bims-mibica 2025-03-02 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–03–02
29 papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer.
A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.
Mitochondrial superoxide regulates pro-inflammatory macrophages.
Glyoxalase 2 coordinates de novo serine biosynthesis.
TOMM20 as a driver of cancer aggressiveness via oxidative phosphorylation, maintenance of a reduced state, and resistance to apoptosis.
BCL-B Promotes Lung Cancer Invasiveness by Direct Inhibition of BOK.
Eugenol Promotes Apoptosis in Leukemia Cells via Targeting the Mitochondrial Biogenesis PPRC1 Gene.
Mitochondrial-Targeted Multifunctional Platinum-Based Nano "Terminal-Sensitive Projectile" for Enhanced Cancer Chemotherapy Efficacy.
Metabolic Regulation by p53: Implications for Cancer Therapy.
Copper-Induced Enhancement of Glioblastoma Tumorigenicity via Cytochrome C Oxidase.
How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production.
The Role of HADHB in Mitochondrial Fatty Acid Metabolism During Initiation of Metastasis in ccRCC.
Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells.
A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.
Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.
Total cardiolipin levels in gastric and colon cancer: evaluating the prognostic potential.
Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.
MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
Risk-stratified treatment of sonrotoclax with chemotherapy in newly diagnosed acute myeloid leukemia: a study protocol.
SQLE-catalyzed squalene metabolism promotes mitochondrial biogenesis and tumor development in K-ras-driven cancer.
Transplantation of gastric epithelial mitochondria into human gastric cancer cells inhibits tumor growth and enhances chemosensitivity by reducing cancer stemness and modulating gastric cancer metabolism.
Mitochondrial metabolism-related features guiding precision subtyping and prognosis in breast cancer, revealing FADS2 as a novel therapeutic target.
Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer.
Viperin expression leads to downregulation of mitochondrial genes through misincorporation of ddhCTP by mitochondrial RNA polymerase.
ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.
β-Catenin Regulates Glycolytic and Mitochondrial Function in T-Cell Acute Lymphoblastic Leukemia.
Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia.
Redox-Activated Proton Transfer through a Redundant Network in the Qo Site of Cytochrome bc1.

Neoplasia. 2025 Feb 24. pii: S1476-5586(25)00022-3. [Epub ahead of print]62 101143

Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer.

Travis Vander Steen, Ingrid Espinoza, Cristina Duran, Guillem Casadevall, Eila Serrano-Hervás, Elisabet Cuyàs, Sara Verdura, George Kemble, Scott H Kaufmann, Robert McWilliams, Sílvia Osuna, Daniel D Billadeau, Javier A Menendez, Ruth Lupu.

  Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (FASNis), a family of targeted metabolic therapeutics recently entering the clinic, could lower the apoptotic threshold in chemoresistant PDAC cells and be synergistic with BH3 mimetics that neutralize anti-apoptotic proteins. Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain. The extent of NADPH accumulation, a consequence of FASN inhibition, paralleled the sensitivity of PDAC cells to the apoptotic effects of TVB FASNis in conventional PDAC cell lines that naturally express varying levels of FASN. FASN inhibition dramatically increased the sensitivity of "FASN-high" expressing PDAC cells to the BCL2/BCL-XL/BCL-W inhibitor ABT-263/navitoclax and the BCL2-selective inhibitor ABT-199/venetoclax, both in vitro and in in vivo xenografted tumors. The ability of TVB FASNis to shift the balance of pro- and anti-apoptotic proteins and thereby push PDAC cells closer to the apoptotic threshold was also observed in cell lines developed from patient-derived xenografts (PDXs) representative of the classical (pancreatic) transcriptomic subtype of PDAC. Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients.

Keywords:  BH3 mimetics; Fatty acid synthase; Gemcitabine; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.neo.2025.101143
Res Sq. 2025 Feb 14. pii: rs.3.rs-5961609. [Epub ahead of print]

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.

Martin Picard, Anna Monzel, Jack Devine, Darshana Kapri, Jose Enriquez, Caroline Trumpff.

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3. All mitochondria share general features, but not all mitochondria are created equal 4.Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes. By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8, we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.

DOI: https://doi.org/10.21203/rs.3.rs-5961609/v1
Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00038-8. [Epub ahead of print]

Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.

Woo Yong Park, Claudia Montufar, Elma Zaganjor.

  Mitochondrial metabolism, signaling, and dynamics are key regulators of cell fate. While glycolysis supports stemness, mitochondrial expansion and oxidative phosphorylation (OXPHOS) facilitate differentiation. This forum presents emerging evidence that the type of substrate, whether amino acids, carbohydrates, or fatty acids, oxidized by mitochondria significantly influences differentiation outcomes.

Keywords:  OXPHOS; amino acids; differentiation; fatty acids; glucose; mitochondria

DOI:  https://doi.org/10.1016/j.tcb.2025.02.004
Nat Metab. 2025 Feb 24.

Mitochondrial superoxide regulates pro-inflammatory macrophages.

DOI: https://doi.org/10.1038/s42255-025-01223-y
Chembiochem. 2025 Feb 23. e202401086

Glyoxalase 2 coordinates de novo serine biosynthesis.

Marissa N Trujillo, Erin Q Jennings, Dominique O Farrera, Naoya Kitamura, Colin C Anderson, Sarah Gehrke, Julie A Reisz, Mogens Johannsen, James R Roede, Angelo D'Alessandro, James Galligan.

  Phosphoglycerate dehydrogenase (PHGDH) is the first enzyme in de novo Ser biosynthesis. Numerous metabolic pathways rely on Ser as a precursor, most notably one-carbon metabolism, glutathione biosynthesis, and de novo nucleotide biosynthesis. To facilitate proliferation, many cancer cells shunt glycolytic flux through this pathway, placing PHGDH as a metabolic liability and feasible therapeutic target for the treatment of cancer. Herein, we demonstrate the post-translational modification (PTM) of PHGDH by lactoylLys. These PTMs are generated through a non-enzymatic acyl transfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Knockout of the primary LGSH regulatory enzyme, glyoxalase 2 (GLO2), results in increased LGSH and resulting lactoylLys modification of PHGDH. These PTMs reduce enzymatic activity, resulting in a marked reduction in intracellular Ser. Using stable isotope tracing, we demonstrate reduced flux through the de novo Ser biosynthetic pathway. Collectively, these data identify PHGDH as a target for modification by lactoylLys, resulting in reduced enzymatic activity and reduced intracellular Ser.

