrane curvature; mitochondria; mitochondrial retrotranslocation; mitochondrial translocation; oligomer; pro-apoptotic; small-angle X-ray scattering

DOI:  https://doi.org/10.1016/j.cell.2025.10.037
bioRxiv. 2025 Nov 13. pii: 2025.11.11.687895. [Epub ahead of print]

Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.

Azusa Terasaki, Alexis T Weiner, Yuhao Tan, Viktoria Szeifert, Keshav Bhatnagar, Cara C Rada, Vishnu Shankar, Courtney Kernick, Mahnoor Mahmood, Lukas Wiggers, Viviana R Rodrigues, Payam A Gammage, Theodore Roth, Jeffrey D Axelrod, Edgar Engleman, Bo Li, Derick Okwan-Duodu.

Hostile conditions in the tumor microenvironment restrict cellular respiration, yet mitochondrial metabolism remains indispensable for tumor growth and the activity of immunosuppressive cells. How tumor ecosystems sustain mitochondrial output has been unclear. Here, we show that cancer cells resolve this paradox by acting as hubs of intercellular mitochondrial redistribution. Using mitochondrial reporter systems, we demonstrate that cancer cells import host-derived mitochondria, integrate them into their endogenous network, and subsequently relay these hybrid organelles to neighboring immune cells. Mitochondria redistribution reprograms recipient neutrophils, macrophages, and CD4+ T cells into highly suppressive states but drives CD8+ T cell exhaustion. Within cancer cells, fusion of incoming mitochondria induces filamentous P5CS assembly, enhances biosynthetic output, and enables the refurbishment of damaged organelles into fully functional units. Disrupting mitochondrial redistribution collapses the immunosuppressive ecosystem and impairs tumor growth. Thus, cancer cells do not hoard resources but orchestrate a redistribution program that fortifies their own metabolic resilience, derails anti-tumor immunity, and sustains immunosuppressive partners.
HIGHLIGHTS: Tumor cells regulate their ecosystem by redistributing mitochondriaRedistributed mitochondria expand immunosuppressive cells but exhausts CD8+ T cellsMitochondria fusion within cancer cells, which precedes redistribution, optimizes metabolic output by triggering conformational changes in P5CSMitochondria fusion allows cancer cells to incorporate and refurbish seemingly incompetent host-derived mitochondria, improving efficiency in the tumor ecosystem.

DOI: https://doi.org/10.1101/2025.11.11.687895
Nat Metab. 2025 Nov 24.

Mitochondrial NAD+ drives liver regeneration.

DOI: https://doi.org/10.1038/s42255-025-01414-7
bioRxiv. 2025 Oct 27. pii: 2025.10.27.684790. [Epub ahead of print]

The proton motive force maintains mtDNA euploidy by balancing mtDNA replication with cell proliferation.

Sneha P Rath, Vamsi K Mootha.

Human mitochondrial DNA (mtDNA) encodes 13 essential components of the electron transport chain (ETC) 1 . A typical cell contains ∼1000s of copies of mtDNA, but how this copy number is stably maintained is unclear. Here, we track mtDNA copy number (mtCN) recovery in K562 cells following transient, chemically induced depletion to uncover principles of mtCN stability. Below a critical mtCN, ETC activity fails to sustain the proton motive force (PMF) and de novo pyrimidine synthesis-both required for mtDNA replication. PMF-dependent processes like Fe-S cluster biogenesis are also disrupted and stress responses are activated that impair cell proliferation and limit further mtCN dilution by cell division. Nonetheless, mtDNA replication and recovery remain possible via mtDNA-independent PMF, generated by complex V reversal, and uridine salvage. Once mtCN is restored, the ETC and forward complex V activity re-engage, stress responses subside, and proliferation recommences. Each cell division then dilutes mtDNA, serving as a built- in brake on mtCN. Our findings suggest that mtCN homeostasis emerges from the balance of two opposing PMF-driven processes - mtDNA replication and cell proliferation - revealing a bioenergetic logic that preserves mtDNA euploidy through repeated cell divisions.

DOI: https://doi.org/10.1101/2025.10.27.684790
Cell Death Dis. 2025 Nov 22.

SNAP23 deficiency triggers Trim21 mitochondrial translocation to suppress TFAM-mediated oxidative metabolism and drive chemoresistance in colorectal cancer.

