bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–11–16
sixteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.
  2. The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.
  3. Tumour sampling conditions perturb the metabolic landscape of clear cell renal cell carcinoma.
  4. Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
  5. Androgen receptors promote oxidative phosphorylation and resistance to palmitate lipotoxicity in ER-mutant breast cancer.
  6. The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
  7. Monitoring the complexity and dynamics of mitochondrial translation.
  8. Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
  9. The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs.
  10. Development of a novel prognostic prediction model using mitochondrial-related genes and single-cell sequencing data for colorectal carcinoma.
  11. PTEN Loss Promotes PI3Kβ Phosphorylation and EPHA2/SRC/p-PI3KβY962 Complex Assembly to Drive Tumorigenesis.
  12. Cellular cAMP Content and Mitochondrial Profile Define Different Subtypes of Ovarian Cancer Cells.
  13. Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
  14. Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort.
  15. Therapeutic remodeling of the ceramide backbone prevents kidney injury.
  16. Reversing the Warburg effect: Discovery of potent pyruvate dehydrogenase kinase inhibitors for inhibiting tumor growth.
  1. Blood. 2025 Nov 14. pii: blood.2025028933. [Epub ahead of print]
    Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.
    Tianyi Ling, Cristiana O'Brien, Jonathan St-Germain, Vincent Rondeau, Mary Shi, Jacob M Berman, Adrianna Kinga Cepa, Paula Saez Raez, Mark Wunderlich, Katharine Carter, Cody Stillwell, Christina R Sexton, Rachel Culp-Hill, Julie A Reisz, Saeer A Adeel, Andy G X Zeng, Suraj Bansal, Emily Tsao, He Tian Tony Chen, John E Dick, Mark D Minden, Andrea Arruda, Maria L Amaya, Anastasia N Tikhonova, Kristin Hope, Angelo D'Alessandro, Brian Raught, Courtney L Jones.
      Acute myeloid leukemia (AML) patients have a poor five-year survival rate highlighting the need for the identification of new approaches to target this disease. AML is highly dependent on glutathione (GSH) metabolism for survival. While the metabolic role of GSH is well-characterized in AML, the contribution of protein glutathionylation-a reversible modification that protects protein thiols from oxidative damage-remains largely unexplored. Therefore, we sought to elucidate the role of protein glutathionylation in AML pathogenesis. Here, we demonstrate that protein glutathionylation is essential for AML cell survival. Specifically, the loss of glutaredoxin 2 (GLRX2), an enzyme that removes glutathione modifications, resulted in selective primary AML cell death while sparing normal human hematopoietic stem and progenitor cells. Unbiased proteomic analysis revealed increased mitochondrial protein glutathionylation upon GLRX2 depletion, accompanied by mitochondrial dysfunction, including impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and increased opening of the mitochondrial permeability transition pore (mPTP). Further investigation identified ATP5PO, a key regulator of mPTP opening and a component of the ATP synthase complex, as a critical GLRX2 target. Disruption of ATP5PO glutathionylation partially restored mPTP function and rescued AML cell viability following GLRX2 depletion. Moreover, both genetic and pharmacologic inhibition of mPTP opening restored the leukemic potential of primary AML specimens in the absence of GLRX2. By disrupting glutathionylation-dependent mitochondrial homeostasis, this study reveals a novel vulnerability in AML that could inform future therapeutic strategies.
    DOI:  https://doi.org/10.1182/blood.2025028933
  2. Sci Adv. 2025 Nov 14. 11(46): eadx7809
    The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.
    Sukrut C Kamerkar, Taewook Kang, Radu V Stan, Edward J Usherwood, Henry N Higgs.
      Mitochondria are pivotal regulators of cellular homeostasis, integrating energy metabolism, biosynthesis, and programmed cell death (apoptosis). During apoptosis, mitochondrial outer membrane permeabilization by BCL-2-associated X protein/BCL-2 Homolog Antagonist Killer (BAX/BAK) pores facilitates release of apoptotic factors, while the role of inner mitochondrial membrane (IMM) remodeling remains less understood. Here, we identify serine beta-lactamase-like protein (LACTB), a filament-forming serine protease and tumor suppressor, as a regulator of IMM dynamics during apoptosis. LACTB suppression reduces cytochrome c release and apoptosis, whereas its overexpression promotes these effects. LACTB does not affect BAX or Drp1 recruitment to mitochondria. Rather, LACTB is required for apoptosis-induced mitochondrial remodeling, independent of OPA1 processing. Intriguingly, LACTB knockdown does not affect mitochondrial shape changes induced by CCCP treatment, suggesting that LACTB action is apoptosis-specific. Purified LACTB binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes, suggesting a direct effect in apoptotic membrane remodeling. Collectively, our findings suggest LACTB to be a mediator of apoptosis-induced IMM remodeling, a possible mechanism for tumor suppression in cancer.