Keywords:  3-phosphoglycerate dehydrogenase (PHGDH); cell metabolism; glycolysis; lactoylation

DOI:  https://doi.org/10.1002/cbic.202401086
Mol Oncol. 2025 Feb 25.

TOMM20 as a driver of cancer aggressiveness via oxidative phosphorylation, maintenance of a reduced state, and resistance to apoptosis.

Ranakul Islam, Megan E Roche, Zhao Lin, Diana Whitaker-Menezes, Victor Diaz-Barros, Eurico Serrano, Maria Paula Martinez Cantarin, Nancy J Philp, Atrayee Basu Mallick, Ubaldo Martinez-Outschoorn.

  Chondrosarcomas are common bone sarcomas frequently resistant to radiation and chemotherapy, with high recurrence rates, development of metastatic disease, and death. Fibrosarcomas are soft tissue sarcomas associated with poor outcomes. Translocase of outer mitochondrial membrane receptor 20 (TOMM20) is a mitochondrial receptor protein associated with cancer aggressiveness in many cancer subtypes, but the mechanisms remain poorly understood. Here, we studied the effects of TOMM20 overexpression and downregulation on the redox state, mitochondrial oxidative phosphorylation (OXPHOS), and tumor growth using fibrosarcoma and chondrosarcoma models. TOMM20 overexpression increased OXPHOS, NADH, and NADPH with reduced cellular reactive oxygen species (ROS). TOMM20 induced resistance to apoptosis, including with BCL-2 and OXPHOS complex IV inhibitors, but with increased sensitivity to an OXPHOS complex I inhibitor. Also, TOMM20 induced cell growth and migration in vitro and promoted tumor growth in vivo. Conversely, knocking down TOMM20 using CRISPR-Cas9 reduced cancer aggressiveness in vivo in both chondrosarcoma and fibrosarcoma mouse models. In conclusion, TOMM20 is a driver of cancer aggressiveness by OXPHOS, apoptosis resistance, and the maintenance of a reduced state.

Keywords:  OXPHOS; ROS; TOMM; apoptosis; mitochondria; redox

DOI:  https://doi.org/10.1002/1878-0261.70002
Cells. 2025 Feb 09. pii: 246. [Epub ahead of print]14(4):

BCL-B Promotes Lung Cancer Invasiveness by Direct Inhibition of BOK.

Palaniappan Ramesh, Amal R Al Kadi, Gaurav M Borse, Maximilian Webendörfer, Gregor Zaun, Martin Metzenmacher, Fabian Doerr, Servet Bölükbas, Balazs Hegedüs, Smiths S Lueong, Joelle Magne, Beiyun Liu, Greisly Nunez, Martin Schuler, Douglas R Green, Halime Kalkavan.

  Expression of BCL-B, an anti-apoptotic BCL-2 family member, is correlated with worse survival in lung adenocarcinomas. Here, we show that BCL-B can mitigate cell death initiation through interaction with the effector protein BOK. We found that this interaction can promote sublethal mitochondrial outer membrane permeabilization (MOMP) and consequently generate apoptosis-flatliners, which represent a source of drug-tolerant persister cells (DTPs). The engagement of endothelial-mesenchymal-transition (EMT) further promotes cancer cell invasiveness in such DTPs. Our results reveal that BCL-B fosters cancer cell aggressiveness by counteracting complete MOMP.

Keywords:  BCL-2 family; BCL-B; BOK; DTP; EMT; cancer; drug-resistance; invasiveness; mitochondrial permeabilization; persister phenotype

DOI:  https://doi.org/10.3390/cells14040246
Cells. 2025 Feb 12. pii: 260. [Epub ahead of print]14(4):

Eugenol Promotes Apoptosis in Leukemia Cells via Targeting the Mitochondrial Biogenesis PPRC1 Gene.

Sayer Al-Harbi, Elham M A Alkholiwy, Syed Osman Ali Ahmed, Mahmoud Aljurf, Reem Al-Hejailan, Abdelilah Aboussekhra.

  Acute myeloid leukemia (AML) is a highly heterogenous and aggressive myeloid neoplasm. To sustain growth and survival, AML cells, like other neoplasms, require energy. This process is orchestrated by mitochondria and is under the control of several genes, such as PPRC1 (PRC), a member of the PGC-1 family, which is a key player in the transcription control of mitochondrial biogenesis. We have shown here that eugenol inhibits cell growth and promotes apoptosis through the mitochondrial pathway in AML cell lines as well as in cells from AML patients but not in cells from healthy donors. Similar effects were also observed on cytarabine-resistant AML cells. Interestingly, eugenol downregulated PPRC1 at both the protein and mRNA levels and reduced mitochondrial membrane potential in AML cells. We have also shown that PPRC1 expression is higher in cancer cells from blood, breast, and other types of cancer relative to normal cells, and high PPRC1 levels correlate significantly with short overall survival (OS). In addition, PPRC1 gene mutations significantly correlate with short OS and/or disease-free survival in several cancers. PPRC1 mutations also correlated significantly with poor OS (p < 0.0001) when tested in a total of 23,456 cancer patients. These findings suggest an oncogenic role of PPRC1 in various types of cancer and the possible eugenol-targeting of this gene for the treatment of AML patients, especially those exhibiting resistance to cytarabine.

Keywords:  AML; PPRC1; apoptosis; cancer; eugenol

DOI:  https://doi.org/10.3390/cells14040260
ACS Nano. 2025 Feb 25.

Mitochondrial-Targeted Multifunctional Platinum-Based Nano "Terminal-Sensitive Projectile" for Enhanced Cancer Chemotherapy Efficacy.