Abudushalamu Yalikun, Bingjie Guan, Jiawei Pan, Haonan Chen, Jingfeng Cai, Ziyan Zhu, Runkai Zhou, Bowen Xie, Youdong Liu, Jikun Li.

Chemoresistance is a major cause of poor prognosis in colorectal cancer (CRC), and its molecular mechanisms urgently need elucidation. The cell membrane protein SNAP23, known for its role in vesicle secretion, also promotes CRC cell growth. However, its role in tumor chemotherapy remains unclear. This study reveals a novel function of SNAP23, independent of vesicle transport, mediating crosstalk between the cell membrane and mitochondria to influence the chemotherapeutic response to oxaliplatin (OXA). Mechanistically, SNAP23 arrests Trim21, causing its accumulation near the cell membrane and away from mitochondria. This reduces the ubiquitination and degradation of the mitochondrial transcription factor A (TFAM), enhancing mitochondrial oxidative metabolism and increasing oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) production, ultimately heightening the sensitivity of cancer cells to OXA. The unique regulatory function of SNAP23 in the chemotherapeutic response of colorectal cancer may provide a potential target for chemotherapy sensitization.

DOI: https://doi.org/10.1038/s41419-025-08252-1
JCI Insight. 2025 Nov 24. pii: e187448. [Epub ahead of print]10(22):

Mitochondrial metabolic rewiring sensitizes mTORC1 inhibitor persister cells to cuproptosis.

Heng Du, Heng-Jia Liu, Magdalena Losko, Yu Chi Yang, Min Yuan, Elizabeth P Henske, John M Asara, Mallika Singh, David J Kwiatkowski.

  Therapeutics blocking PI3K/mTOR complex 1 (mTORC1) are commonly used for tumor treatment, and at times achieve major responses, yet minimal residual disease (MRD) persists, leading to tumor relapse. We developed multiple MRD models both in vitro (rapamycin persistent, RP) and in vivo after mTORC1 inhibition. All 11 RP/MRD cell lines showed complete growth and signaling insensitivity to rapamycin but variable sensitivity to bi-steric mTORC1 inhibitors, with MtorS2035 mutations identified in 4 of 7 RP cell lines. Multiomic analyses identified a pronounced shift toward oxidative phosphorylation and away from glycolysis with increased mitochondrial number in all RP/MRD models. MYC and SWI/SNF expression was significantly enhanced. Both the SWI/SNF inhibitor AU-15330 and the mitochondrial complex I oxidative phosphorylation inhibitor IACS-010759 showed pronounced synergy with bi-steric mTORC1 inhibitors to cause cuproptotic cell death in RP/MRD cells, suggesting these combinations as a potential patient treatment strategy for rapalog resistance.

Keywords:  Cancer; Epigenetics; Metabolism; Mitochondria; Oncology

DOI:  https://doi.org/10.1172/jci.insight.187448
Int J Mol Sci. 2025 Nov 19. pii: 11180. [Epub ahead of print]26(22):

Spectrum and Impact of Mitochondrial DNA Mutations in Ovarian Cancer.

Samantha Su Ping Low, Laura Greaves, Ryan Silk, Colin A Semple, Charlie Gourley.

  Mitochondrial DNA (mtDNA) mutations are prevalent across cancer genomes, and growing evidence implicates their multifaceted role in energy metabolism with tumorigenesis. Ovarian cancer, in particular, demonstrates high mtDNA copy numbers and increased incidences of truncating and missense mtDNA mutations, with heteroplasmy levels predictive of prognosis. This review provides a comprehensive description of published mtDNA sequencing data in ovarian cancer, the majority being high-grade serous samples, encompassing both coding and non-coding regions. MtDNA mutations within non-coding regions, such as the D-loop control region, can affect mtDNA replication and transcription, hence affecting overall mtDNA copy numbers, while mtDNA mutations within coding regions can directly impact respiratory complex function and downstream metabolic pathways. MtDNA mutations may serve as clinically valuable diagnostic biomarkers for ovarian cancer and predictors for chemoresistance. We also explore ongoing efforts to deepen our understanding of mitochondrial oncogenetics through the creation of novel cancer models enabled by mitochondrial gene editing techniques. Developing robust human ovarian cancer cell models will be critical to elucidate mechanistic and phenotypic consequences of mtDNA mutations, assess drug response and resistance and identify new therapeutic targets to advance precision oncology in this emerging field.