    DOI:  https://doi.org/10.1126/sciadv.adx7809
  3. Nat Commun. 2025 Nov 10. 16(1): 9896
    Tumour sampling conditions perturb the metabolic landscape of clear cell renal cell carcinoma.
    Cissy Yong, Christina Schmidt, Ming Yang, Alexander Von Kriegsheim, Anne Y Warren, Shubha Anand, James N Armitage, Antony C P Riddick, Thomas J Mitchell, Vishal Patil, Kourosh Saeb-Parsy, Sakari Vanharanta, Grant D Stewart, Christian Frezza.
      Human isotopic tracer studies are key for in vivo studies of cancer metabolism. Yet, the effects of sampling conditions on the tissue metabolome remain understudied. Here, we perform a 13C-glucose study coupled with metabolomic, transcriptomic, and proteomic profiling in patients with clear cell renal cell carcinoma (ccRCC) to assess the impact of ischaemia on tissues sampled intraoperatively and post-surgical resection, where tissues are exposed to varying degrees of warm ischaemia. Although several metabolic features were preserved, including suppressed TCA cycle activity, ischaemia masked other metabolic phenotypes of ccRCC, such as suppressed gluconeogenesis. Notably, normal kidneys were more metabolically susceptible to ischaemia than the ccRCC tumours. Despite their overall stability, ischaemia caused subtle changes in the proteome and transcriptome. Using orthotopic ccRCC-derived xenografts, we evidenced that prolonged ischaemia disrupted the tissue metabolome stability. Overall, minimising tissue ischaemia is pivotal in accurately profiling cancer metabolism in patient studies.
    DOI:  https://doi.org/10.1038/s41467-025-65676-1
  4. Nat Metab. 2025 Nov 13.
    Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
    Abigail Strefeler, Zakery N Baker, Sylvain Chollet, Mads M Foged, Rachel M Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J Pagliarini, Alexis A Jourdain.
      Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited therapeutic target against cancer, autoinflammatory disorders and viral infections. However, regulation of nucleotide metabolism remains incompletely understood. Here, we reveal regulators of de novo pyrimidine synthesis. Using uridine-sensitized CRISPR-Cas9 screening, we show that coenzyme Q (CoQ) is dispensable for pyrimidine synthesis, in the presence of the demethoxy-CoQ intermediate as alternative electron acceptor. We further report that the ADP-ribose pyrophosphatase NUDT5 directly binds PPAT, the rate-limiting enzyme in purine synthesis, which inhibits its activity and preserves the phosphoribosyl pyrophosphate (PRPP) pool. In the absence of NUDT5, hyperactive purine synthesis exhausts the PRPP pool at the expense of pyrimidine synthesis, which promotes resistance to purine and pyrimidine nucleobase analogues. Of note, the interaction between NUDT5 and PPAT is disrupted by PRPP, highlighting an intricate allosteric regulation. Overall, our findings reveal a fundamental mechanism of nucleotide balance and position NUDT5 as a regulator of nucleobase analogue metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01419-2
  5. Endocrinology. 2025 Nov 11. pii: bqaf168. [Epub ahead of print]
    Androgen receptors promote oxidative phosphorylation and resistance to palmitate lipotoxicity in ER-mutant breast cancer.
    Dane T Sessions, Dillon P Boulton, Nicole S Spoelstra, M Cecilia Caino, Min Yu, Andrew Goodspeed, Jennifer K Richer.