Qiang Zhang, Jiamin Lin, Jun Li, Yitian Zhou, Zhiqiang Bi, Hao Yang, Wenli Lu, Tianming Lu, Ruoning Qian, Xi Yang, Yuanyuan Guo, Xiaoqing Xin, Lesan Yan, Shanshan Wang, Ruogu Qi.

  Platinum-based anticancer drugs exert their effects by forming adducts within nuclear DNA (nDNA), inhibiting transcription and inducing apoptosis in cancer cells. However, tumor cells have evolved mechanisms to resist these drugs. Given mitochondria's role in cancer and their lack of nucleotide excision repair (NER), targeting mitochondrial DNA (mtDNA) offers a strategy. Herein, a platinum-based terminal-sensitive projectile (TSB) which comprises a heterofunctional tetravalent platinum prodrug as the primary warhead, complemented by a guidance system incorporating triphenylphosphine (TPP) and a secondary warhead, FFa (Fenofibric acid) was developed. TSB was then encapsulated within IR780 coupling DSPE-PEG2K for enhanced delivery (NTSB). This design allows the TSB to be precisely targeted into intertumoral mitochondria as its targeting terminal, releasing free oxaliplatin (OXA) and FFa upon reaching its terminal destination. The accumulation of OXA leads to cross-linking with mtDNA, causing mitochondrial dysfunction, while FFa disrupts the electron transport chain (ETC), impairing oxidative phosphorylation (OXPHOS). Furthermore, under near-infrared (NIR) irradiation, the IR780 component generates a phototherapeutic thermal effect and reactive oxygen species (ROS), which deplete intracellular glutathione (GSH) levels and facilitate Pt cross-linking with mtDNA. Both in vitro and in vivo studies have demonstrated that this comprehensive approach significantly enhances the sensitivity of tumor cells to platinum-based chemotherapeutic drugs.

Keywords:  cancer chemotherapy; electron transport chain; mitochondrial DNA; nano prodrugs; platinum

DOI:  https://doi.org/10.1021/acsnano.4c15456
Mol Cells. 2025 Feb 20. pii: S1016-8478(25)00022-6. [Epub ahead of print] 100198

Metabolic Regulation by p53: Implications for Cancer Therapy.

Ki Yeon Koo, Kwanho Moon, Hwa Seob Song, Min-Sik Lee.

  The tumor suppressor p53, long known for its roles in maintaining genomic integrity and suppressing tumorigenesis, has recently been recognized as a key regulator of cellular metabolism. Here, we review p53's emerging metabolic functions, highlighting its ability to orchestrate glucose, amino acid, and lipid metabolism. By promoting oxidative phosphorylation while inhibiting glycolysis and anabolic pathways, wild-type p53 counters metabolic reprogramming characteristic of cancer cells, such as the Warburg effect, and protects cells from mild cellular stresses. In contrast, mutant p53 disrupts these processes, fostering metabolic adaptations that support tumor progression. These findings pave the way for therapeutic approaches targeting p53-driven metabolic vulnerabilities in cancer.

Keywords:  Cancer metabolism; Metabolic reprogramming; Tumor suppressor; p53 (TP53)

DOI:  https://doi.org/10.1016/j.mocell.2025.100198
Antioxidants (Basel). 2025 Jan 24. pii: 142. [Epub ahead of print]14(2):

Copper-Induced Enhancement of Glioblastoma Tumorigenicity via Cytochrome C Oxidase.

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

  Copper is an essential trace element, yet chronic copper exposure can lead to toxicity in humans, and high levels of copper have been found in the blood or tumors of patients with various forms of cancer and may affect cancer severity and response to treatment. Copper is required for the activation of cytochrome c oxidase (CcO), the mitochondrial complex that facilitates oxidative phosphorylation (OXPHOS)-mediated ATP production. We recently reported that the increased activation of CcO underlies the acquisition of treatment resistance in glioblastoma (GBM) cells. However, the potential role of copper in GBM progression or treatment resistance has not been investigated. Here, we present evidence that exposure to 20 µM copper, the maximum allowable limit for public water supplies set by the U.S. Environmental Protection Agency, promotes GBM tumor growth and reduces overall survival in vivo and increases GBM cell resistance to radiation and chemotherapy in vitro. In vitro exposure to 20 µM copper substantially increased the activity of CcO, elevated the rate and level of ATP production, and triggered a metabolic shift to an OXPHOS phenotype in GBM cells. Furthermore, copper exposure led to a substantial increase in the accumulation of glutathione and glutathione precursors in these cells. These findings establish copper as a tumor promoter in GBM and suggest that copper mediates these effects through the upregulation of CcO activity, which enhances OXPHOS metabolism and glutathione production.

Keywords:  copper; cytochrome c oxidase; glioblastoma; oxphos

DOI:  https://doi.org/10.3390/antiox14020142
Cells. 2025 Feb 11. pii: 257. [Epub ahead of print]14(4):

How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production.

Raquel Adams, Nasrin Afzal, Mohsin Saleet Jafri, Carmen A Mannella.

  Cells in heart muscle need to generate ATP at or near peak capacity to meet their energy demands. Over 90% of this ATP comes from mitochondria, strategically located near myofibrils and densely packed with cristae to concentrate ATP generation per unit volume. However, a consequence of dense inner membrane (IM) packing is that restricted metabolite diffusion inside mitochondria may limit ATP production. Under physiological conditions, the flux of ATP synthase is set by ADP levels in the matrix, which in turn depends on diffusion-dependent concentration of ADP inside cristae. Computer simulations show how ADP diffusion and consequently rates of ATP synthesis are modulated by IM topology, in particular (i) number, size, and positioning of crista junctions that connect cristae to the IM boundary region, and (ii) branching of cristae. Predictions are compared with the actual IM topology of a cardiomyocyte mitochondrion in which cristae vary systematically in length and morphology. The analysis indicates that this IM topology decreases but does not eliminate the "diffusion penalty" on ATP output. It is proposed that IM topology normally attenuates mitochondrial ATP output under conditions of low workload and can be regulated by the cell to better match ATP supply to demand.