Keywords:  gene editing; heteroplasmy; mitochondrial DNA; ovarian cancer; somatic mutations

DOI:  https://doi.org/10.3390/ijms262211180
Front Oncol. 2025 ;15 1625797

Multiomics analyses of human colorectal cancer reveal changes in mitochondrial metabolism associated with chemotherapy resistance.

Shiyi Chen, Qian Li, Wei Zheng.

   Background: Mitochondria are essential organelles involved in energy production, cellular metabolism, and signal transduction. They have important impacts on tumorigenesis and cancer progression. Nevertheless, the associations between mitochondrial metabolic processes and chemotherapy resistance in colorectal cancer (CRC) are not well understood.
Methods: We generated a chemotherapy-resistant colorectal cancer cell line, HCT-15/DOX, via doxorubicin (DOX) induction. We then performed proteomic and metabolomic analyses via LC-MS/MS technology on both the parental and the DOX-resistant cell lines. Additionally, transmission electron microscopy was used to examine changes in mitochondrial morphology between the two cell lines.
Results: The results revealed significant dysregulation of 185 proteins and 1099 metabolites in HCT-15/DOX cells relative to parental cells, highlighting the impact of chemotherapy resistance on cellular processes. The key functional proteins that were identified included upregulated SDHA, BCKDHB, CRYZ, NUDT6, CPT1A, and POLG, and downregulated CRAT, FDPS, SFXN1, and ATAD3B. Additionally, through combined multiomics pathway enrichment analysis, pyrimidine metabolism, purine metabolism, ascorbate and aldarate metabolism, propanoate metabolism, and the citrate cycle (TCA cycle) were identified as important metabolic processes associated with CRC chemotherapy resistance. Transmission electron microscopy analysis revealed that HCT-15/DOX cells had increased mitochondrial number, length, and area.
Conclusions: This research highlights notable differences in mitochondrial morphology and diverse mitochondrial metabolic functions between parental and DOX-resistant HCT-15 CRC cells. The findings of the present study provide insights into the mitochondrial metabolic changes associated with CRC chemotherapy resistance, offering valuable insights into the mechanisms underlying these changes and identifying potential therapeutic targets for addressing CRC chemotherapy resistance.

Keywords:  chemotherapy resistance; colorectal cancer; metabolomics; mitochondrial metabolism; proteomics

DOI:  https://doi.org/10.3389/fonc.2025.1625797
bioRxiv. 2025 Oct 06. pii: 2025.10.06.680730. [Epub ahead of print]

Age distinguishes selection from causation in cancer genomes.

David Cheek, Martin Blohmer, Martin Nowak, Tibor Antal, Kamila Naxerova.

Cancer genome sequencing efforts have revealed hundreds of genes under positive selection, many of which are now being developed as therapeutic targets. However, positively selected mutations also populate our aging tissues in the absence of cancer. For most mutations, it is currently unknown whether they are recurrently found in cancer genomes because they cause cancer or because they expand during normal tissue evolution and are passively inherited. Here, we develop a mathematical and statistical framework that distinguishes these two factors. We discover - across thousands of cancer and normal tissue genomes - that mutations that most strongly increase cancer risk are enriched in younger patients' cancers, whereas mutations that are positively selected in normal tissue without causing cancer are enriched in older patients. Focusing on a particularly data-rich cancer type, acute myeloid leukemia, we show that genetic differences between young- and adult-onset cancers can largely be explained by the cumulative effects of normal tissue evolution, contradicting the long-standing notion that childhood cancers require a distinct set of causal mutations. Our framework establishes patient age as a powerful resource for clarifying whether positively selected mutations in cancer genomes are truly disease-promoting.

DOI: https://doi.org/10.1101/2025.10.06.680730
Nat Commun. 2025 Nov 27.

N-terminal α-amino SUMOylation promotes phosphorylation-independent cofilin-1 translocation to the mitochondrial matrix and induces apoptosis.

Qi Deng, Xiaokun Gu, Jiaqian Feng, Jinhua Xiang, Xinyue Li, Weiji Weng, Gerald W Zamponi, Ou Huang, Si-Jian Pan, Yong Li.