      Aromatase inhibitors (AI) are first-line therapy for postmenopausal women with estrogen receptor-expressing (ER+) breast cancer (BC). AI therapy effectively reduces recurrence and extends lifespan for patients with ER+ breast cancer through long term estrogen deprivation (LTED) resulting from inhibition of the enzyme aromatase that converts androgens to estrogens. However, up to 50% of ER+ BC recurs as AI resistant metastatic disease within 10 years of diagnosis. AI resistant BC upregulates androgen receptors (AR) and mitochondrial oxidative phosphorylation (OXPHOS) and requires OXPHOS and fatty acid oxidation (FAO). The liver and lung, common ER+ BC metastatic sites, have high abundance of the saturated fatty acid palmitate (PA). We asked whether AR signaling regulates OXPHOS in the context of LTED. Using mutant ER-expressing MCF7 and T47D BC cell lines with AR antagonism via the anti-androgen enzalutamide and with shRNA knockdown, we demonstrate that AR supports cell growth, OXPHOS, FAO, and resistance to PA lipotoxicity. We identify AR as a positive regulator of the carnitine acyltransferase family enzyme CRAT that promotes OXPHOS capacity. These studies identify AR as pro-tumor in the LTED setting and as a therapeutic target for ER-mutant BC that develops under the selective pressure of AI therapy.
    Keywords:  androgen receptor; breast cancer; estrogen receptor; fatty acid oxidation; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1210/endocr/bqaf168
  6. Sci Adv. 2025 Nov 14. 11(46): eaea4660
    The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
    Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.
    DOI:  https://doi.org/10.1126/sciadv.aea4660
  7. Mol Cell. 2025 Nov 12. pii: S1097-2765(25)00863-9. [Epub ahead of print]
    Monitoring the complexity and dynamics of mitochondrial translation.
    Taisei Wakigawa, Mari Mito, Yushin Ando, Haruna Yamashiro, Kotaro Tomuro, Haruna Tani, Kazuhito Tomizawa, Takeshi Chujo, Asuteka Nagao, Takeo Suzuki, Osamu Nureki, Fan-Yan Wei, Yuichi Shichino, Yuzuru Itoh, Tsutomu Suzuki, Shintaro Iwasaki.
      Since mitochondrial translation leads to the synthesis of the essential oxidative phosphorylation (OXPHOS) subunits, exhaustive and quantitative delineation of mitoribosome traversal is needed. Here, we developed a variety of high-resolution mitochondrial ribosome profiling derivatives and revealed the intricate regulation of mammalian mitochondrial translation. Harnessing a translation inhibitor, retapamulin, our approach assessed the stoichiometry and kinetics of mitochondrial translation flux, such as the number of mitoribosomes on a transcript, the elongation rate, and the initiation rate. We also surveyed the impacts of modifications at the anticodon stem loop in mitochondrial tRNAs (mt-tRNAs), including all possible modifications at the 34th position, in cells deleting the corresponding enzymes and derived from patients, as well as in mouse tissues. Moreover, a retapamulin-assisted derivative and mito-disome profiling revealed mitochondrial translation initiation factor (mtIF) 3-mediated translation initiation from internal open reading frames (ORFs) and programmed mitoribosome collision sites across the mitochondrial transcriptome. Our work provides a useful platform for investigating protein synthesis within the energy powerhouse of the cell.
    Keywords:  MELAS; Ribo-Seq; disome; kinetics; mitochondria; mitoribosomes; mtIF3; ribosome profiling; tRNA modification; translation
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.022
  8. Autophagy. 2025 Nov 13.
    Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
    Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.
      Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.
    Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2589909
  9. Nat Commun. 2025 Nov 14. 16(1): 10012
    The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs.
    Treg Grubb, Pooneh Koochaki, Sayed Matar, Fatme Ghandour, Marc Machaalani, Eddy Saad, Cerise Tang, Eduard Reznik, Jesminara Khatun, Carleigh Salem, Noah Dubasik, David A Orlando, Matthew G Guenther, Gyanu Parajuli, Raghvendra M Srivastava, Steven R Martinez, Jesse A Coker, Ritesh R Kotecha, A Ari Hakimi, John M Asara, Timothy A Chan, Sakari Vanharanta, Shaun R Stauffer, William G Kaelin, Sabina Signoretti, Toni K Choueiri, Abhishek A Chakraborty.
      Epigenetic dysregulation, including accumulation of Histone H3 lysine 27 acetylation (H3K27ac), is a hallmark of pVHL-deficient clear cell Renal Cell Carcinomas (ccRCCs). Using an in vivo positive selection ORF screen in poorly tumorigenic pVHL-proficient cells and mechanistic studies in pVHL-deficient cells, we discovered that the aspartate (Asp) and glutamate (Glu) transporter, SLC1A1/EAAT3, is a metabolic dependency in ccRCC. pVHL loss promotes Hypoxia Inducible Factor (HIF)-independent SLC1A1 expression via H3K27ac dysregulation. SLC1A1 inactivation, genetically or pharmacologically, depletes Asp/Glu-derived metabolites (e.g., Tricarboxylic acid cycle and nucleotide intermediates), impedes ccRCC growth, and sensitizes ccRCCs to anti-metabolite drugs (e.g., glutaminase blockers). In human tumors, higher SLC1A1 expression is associated with reduced immune infiltration, oncogenic metabolic programs, and advanced stage/metastatic disease. Finally, in ccRCC animal models, SLC1A1 inactivation diminishes lung metastasis and the outgrowth of established renal tumors. Altogether, our studies credential SLC1A1 as an actionable, HIF-independent, metabolic dependency in pVHL-deficient ccRCCs.