Keywords:  ATP synthesis; cristae; electron tomography; membrane topology; metabolic modeling; metabolite diffusion; mitochondria

DOI:  https://doi.org/10.3390/cells14040257
Mol Carcinog. 2025 Feb 24.

The Role of HADHB in Mitochondrial Fatty Acid Metabolism During Initiation of Metastasis in ccRCC.

Xin Li, Mengmeng Wu, Guijuan Chen, Wenliang Ma, Yi Chen, Yibing Ding, Ping Dong, Weidong Ding, Luqing Zhang, Lei Yang, Weidong Gan, Dongmei Li.

  The initiation and progression of clear cell renal cell carcinoma (ccRCC) are closely linked to significant metabolic alterations. Specifically, lipid metabolism alterations and their association with the high invasiveness in ccRCC require further investigation. After conducting RNA-sequencing (RNA-seq), we discovered that Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Beta (HADHB) was significantly downregulated in the highly invasive ccRCC cell line. It was found that the expression of HADHB in ccRCC tumor tissues was lower than that in paracancer tissues, which is associated with poor patient prognosis. Subsequently, we confirmed that highly invasive ccRCC exhibited an increased lipid accumulation due to the suppression of mitochondrial fatty acid transport and enhanced conversion of fatty acids to triglycerides within cancer cells. Specifically, the downregulation of HADHB inhibited mitochondrial fatty acid β-oxidation (FAO) in cancer cells, leading to partial impairment of mitochondrial function and decreased ATP production. However, this trade-off involving the reduction of a high-yield ATP production conferred an advantage by reducing reactive oxygen species (ROS) generation within cancer cells, thereby protecting them from oxidative stress and enhancing their invasive potential. Furthermore, the downregulation of HADHB promoted epithelial-mesenchymal transition (EMT) and angiogenesis in cancer cells, accelerating the progression of ccRCC and endowing ccRCC cells with metastatic capabilities.

Keywords:  clear cell renal cell carcinoma; epithelial−mesenchymal transition; fatty acid β‐oxidation; metabolic reprogramming; tumor metastasis

DOI:  https://doi.org/10.1002/mc.23898
Mol Ther Nucleic Acids. 2025 Mar 11. 36(1): 102449

Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells.

Kyrie Wilson, Charles Holjencin, Hwaran Lee, Balasubramaniam Annamalai, Masaaki Ishii, Jeremy L Gilbert, Andrew Jakymiw, Bärbel Rohrer.

  Gene therapy approaches for mitochondrial DNA (mtDNA)-associated damage/diseases have thus far been limited, and despite advancements in single gene therapy for mtDNA mutations and progress in mitochondrial transplantation, no method exists for restoring the entire mtDNA molecule in a clinically translatable manner. Here, we present for the first time a strategy to deliver an exogenous, fully intact, and healthy mtDNA template into cells to correct endogenous mtDNA mutations and deletions, with the potential to be developed into an efficient pan-therapy for inherited and/or acquired mtDNA disorders. More specifically, the novel therapeutic nanoparticle complex used in our study was generated by combining a cell-penetrating peptide (CPP) with purified mtDNA, in conjunction with a mitochondrial targeting reagent. The generated nanoparticle complexes were found to be taken up by cells and localized to mitochondria, with exogenous mtDNA retention/maintenance, along with mitochondrial RNA and protein production, observed in mitochondria-depleted ARPE-19 cells at least 4 weeks following a single treatment. These data demonstrate the feasibility of restoring mtDNA in cells via a CPP carrier, with the therapeutic potential to correct mtDNA damage independent of the number of gene mutations found within the mtDNA.

Keywords:  MT: Delivery Strategies; age-related diseases; cell-penetrating peptide; mitochondria; mitochondrial DNA; mitochondrial transplantation; mtDNA; mtDNA gene therapy; mtDNA mutations; nucleic acid delivery

DOI:  https://doi.org/10.1016/j.omtn.2025.102449
Nature. 2025 Feb 26.

A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.

Hefei Zhang, Xuhang Li, L Tenzin Tseyang, Gabrielle E Giese, Hui Wang, Bo Yao, Jingyan Zhang, Rachel L Neve, Elizabeth A Shank, Jessica B Spinelli, L Safak Yilmaz, Albertha J M Walhout.

Metabolic flux, or the rate of metabolic reactions, is one of the most fundamental metrics describing the status of metabolism in living organisms. However, measuring fluxes across the entire metabolic network remains nearly impossible, especially in multicellular organisms. Computational methods based on flux balance analysis have been used with genome-scale metabolic network models to predict network-level flux wiring1-6. However, such approaches have limited power because of the lack of experimental constraints. Here, we introduce a strategy that infers whole-animal metabolic flux wiring from transcriptional phenotypes in the nematode Caenorhabditis elegans. Using a large-scale Worm Perturb-Seq (WPS) dataset for roughly 900 metabolic genes7, we show that the transcriptional response to metabolic gene perturbations can be integrated with the metabolic network model to infer a highly constrained, semi-quantitative flux distribution. We discover several features of adult C. elegans metabolism, including cyclic flux through the pentose phosphate pathway, lack of de novo purine synthesis flux and the primary use of amino acids and bacterial RNA as a tricarboxylic acid cycle carbon source, all of which we validate by stable isotope tracing. Our strategy for inferring metabolic wiring based on transcriptional phenotypes should be applicable to a variety of systems, including human cells.

DOI: https://doi.org/10.1038/s41586-025-08635-6
Cell Stem Cell. 2025 Feb 17. pii: S1934-5909(25)00013-X. [Epub ahead of print]

Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.

Zemin Song, Yali Cui, Lilan Xin, Ruijing Xiao, Jingjing Feng, Conghui Li, Zhinang Yin, Honghong Wang, Qiuzi Li, Mengxuan Wang, Baoyi Lin, Yiming Zhang, Ying Zhou, Li Huang, Yanli He, Xiaoqing Li, Xiaoyan Liu, Shangqin Liu, Fuling Zhou, Zheng Liu, Hai-Bing Zhou, Pingping Fang, Kaiwei Liang.