Cofilin is a central regulator of actin filament turnover, traditionally thought to act through phosphorylation-dependent control of filament assembly. However, its mitochondrial functions remain poorly understood. Here we show that N-terminal α-amino SUMOylation, rather than phosphorylation or actin interaction, governs cofilin-1 translocation to mitochondria and activation of the apoptotic pathway. This modification strengthens the association of cofilin-1 with the mitochondrial import receptors Tom20 and Tom70 through the molecular chaperone HSP70, enabling its delivery to the mitochondrial matrix. Once imported, SUMO-modified cofilin-1 binds cytochrome c1, promotes the dissociation of cytochrome c from complex III, and initiates mitochondrial-mediated apoptosis. These findings redefine cofilin-1 as a regulator of mitochondrial integrity independent of its actin-related roles, uncovering a mechanism by which SUMOylation directs protein targeting and apoptotic signaling. This work broadens current understanding of mitochondrial regulation and may inform therapeutic strategies for diseases linked to defective cell death.

DOI: https://doi.org/10.1038/s41467-025-66859-6
bioRxiv. 2025 Oct 23. pii: 2025.10.22.684010. [Epub ahead of print]

Macropinocytosis enables metabolic recycling of extracellular DNA in cancer cells.

Wen-Hsuan Yang, Olivia T Stamatatos, Evdokia Michalopoulou, Ava Sann, Paolo Cifani, Linda Van Aelst, Justin R Cross, Tse-Luen Wee, Michael J Lukey.

Avid nutrient consumption is a metabolic hallmark of cancer and leads to regional depletion of key metabolites within the tumor microenvironment (TME). Cancer cells consequently employ diverse strategies to acquire the fuels needed for growth, including bulk uptake of the extracellular medium by macropinocytosis. Here, we show that breast and pancreatic cancer cells macropinocytically internalize extracellular DNA (exDNA), an abundant component of the TME, and deliver it to lysosomes for degradation. This provides a supply of nucleotides that sustains growth when de novo biosynthesis is impaired by glutamine restriction or pharmacological blockade. Mechanistically, this process is dependent on the non-redundant lysosomal equilibrative nucleoside transporter SLC29A3 (ENT3), which mediates the export of nucleosides from the lysosomal lumen into the cytosol. Accordingly, genetic ablation of SLC29A3 or pharmacological disruption of lysosomal function prevents exDNA scavenging and potently sensitizes breast tumors to antimetabolite chemotherapy in vivo . These findings reveal a previously unrecognized nutrient acquisition pathway through which cancer cells recycle exDNA into metabolic building blocks and highlight SLC29A3 as a mediator of metabolic flexibility and a potential target to improve chemotherapy response.

DOI: https://doi.org/10.1101/2025.10.22.684010
BMC Cancer. 2025 Nov 22.

ASAH1-mediated sphingolipid metabolic reprogramming in venetoclax resistance of AML: beyond the monocytic phenotypes.

Lei Zhao, Xinrong Xiang, Ailing Zhong, Hongbin Yu, Jinjun Yang, Mengran Chen, Hong Ding, Chenlu Yang, Yu Wu.

   BACKGROUND: Venetoclax (VEN) in combination with hypomethylating agents has emerged as a pivotal therapy for elderly acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. However, monocytic AML exhibit greater resistance to VEN-based regimens compared to non-monocytic AML. Identifying exploitable vulnerabilities will mitigate resistance and relapse.
METHODS: We conducted a comprehensive analysis of VEN resistance mechanisms in monocytic AML by integrating bulk AML datasets, single-cell RNA sequencing (scRNA-seq) of AML patient bone marrow and patient-derived xenograft (PDX) models, as well as lipidomic sequencing of induced VEN-resistant cell lines. Additionally, we examined the monocytic markers in VEN-resistant cell lines and assessed VEN sensitivity after knocking down the key sphingolipid metabolism gene ASAH1.
RESULTS: Analysis of bulk RNA-seq data revealed elevated expression of sphingolipid metabolism genes in the French-American-British (FAB) M5 subtype, which exhibited poor response to VEN-based treatment. Further analysis of scRNA-seq data showed that monocytic AML cells surviving VEN treatment demonstrated the highest sphingolipid metabolism score, particularly in CD14⁺ITGAX⁺ monocytic AML cells. Notably, induced VEN-resistant cell lines exhibited significantly increased monocytic markers and differential sphingolipid metabolism profiles compared to parental cells. Among the key regulators of sphingolipid metabolism, ASAH1 was upregulated, while SPHK1 was downregulated. Knocking down ASAH1 enhanced VEN sensitivity without reducing the expression of monocytic markers CD14/CD64。.
CONCLUSIONS: These findings suggest that aberrant sphingolipid metabolism contribute to AML resistance to VEN.