  Mitochondria are integrated within the cytoskeleton for structural integrity and functional regulation, yet the pathological exploitation of these interactions in cell fate decisions remains largely unexplored. Here, we identify a cytoskeleton-mitochondria remodeling mechanism underlying leukemic transformation by the core-binding factor subunit beta and smooth muscle myosin heavy-chain fusion (CBFβ-SMMHC). This chimera reconstructs a cytosolic filamentous cytoskeleton, inducing NMIIA phosphorylation and INF2-dependent filamentous actin (F-actin) assembly, which enhance cellular stiffness and tension, leading to calcium-mediated mitochondrial constriction, termed cytoskeletal co-option of mitochondrial constriction (CCMC). CCMC can also be triggered through diverse approaches independent of CBFβ-SMMHC, reconstructing a similar cytoskeleton and recapitulating acute myeloid leukemia (AML) with consistent immunophenotypes and inflammatory signatures. Notably, CCMC generates TOM20-PDH+mtDNA+ mitochondrial-derived vesicles that activate cGAS-STING signaling, with Sting knockout abrogating CCMC-induced leukemogenesis. Targeted inhibition of CCMC or STING suppresses AML propagation while sparing normal hematopoiesis. These findings establish CCMC as an intrinsic mechano-oncogenic process linking genetic mutations with cytoskeletal remodeling to oncogenic transformation, highlighting its promise as a therapeutic target.

Keywords:  CBFβ-SMMHC; CCMC; HSPCs; MDV; cGAS-STING signaling; cytoskeletal co-option of mitochondrial constriction; cytoskeleton; hematopoietic stem and progenitor cells; mitochondrial-derived vesicle

DOI:  https://doi.org/10.1016/j.stem.2025.01.013
Lipids Health Dis. 2025 Feb 27. 24(1): 76

Total cardiolipin levels in gastric and colon cancer: evaluating the prognostic potential.

Pavels Dimitrijevs, Ilona Freiliba, Andrejs Pčolkins, Marcis Leja, Pavel Arsenyan.

   BACKGROUND: Cardiolipin (CL) is a signature phospholipid of mitochondria that maintains the integrity of mitochondrial membrane and supports proper mitochondrial function. Alterations in CL level and composition can impair or, conversely, improve mitochondrial function and bioenergetics, both of which are critical for cancer metabolism. However, conflicting reports on CL levels across different cancer types and limited research using human patient samples limit our understanding of its diagnostic potential.
METHODS: This cross-sectional study explores CL concentrations in gastric and colon cancer tissues using a CL-specific fluorescent probe MitoCLue and compares them to adjacent healthy tissues.
RESULTS: In gastric cancer, CL levels showed no significant differences between tumor and healthy tissues, suggesting that metabolic shifts in gastric cancer do not affect total CL content. In contrast, colon cancer tissues exhibited a significant 33% increase in CL levels, indicating mitochondrial adaptation and/or increase in mitochondrial mass in colon cancer. No associations were found between CL levels and patient demographic factors; although a weak correlation with body mass index was noted.
CONCLUSION: We successfully applied MitoCLue to quantitatively assess the total CL level in healthy and tumor tissues from patients with gastric or colon cancer. The distinct CL levels in gastric and colon cancer suggest that there are cancer-type specific mitochondrial adaptations, reflecting unique bioenergetic demands and metabolic reprogramming pathways. While a 33% increase in CL levels was observed in colon cancer tissues compared to healthy adjacent tissues, this modest variation may limit its utility as a standalone biomarker.

Keywords:  Biomarker; Cardiolipin; Colon cancer; Diagnostic; Gastric cancer

DOI:  https://doi.org/10.1186/s12944-025-02499-5
Cell Stem Cell. 2025 Feb 19. pii: S1934-5909(25)00012-8. [Epub ahead of print]

Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.

Indranil Singh, Daniel Fernandez-Perez, Pedro Sanchez Sanchez, Alejo E Rodriguez-Fraticelli.

  Cancer cells display wide phenotypic variation even across patients with the same mutations. Differences in the cell of origin provide a potential explanation, but traditional assays lack the resolution to distinguish clonally heterogeneous subsets of stem and progenitor cells. To address this challenge, we developed simultaneous tracking of recombinase activation and clonal kinetics (STRACK), a method to trace clonal dynamics and gene expression before and after the acquisition of cancer mutations. Using mouse models, we studied two leukemic mutations, Dnmt3a-R878H and Npm1c, and found that their effect was highly variable across different stem cell states. Specifically, a subset of differentiation-primed stem cells, which normally becomes outcompeted with time, expands with both mutations. Intriguingly, Npm1c mutations reversed the intrinsic bias of the clone of origin, with differentiation-primed stem cells giving rise to more primitive malignant states. Thus, we highlight the relevance of single-cell lineage tracing to unravel early events in cancer evolution and posit that different cellular histories carry distinct cancer phenotypic potential.

Keywords:  Dnmt3a; Npm1; cancer initiation; cell barcoding; cell of origin; clonal hematopoiesis; lineage tracing; myeloid leukemia; myeloid malignancies; single-cell

DOI:  https://doi.org/10.1016/j.stem.2025.01.012
Cell Metab. 2025 Feb 20. pii: S1550-4131(25)00017-8. [Epub ahead of print]

MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.

Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Luca Scorrano, Maria Eugenia Soriano.

  Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.

Keywords:  ATAD3A; OPA1; cristae remodeling; interactome; mitochondria; mitochondrial complexes; mitoribosome stability

DOI:  https://doi.org/10.1016/j.cmet.2025.01.017
Future Oncol. 2025 Feb 26. 1-6

Risk-stratified treatment of sonrotoclax with chemotherapy in newly diagnosed acute myeloid leukemia: a study protocol.

Yunxiang Zhang, Min Wu, Zhen Jin, Li Yang, Xufei Huang, Weiming Li, Hongming Zhu, Wenfang Wang, Qiusheng Chen, Ligen Liu, Zhichao Chen, Shaoyuan Wang, Junmin Li.

  Acute myeloid leukemia (AML) treatment relied on anthracyclines and cytarabine based intensive chemotherapy. However, clinical outcomes are unsatisfied for patients with intermediate/adverse cytogenetics based on European Leukemia Net (ELN) risk stratification 2022 (ELN 2022), and relapses also remain common even in patients with favorable-risk cytogenetics with measurable residual disease (MRD). There is an urgent unmet need for optimizing intensive chemotherapy regimens with novel agents, to enhance the MRD-negative rate, achieve durable remission, and improve the prognosis of AML. Preliminary results showed that adding a B-cell lymphoma-2 (BCL-2) inhibitor to intensive chemotherapy could improve treatment efficacy. Sonrotoclax is a potent, selective, next-generation BCL-2 inhibitor that effectively inhibits both the wide-type BCL-2 and several BCL-2 mutants. We hypothesize that the addition of sonrotoclax to intensive chemotherapy may enhance the treatment efficacy for AML without untoward toxicity. Here, we describe the rationale and design of a single-arm, multicenter, phase 2 study evaluating the efficacy and safety of sonrotoclax combined with chemotherapy as an induction therapy in newly diagnosed patients with AML who are fit for intensive chemotherapy, followed by stratified subsequent consolidation and maintenance treatment based on patients' ELN2022 at diagnosis and MRD results after induction.Clinical Trail Registration: NCT06497062.

Keywords:  Acute myeloid leukemia; B-cell lymphoma-2 inhibitor; European Leukemia Net; intensive chemotherapy; measurable residual disease; risk stratification; sonrotoclax

DOI:  https://doi.org/10.1080/14796694.2025.2469487
Cancer Lett. 2025 Feb 25. pii: S0304-3835(25)00150-8. [Epub ahead of print] 217586

SQLE-catalyzed squalene metabolism promotes mitochondrial biogenesis and tumor development in K-ras-driven cancer.

Junchen Pan, Rui Liu, Wenhua Lu, Hongyu Peng, Jing Yang, Qianrui Zhang, Tiantian Yu, Bitao Huo, Xiaoying Wei, Haixi Liang, Lin Zhou, Yameng Sun, Yumin Hu, Shijun Wen, Jie Fu, Paul J Chiao, Xiaojun Xia, Jinyun Liu, Peng Huang.

  It is well known that activation of oncogenic K-ras alone is insufficient to drive tumor development and that additional factors are needed for full malignant transformation, but the metabolic pathways and regulatory mechanisms that facilitate K-ras-driven cancer development remain to be characterized. Here we show that SQLE, a key enzyme in cholesterol synthesis, is upregulated in K-ras-driven cancer and its high expression is correlated with poor clinical outcome. K-ras regulates SQLE expression in a biphasic manner through reactive oxygen species and MYC signaling. Surprisingly, the pro-oncogenic role of SQLE is not mediated by promoting cholesterol synthesis, but by metabolic removal of squalene and thus mitigating its suppressive effect on the PGC-1α-mediated mitochondrial biogenesis and metabolism. Genetic silencing of SQLE in pancreatic cancer cells causes an accumulation of cellular squalene, which binds to Sp1 protein and causes a formation of a tight Sp1-TFAP2E promoter DNA complex with a highly negative binding score. This aberrant squalene/Sp1/ TFAP2E promoter complex hinders the expression of TFAP2E and its downstream molecule PGC-1α, leading to suppression of mitochondrial metabolism and an almost complete inhibition of tumor formation in vivo. Importantly, administration of pharmacological squalene to mice bearing pancreatic cancer xenografts could significantly inhibit tumor growth. Our study has revealed a previously unrecognized role of SQLE in regulating gene expression and mitochondrial metabolism to facilitate K-ras-driven cancer development, and identified SQLE as a novel therapeutic target for potential treatment of pancreatic cancer.

Keywords:  K-ras; PGC-1α; SQLE; Sp1; mitochondria; pancreatic cancer; squalene

DOI:  https://doi.org/10.1016/j.canlet.2025.217586
Stem Cell Res Ther. 2025 Feb 23. 16(1): 87

Transplantation of gastric epithelial mitochondria into human gastric cancer cells inhibits tumor growth and enhances chemosensitivity by reducing cancer stemness and modulating gastric cancer metabolism.

Hsin-Yi Tsai, Kuen-Jang Tsai, Deng-Chyang Wu, Yaw-Bin Huang, Ming-Wei Lin.

   BACKGROUND: Gastric cancer is the malignant disease. The problems associated with cancer stemness and chemotherapy resistance in gastric cancer therapy remain unresolved. Glucose-regulated protein 78 (GRP78) is a biomarker of gastric cancer and modulates cancer stemness and chemoresistance. Previous studies have shown that mitochondrial transplantation from healthy cells is a promising method for treating various diseases and that the regulation of mitochondrial metabolism is crucial for modulating the stemness and chemoresistance of cancer cells. The aim of this study was to investigate the therapeutic effect of mitochondrial transplantation from normal gastric epithelial cells into gastric cancer and the associated mechanisms.
METHODS: The expression of cancer stemness markers, intracellular oxidative stress, or apoptotic-related proteins were evaluated via flow cytometry. Western blotting was used to investigate the molecular mechanism involved in MKN45 or AGS human gastric cancer cells after transplantation with human gastric epithelial mitochondria. The mitochondrial metabolic function of gastric cancer cells was determined via a Seahorse bioanalyzer, and extracellular lactate was evaluated via bioluminescent assay. The viability of 5-fluorouracil (5-FU)-treated gastric cancer cells was detected via a CCK-8 assay. Furthermore, a xenograft tumor animal study was performed to validate the therapeutic effects of human gastric epithelial mitochondrial transplantation in gastric cancer. Immunohistochemistry and Western blotting were then used to assess the expressions related to cancer stemness and mitochondrial metabolism-related proteins in tumor tissues.
RESULTS: Transplanting human gastric epithelial mitochondria downregulates gastric cancer mitochondrial biogenesis, glycolysis, GRP78-mediated cancer stemness, and increases oxidative stress, cell apoptosis under hypoxic conditions and chemosensitivity in response to 5-FU treatment. Moreover, the transplantation of epithelial mitochondria into gastric tumors inhibited the tumor growth in vivo tumor graft animal models. Therefore, mitochondrial transplantation can be considered for the treatment of gastric cancer.