Keywords:  Acute myeloid leukemia; Drug resistance; Monocytic; Sphingolipid; Venetoclax

DOI:  https://doi.org/10.1186/s12885-025-15272-9
Biosystems. 2025 Nov 21. pii: S0303-2647(25)00247-3. [Epub ahead of print] 105637

Chemiosmotic vs Conformational Models of Oxidative Phosphorylation: Theory and Mechanistic Insights.

Sungchul Ji.

  The chemiosmotic model of oxidative phosphorylation (oxphos) proposed by Peter Mitchell in 1961 was revisited and its basic mechanistic assumptions that oxphos is driven by protonmotive force either across or within the mitochondrial inner membrane were re-evaluated in light of recent findings. Available evidence strongly suggests that non-chemiosmotic mechanisms such as the conformon or detailed conformational change-mediated mechanisms, including Nath's torsional mechanism of energy transduction and ATP synthesis, are needed to explain the phenomenon of oxphos in enzymologically and quantum-mechanically realistic terms. An in-depth analysis of oxphos, taking into account recent findings reveal the logical errors or fallacies in dismissing conformational change-based models in favor of the chemiosmotic theory, and suggest the principal mechanistic events underlying chemomechanical coupling in bioenergetic processes.in general.

Keywords:  Generalized Franck-Condon Principle; Principle of Slow and Fast Processes; conformation vs. configuration; conformational change as the mediator for chemomechanical coupling; conformational strains of biopolymers; conformons; kinematics vs. dynamics mechanisms; three principles underlying chemomechanical coupling. Nath's torsional mechanism of energy transduction and ATP synthesis; transition states

DOI:  https://doi.org/10.1016/j.biosystems.2025.105637
Cells. 2025 Nov 10. pii: 1759. [Epub ahead of print]14(22):

Na+/H+ Exchanger 1 Inhibition Overcomes Venetoclax Resistance in Acute Myeloid Leukemia.

Shin Young Hyun, Eun Jung Na, Yu Ri Kim, Yoo Hong Min, June-Won Cheong.

  Despite advances with novel targeted agents (e.g., BCL-2 or IDH inhibitors) combined with chemotherapy for acute myeloid leukemia (AML), drug resistance persists. We investigated whether blocking Na+/H+ exchanger 1 (NHE1) could enhance AML cell sensitivity to the BCL-2 inhibitor venetoclax and sought to determine the molecular mechanisms. Our results demonstrated that co-treatment with venetoclax and the NHE1 inhibitor 5-(N,N-hexamethylene) amiloride (HMA) synergistically induced apoptosis in both venetoclax-sensitive and -resistant leukemic cell lines. Specifically, the combination significantly increased apoptosis in venetoclax-resistant THP-1 cells to 72.28% (17.79% with 100 nM venetoclax and 10.15% with 10 μM HMA alone; p < 0.001). Conversely, another venetoclax-resistant line, U-937, showed no significant apoptotic response to the combination. In THP-1 cells, this synergy was mediated via a caspase-dependent programmed cell death pathway, evidenced by an increased BAX/BCL-2 ratio, mitochondrial cytochrome c release, and subsequent caspase-9 and caspase-3 activation. Furthermore, co-treatment downregulated the anti-apoptotic protein MCL-1 and reduced PI3K and Akt phosphorylation, suggesting that inhibition of these survival pathways also contributed to the synergistic effect. Inhibition of NHE1 may substantially enhance venetoclax sensitivity in certain AML models, particularly in venetoclax-resistant THP-1 cells but not in U-937, highlighting biological diversity and the probable involvement of alternative survival pathways.

Keywords:  Na-H exchanger 1; PI3K/Akt pathway; acute myeloid leukemia; resistance; venetoclax

DOI:  https://doi.org/10.3390/cells14221759
Discov Oncol. 2025 Nov 29.

Therapeutic potential of metformin-based combination therapy in acute myeloid leukemia.

Mobina Nakhaei Shamahmood, Abolfazl Miri, Mohammad Javad Yousefi, Fatemeh Mezginejad.