Keywords:  Apoptosis; Cancer stemness; Chemoresistance; GRP78; Gastric cancer; Metabolism; Mitochondrial transplantation

DOI:  https://doi.org/10.1186/s13287-025-04223-7
Transl Oncol. 2025 Feb 21. pii: S1936-5233(25)00061-0. [Epub ahead of print]54 102330

Mitochondrial metabolism-related features guiding precision subtyping and prognosis in breast cancer, revealing FADS2 as a novel therapeutic target.

Yakun Kang, You Meng, Jiangdong Jin, Yuhan Dai, Fei Li, Nuo Chen, Hui Xie, Yangyang Cui.

   BACKGROUND: Breast cancer is one of the most prevalent malignant tumors in women. Mitochondria, essential for cellular function, have altered metabolic activity in cancer cells, influencing tumor regulation and clinical outcomes. The connection between mitochondrial metabolism-related genes and breast cancer prognosis remains underexplored. This study aims to investigate the role of these genes in breast cancer by constructing risk models.
METHODS: Breast cancer transcriptome data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and mitochondrial gene data were sourced from the MitoCarta3.01 database. Clustering analysis was conducted using the "ConsensusClusterPlus" package, followed by Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. A prognostic model was built using Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) algorithms. Immune cell infiltration levels were assessed via CIBERSORT and MCPcounter algorithms. Validation of key gene expression was performed on breast cancer tissue specimens and cell models to explore their biological functions in breast cancer cells.
RESULTS: The LASSO regression analysis of the TCGA BRCA dataset identified four prognosis-related mitochondrial metabolism genes: MYH11, LTF, FADS2, and PSPHP1. Validation using the GEO dataset confirmed that patients with high-risk scores (based on these four genes) had shorter overall survival compared to those with lower risk scores. Immunological analysis revealed that high-risk patients were less responsive to immunotherapy but more sensitive to conventional chemotherapies. This suggests that combining chemotherapy with immunotherapy might enhance T cell-based treatments. Univariate and multivariate Cox regression confirmed that the mitochondrial gene model was an independent predictor of overall survival, and a nomogram was developed to predict patient prognosis. Tissue validation showed consistent expression patterns with bioinformatic predictions. Functional assays confirmed that FADS2 was highly expressed in breast cancer cells, and its knockout significantly reduced cell invasion, migration, and colony formation.
CONCLUSION: This study reveals that mitochondrial metabolism-related genes are closely associated with breast cancer progression, clinical outcomes, and genetic alterations. The findings may offer new avenues for treatment strategies, early intervention, and prognosis prediction in breast cancer.

Keywords:  Breast cancer; FADS2; Immune infiltration; Mitochondrial metabolism; Prognostic features

DOI:  https://doi.org/10.1016/j.tranon.2025.102330
Cancer Res. 2025 Feb 24.

Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer.

Yanyun Lin, Yanhong Zhang, Tianze Huang, Junguo Chen, Guanman Li, Bin Zhang, Liang Xu, Kai Wang, Hui He, Hao Chen, Danling Liu, Shuang Guo, Xiaosheng He, Ping Lan.

Metabolic reprogramming is a hallmark of cancer. Rewiring of amino acid metabolic processes provides the basis for amino acid deprivation therapies. In this study, we found that arginine biosynthesis is limited in colorectal cancer (CRC) due to the deficiency of ornithine transcarbamylase (OTC). Accordingly, CRC cells met the demand for arginine by increasing external uptake. The addiction to environmental arginine resulted in the susceptibility of CRC to arginine deprivation, which dramatically decreased proliferation in CRC cells and promoted these cells to enter a reversible quiescence state. Arginine deprivation induced quiescence by activating the AMPK-p53-p21 pathway. RNA sequencing data indicated that CRC cells may be vulnerable to ferroptosis during arginine deprivation, and the combination of ferroptosis inducers and arginine deprivation strongly impeded tumor growth in vivo. These findings suggest that dietary modification combined with ferroptosis induction could be a potential therapeutic strategy for CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1940
J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00208-X. [Epub ahead of print] 108359

Viperin expression leads to downregulation of mitochondrial genes through misincorporation of ddhCTP by mitochondrial RNA polymerase.

Srijoni Majhi, Pronay Roy, Minshik Jo, Jiying Liu, Rebecca Hurto, Lydia Freddolino, E Neil G Marsh.

Increasing lines of evidence link the expression of the interferon-stimulated gene RSAD2, encoding the antiviral enzyme, viperin, to autoimmune disease. Autoimmune diseases are characterized by chronic over-production of cytokines such as interferons that upregulate the inflammatory response. Immune cells exposed to interferon selectively downregulate transcription of the mitochondrially-encoded components of the oxidative phosphorylation system, which leads to mitochondria becoming dysfunctional and impairing their ability to produce ATP. But the mechanism by which downregulation occurs has remained unknown. Here we show that 3'-deoxy-3',4'-didehydrocytidine triphosphate (ddhCTP) which is synthesized by viperin suppresses mitochondrial transcription by causing premature chain termination when misincorporated by the mitochondrial RNA polymerase (POLRMT). We show that expression of viperin in human cell lines downregulates mitochondrially encoded gene expression. A similar effect is observed across multiple cell lines when cells are exposed to ddhC, the precursor to ddhCTP. The pattern of gene downregulation fits well with a simple, quantitative model describing chain-termination. In vitro measurements with purified POLRMT demonstrate that ddhCTP competes effectively with CTP, leading to its misincorporation into RNA. These findings reveal a new molecular mechanism for mitochondrial transcriptional regulation that explains the reduction in mitochondrially-encoded transcript levels in response to chronic interferon stimulation, characteristic of inflammatory diseases.

DOI: https://doi.org/10.1016/j.jbc.2025.108359
Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00036-4. [Epub ahead of print]

ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.

Philippe Pihán, Lisa M Ellerby, Claudio Hetz.