   BACKGROUND: Acute myeloid leukemia (AML) is the most prevalent form of acute leukemia. Despite great efforts, the overall prognosis for patients with AML remains poor, and the mortality rate due to relapse is also considerable. Consequently, the disease poses treatment challenges. Several studies have indicated that metformin may serve as a beneficial adjunct to traditional anti-leukemia medications, especially enhancing their effectiveness against drug resistance; however, it is not effective when used as a standalone treatment. In this context, combination therapies are currently being explored as a promising treatment option.
METHODS: This study is a narrative review. A comprehensive literature search across multiple databases, including PubMed, Google Scholar, Scopus, Embase and Cochrane, yielded 103 relevant articles up to July 2024. From an initial total of 103 articles, we excluded unrelated and duplicate articles, as well as those for which the full text was unavailable and review articles. Ultimately, 32 articles were included in the study. During the database search, we employed search terms such as AML, combination, and metformin to find relevant articles.
RESULTS: According to the results of the studies, the combination of metformin with gilteritinib, sorafenib, 6-benzylthionosine, venetoclax, diclofenac, diflunisal, and cytarabine reduces intracellular ATP levels, inhibits glycolysis, halts the cell cycle, diminishes oxidative phosphorylation, increases the expression of anti-apoptotic proteins and increases cytotoxicity. This combination also induces apoptosis, reduces cell growth, and ultimately leads to a significant decrease in the burden of AML and an increase in overall survival for these patients.
CONCLUSIONS: Therefore, combining these drugs with metformin may enhance the synergistic effect and improve the treatment of AML patients.

Keywords:  AML; Combination; Metformin

DOI:  https://doi.org/10.1007/s12672-025-04205-4
bioRxiv. 2025 Oct 15. pii: 2025.10.13.682189. [Epub ahead of print]

Intrinsic errors in mitochondrial translation trigger a decline in cell fitness.

Güleycan Lutfullahoglu Bal, Kah Ying Ng, Eli Berzell, Ani Akpinar, Alex E Ekvik, Lidiia Koludarova, Seyedehshima Naddafi, Clemens Raths, Tania Vane-Tempest, Jordyn J VanPortfliet, Sarah O'Keefe, Arafath K Najumudeen, Tuula A Nyman, James B Stewart, A Phillip West, Brendan J Battersby.

Defects in the faithful expression of the human mitochondrial genome underlies disease states, from rare inherited disorders to common pathologies and the aging process itself. The ensuing decrease in the capacity for oxidative phosphorylation alone cannot account for the phenotype complexity associated with disease. Here, we address how aberrations in mitochondrial nascent chain synthesis per se exert a decline in cell fitness using a classic model of mitochondrial induced premature aging. We identify how intrinsic errors during mitochondrial nascent chain synthesis destabilize organelle gene expression, triggering intracellular stress responses that rewire cellular metabolism and cytokine secretion. Further, we show how these mechanisms extend to pathogenic variants associated with inherited human disorders. Together, our findings reveal how aberrations in mitochondrial protein synthesis can sensitize a cell to metabolic challenges associated with disease and pathogen infection independent of oxidative phosphorylation.
Teaser/One-Sentence Summary: Aberrations in mitochondrial translation elongation trigger activation of intracellular stress responses associated with disease and aging.

DOI: https://doi.org/10.1101/2025.10.13.682189
Nat Commun. 2025 Nov 26.

Very long-chain fatty acids drive 1-deoxySphingolipid toxicity.

Adam Majcher, Gergely Karsai, Elkhan Yusifov, Martina Schaettin, Ermanno Malagola, Peter Horvath, Jinmei Li, Sofía Rodriguez-Gallardo, Kuniyoshi Shimizu, Gai Zhibo, Raghvendra Dubey, Tim Peterson, Takeshi Harayama, Thorsten Hornemann.

1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids formed when serine palmitoyltransferase incorporates L-alanine instead of L-serine. Elevated 1-deoxySLs are associated with hereditary sensory neuropathy type 1 and diabetic neuropathy, but the molecular basis of their toxicity remains unclear. Here we show that toxicity is mediated by very long-chain (VLC) 1-deoxy-dihydroceramides (1-deoxyDHCer), particularly nervonyl-1-deoxyDHCer (m18:0/24:1) and lignoceryl-1-deoxyDHCer (m18:0/24:0). Using a CRISPR interference screen, we identify ELOVL1 and CERS2 as essential enzymes driving the formation of these toxic species. Genetic modulation or pharmacological inhibition of ELOVL1 prevents VLC 1-deoxyDHCer accumulation, rescuing the toxicity in cellular and neuronal models. Mechanistic studies reveal that m18:0/24:1 disrupts mitochondrial integrity and induces the mitochondrial permeability transition pore formation and BAX activation, leading to cell death. These findings establish a direct link between 1-deoxySL chemical structure and cytotoxicity and highlight ELOVL1 inhibition as a potential therapeutic strategy for 1-deoxySL-associated diseases.