  Tight mitochondria-endoplasmic reticulum (ER) contacts (MERCS) play essential roles in cellular homeostasis. Brar et al. reveal a novel mechanism where mitochondrial mRNAs escape global translational repression at novel context-specific MERCS during ER stress, uncovering spatially regulated translation as a critical adaptive strategy to cope with cellular stress.

Keywords:  ATAD3A; PERK; endoplasmic reticulum stress; mitochondria–ER contact sites (MERCS); spatial translation regulation

DOI:  https://doi.org/10.1016/j.tcb.2025.02.002
Biomedicines. 2025 Jan 24. pii: 292. [Epub ahead of print]13(2):

β-Catenin Regulates Glycolytic and Mitochondrial Function in T-Cell Acute Lymphoblastic Leukemia.

Ling Zhang, Yu Zhao, Shuoting Wang, Jian Zhang, Xiaohui Li, Shuangyin Wang, Taosheng Huang, Jinxing Wang, Jiajun Liu.

  Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by a poor prognosis. β-catenin is implicated in the progression of T-ALL, yet the precise mechanisms of β-catenin involvement in the pathogenesis of T-ALL, particularly concerning metabolic processes, remain inadequately elucidated. Methods: A β-catenin knockout cell line was generated in the human leukemic cell line Jurkat using the CRISPR-Cas9 technique. Subsequently, assays were performed to evaluate cell proliferation, apoptosis, and metabolic activity. Comparative transcriptomic analysis was conducted between control cells and β-catenin knockout cells. Finally, a mouse xenograft model was employed to assess whether β-catenin knockout attenuates tumor growth and infiltration in vivo. Results: The deletion of β-catenin significantly inhibited proliferation and induced apoptosis. Additionally, the silencing of β-catenin led to the inhibition of glycolysis and a reduction in both mitochondrial mass and membrane potential. These results indicate that β-catenin may play a crucial role in regulating cell proliferation and apoptosis through the modulation of glycolytic activity and mitochondrial function in T-ALL. Conclusions: In summary, our findings uncover a novel mechanism by which β-catenin influences glycolysis and mitochondrial function in the progression of T-ALL, thereby identifying a potential therapeutic target for patients with relapsed T-ALL.

Keywords:  T-cell acute lymphoblastic leukemia; glycolysis; mitochondrial function; β-catenin

DOI:  https://doi.org/10.3390/biomedicines13020292
Leukemia. 2025 Feb 25.

Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia.

Courtney D DiNardo, Wei-Ying Jen, Koichi Takahashi, Tapan M Kadia, Sanam Loghavi, Naval G Daver, Lianchun Xiao, Patrick K Reville, Ghayas C Issa, Nicholas J Short, Koji Sasaki, Sa A Wang, Jillian K Mullin, Sherry Pierce, Corey Bradley, Gautam Borthakur, Abhishek Maiti, Yesid Alvarado, Naveen Pemmaraju, Alessandra Ferrajoli, Mahesh Swaminathan, Maro Ohanian, Hussein A Abbas, Danielle Hammond, Jan Burger, Fadi Haddad, Guillermo Montalban-Bravo, Kelly Chien, Lucia Masarova, Musa Yilmaz, Nitin Jain, Michael Andreeff, Guillermo Garcia-Manero, Steven Kornblau, Farhad Ravandi, Elias Jabbour, Marina Y Konopleva, Hagop M Kantarjian.

Intensive chemotherapy remains the standard for newly diagnosed (ND) acute myeloid leukemia (AML); however, relapse risk remains high. Additionally, most patients with relapsed/refractory (RR) AML have poor outcomes. We report the long-term experience of 138 patients, 77 ND and 61 RR, treated with FLAG-IDA in combination with venetoclax. In the ND cohort, the overall response rate (ORR) was 97%, with a composite complete remission (CRc) rate of 95% and undetectable measurable residual disease (MRD) status by flow cytometry in 90%. The 3-year OS and EFS rates were 66 and 64%, respectively. Outcomes were similar across European LeukemiaNet (ELN) 2022 risk groups. Sixty-four percent transitioned to allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR1. In the RR cohort, the ORR was 67%; CRc rate 41% and flow negative MRD rate 74%; 57% transitioned to allo-SCT. The patients with RR AML in first salvage with wild-type TP53 status had particularly favorable outcomes, with an ORR of 79%, CRc rate of 74% (76% MRD undetectable) and 3-year OS rate of 51%. Infectious and hematologic adverse events were common, with low 30- and 60-day mortality similar to other intensive chemotherapy regimens. FLAG-IDA + VEN is effective for remission induction in both ND and RR AML.ClinicalTrials.gov Identifier: NCT03214562.

DOI: https://doi.org/10.1038/s41375-025-02531-8
J Chem Inf Model. 2025 Feb 26.

Redox-Activated Proton Transfer through a Redundant Network in the Qo Site of Cytochrome bc1.

Guilherme M Arantes.

Proton translocation catalyzed by cytochrome bc1 (respiratory complex III) during coenzyme-Q redox cycling is a critical bioenergetic process, yet its detailed molecular mechanism remains incompletely understood. In this study, the energetics of the long-range proton transfers through multiple proton-conducting wires in the Qo site of the bc1 complex was investigated computationally using hybrid QM/MM simulations and a specialized reaction coordinate. Key reactive groups and proton transfer mechanisms were characterized, confirming the propionate-A group of heme bL as a plausible proton acceptor. Upon coenzyme-Q oxidation, a Grotthuss hopping mechanism is activated, facilitating proton transfer along three distinct pathways with comparable barriers and stability. These pathways operate redundantly, forming a robust proton-conducting network, and account for the unusual experimental behavior observed in single-point mutations. Energetic analyses exclude charged closed-shell species as likely intermediates and propose a reaction sequence for coenzyme-Q oxidation proceeding as QH2 → QH• → Q0, either via coupled proton-electron transfers or stepwise mechanisms involving open-shell intermediates. These findings elucidate mechanistic details of the Q-cycle and improve our understanding of the catalytic reactions supporting redox-activated proton transfer in respiratory enzymes.

DOI: https://doi.org/10.1021/acs.jcim.4c02361