DOI: https://doi.org/10.1038/s41467-025-66687-8
bioRxiv. 2025 Oct 31. pii: 2025.10.30.685682. [Epub ahead of print]

Glycolytic ATP production enables rapid mammalian cell growth.

Matthew A Kukurugya, Shuying Zhang, Brandon T Ha, Alex E Ekvik, Denis V Titov.

Proliferating cells must produce ATP rapidly enough to meet the energy demands of growth and maintenance. While microbes show a linear coupling between ATP production rate and growth, whether this principle holds in mammalian cells has remained unclear and it has been suggested that most ATP is allocated to cell maintenance, regardless of growth rate. Here, we quantified lactate production, oxygen consumption, and proliferation across twelve mammalian cell lines and found a strong linear relationship between total ATP production and growth with the majority of ATP allocated to macromolecular synthesis. By inhibiting glycolysis, inhibiting respiration, or reducing translation, cells shift along this ATP-growth line in predictable directions, indicating bidirectional coupling between ATP supply and demand. A genetically encoded ATP hydrolysis sink increased ATP turnover yet slowed proliferation, demonstrating that ATP production capacity can limit growth. Together, these results show that respiration alone cannot generate enough ATP to support the growth rates of rapidly dividing cells, whereas glycolysis can. Our results provide a quantitative rationale for the Warburg Effect, where cells rely on glycolysis to achieve doubling times faster than 30 hours. Our results establish ATP production rate as a quantitative constraint on growth across species.

DOI: https://doi.org/10.1101/2025.10.30.685682
bioRxiv. 2025 Oct 15. pii: 2025.10.14.682414. [Epub ahead of print]

Dynamic BH3 profiling predicts clinical outcomes in acute myeloid leukemia.

Emma-Jayne Minihane, Leah Krotee, Jason Wu, Lindsey Thornton, Geoffrey Fell, Sonja Herter, Jeremy Ryan, Amulya Jakkani, Kate Marinchev, Andrew A Lane, Marlise R Luskin, Eric S Winer, Evan C Chen, Shai Shimony, Martha Wadleigh, Rahul Vedula, Virginia O Volpe, Christopher Reilly, Ilene Galinsky, Daniel J DeAngelo, Richard M Stone, Donna S Neuberg, Anthony Letai, Jacqueline S Garcia.

Predictive biomarkers can potentially meet the need for improved drug assignment in acute myeloid leukemia (AML). Fewer than half of AML patients have actionable mutations: consequently, targeted therapy achieves remission in only a fraction of those who have them. Dynamic BH3 Profiling (DBP), a functional assay, can measure changes in ex vivo drug-induced apoptotic priming in multiple cancers. To assess the feasibility and predictive capacity of DBP in AML, we prospectively tested DBP using a fixed-drug panel in myeloblasts from 92 patients. We generated a database combining genetic and functional annotation. Established AML clinical and genetic prognostic characteristics were associated with drug-induced apoptotic priming. We observed distinct inter patient sensitivities to single drugs or combinations with the BCL2-inhibitor venetoclax, and intra patient apoptotic priming differences based on CD123-expression within distinct cell subpopulations. DBP further predicted the likelihood of remission to chemotherapy and targeted agents, supporting its use to identify optimal personalized therapy.
Statement of significance: Dynamic BH3 profiling provides patient-specific drug vulnerability data in real-time to inform prognosis and therapy selection.
Key takeaways: Dynamic BH3 profiling can be performed on bone marrow and leukemic blood from AML patients in 48 hours.Known clinical prognostic factors associate with drug-induced apoptotic priming in AML.Drug-induced apoptotic priming identifies drug vulnerabilities in individual patients and predicts clinical response to chemotherapy and small molecule inhibitors.

DOI: https://doi.org/10.1101/2025.10.14.682414
Endocr Relat Cancer. 2025 Nov 26. pii: ERC-25-0174. [Epub ahead of print]

Targeting METTL3 Induces a Metabolic Vulnerability in ER+ Breast Carcinoma Cells.

Mary H Sumlut, Jing Feng, Xiang Zhang, Susan Dougherty, Yoannis Imbert Fernandez, Carolyn M Klinge, Brian F Clem.

  Epitransciptomic marks, such as N6-methyladenosine (m6A) within RNA transcripts, have been implicated in multiple pro-tumorigenic activities. These modifications are controlled by writers, readers, and erasers, including the METTL3 m6A-methyltransferase. Recently, changes in expression or activity of epitranscriptomic enzymes have been shown to modulate metabolic pathways in multiple tumor types, including within endocrine-sensitive and -resistant estrogen receptor-positive (ERα+) breast cancer (ER+BC) cells. Yet, a broad analysis of metabolic alterations, specifically with respect to METTL3 inhibition, has not been explored in these BC subtypes. Herein, we investigated the magnitude of pharmacological targeting of METTL3 (STM2457) on overall cellular metabolism in endocrine-sensitive (MCF-7 and ZR-75-1) and -resistant (LCC9 and ZR-75-1-4-OHT) ER+BC cells. We found that STM2457 selectively decreased glycolytic activity in resistant cells and led to altered hexokinase 2 expression in LCC9 cells. STM2457 suppressed mitochondrial activity, while isotope tracing found diminished TCA glucose oxidation in MCF-7 and LCC9 cell lines. This was accompanied by increased glutamine uptake and glutaminolysis, which was more pronounced in the endocrine resistant LCC9 cells. We also observed differential expression of glutaminase 1 (GLS1) splice variants in the MCF-7 cells and an increase in the ASCT2 glutamine transporter. To determine combinatorial targeting potential, we co-treated cells with STM2457 and CB-839, which is a GLS1 inhibitor. CB-839 increased the potency of STM2457 only in the LCC9 and ZR-75-1-4-OHT endocrine-resistant cells. Our collective findings suggest that METTL3 inhibition leads to selective glycolytic and oxidative metabolic changes between these endocrine-sensitive and resistant BC cells that can be exploited for combinatorial therapy.

Keywords:  METTL3 inhibition; STM2457; epitranscriptomic; estrogen receptor-positive breast cancer; metabolism

DOI:  https://doi.org/10.1530/ERC-25-0174
Cell Rep Med. 2025 Nov 26. pii: S2666-3791(25)00540-3. [Epub ahead of print] 102467

A triple-action PROTAC for wild-type p53 cancer therapy.

Gregory H Bird, Utsarga Adhikary, Michael J Schmidt, Marina Godes, Bethany Tesar, Christina M Camara, Joao A Paulo, Julia F Vidlak, Thomas M DeAngelo, Marilyn Marquez, Prafulla Gokhale, Ruitong Li, Shannan J Ho Sui, Michael D Cameron, Steven P Gygi, Loren D Walensky.

  Despite the central role of p53 suppression in cancer pathogenesis, the promise of therapeutic p53 reactivation remains unrealized, with targeted and combination chemotherapies limited by efficacy, toxicity, and delivery. To overcome these challenges, we introduce a triple-action proteolysis targeting chimera (TAPTAC) that simultaneously targets three oncogenic mechanisms to reactivate apoptosis. TAPTAC1 diverts HDM2 from degrading p53 to eliminating oncogenic targets such as BET proteins, while also blocking HDMX-mediated sequestration, thereby maximizing p53 reactivation in concert with cancer protein degradation. TAPTAC1 outperforms combination treatments and PROTACs that target HDM2 and BET proteins, but not HDMX, and is broadly effective in wild-type (WT) p53 cancers, including mouse models of osteosarcoma and leukemia. Importantly, TAPTAC1 leverages cancer dependency on HDM2 to enhance selectivity and mitigate toxicity. With WT p53 retained in 90% of pediatric and 50% of adult cancers, TAPTACs provide a therapeutic platform for addressing key limitations of prior anti-cancer strategies.

Keywords:  Apoptosis; BET inhibitor; BRD4; Cancer; HDM2; HDMX; PROTAC; TAPTAC; degrader; p53; stapled p53 peptide; therapeutics

DOI:  https://doi.org/10.1016/j.xcrm.2025.102467