    DOI:  https://doi.org/10.1038/s41467-025-64983-x
  10. Transl Gastroenterol Hepatol. 2025 ;10 65
    Development of a novel prognostic prediction model using mitochondrial-related genes and single-cell sequencing data for colorectal carcinoma.
    Shuang Xie, Jixin Zhang, Bo Sun, Xiaotian Dong, Xingguo Wang, Jian Song, Chunxu Zhang, Xianli He.
       Background: Colorectal carcinoma (CRC) is a prevalent malignancy worldwide. Due to suboptimal screening practices, CRC is frequently diagnosed at an advanced stage. The role of mitochondrial abnormalities in the advancement of CRC is significant, but the prognostic effect of mitochondrial genes remains unclear. Recent research emphasizes mitochondrial dysfunction's key role in oncogenesis and cancer progression. Mitochondria are vital for cellular metabolism, energy production, and regulating processes like apoptosis, redox homeostasis, and signal transduction. Their dysfunction causes metabolic reprogramming, heightened oxidative stress, and cell death resistance. Though mitochondrial abnormalities link to CRC's aggressive phenotypes, the prognostic value of a comprehensive set of mitochondrial genes remains unclear, leaving a critical knowledge gap. The primary objective of this study was to systematically investigate the prognostic potential of mitochondrial genes in CRC and to develop a novel, reliable risk-scoring model. We aimed to identify key mitochondrial genes associated with patient survival, construct a predictive signature, and validate its efficacy in independently prognosticating overall survival (OS).
    Methods: This study used single-cell RNA sequencing (scRNA-seq) data of CRC tissues from The Cancer Genome Atlas (TCGA), and a comprehensive set of 1,650 mitochondrial genes from MitoCarta 3.0. A differential gene expression analysis, gene set enrichment analysis (GSEA), pathway analysis, and Cox proportional hazards regression analysis were conducted.
    Results: The Cox regression analysis identified five mitochondrial genes (i.e., CPT2, ACSL6, MOCS1, TERT, and PTRH1). These five genes were used to establish a reliable risk-scoring system. Patients with elevated risk scores had more severe clinical manifestations and worse survival outcomes. These results were corroborated in an external validation set (GSE17536 cohort). A predictive model was developed based on these genes that had robust predictive capabilities with areas under the curve (AUCs) of 0.75, 0.77, and 0.78 in the prediction of the 1-, 3-, and 5-year OS of CRC patients, respectively. Additionally, the correlation between the risk score and immune microenvironment characteristics (e.g., immune infiltration patterns, stromal/immune scores) further substantiated the predictive power of the model.
    Conclusions: This study established a novel prognostic model for CRC based on mitochondrial genes, thereby extending the understanding of the disease's progression. Subsequent studies should seek to validate these findings within a broader cohort of patients and explore the potential therapeutic roles of the identified mitochondrial genes in the management of CRC.
    Keywords:  Colorectal carcinoma (CRC); mitochondrial-related genes prediction model; prognosis
    DOI:  https://doi.org/10.21037/tgh-25-89
  11. Cancer Discov. 2025 Nov 17.
    PTEN Loss Promotes PI3Kβ Phosphorylation and EPHA2/SRC/p-PI3KβY962 Complex Assembly to Drive Tumorigenesis.
    Shuang Tang, Qian Zhou, Johann S Bergholz, Tao Jiang, Weihua Wang, Renlei Ji, Wendi Huang, Jiachen Wu, Yutong Li, Xiaochun Wan, Xiadi He, Qianchen Jing, Menghong Sun, Jared L Johnson, Tomer M Yaron-Barir, Da-Qiang Li, Bo Dai, Zefeng Wang, Xiaoling Li, Lewis C Cantley, Thomas M Roberts, Jean J Zhao.
      Loss of tumor suppressor PTEN drives cancer progression and therapeutic resistance, yet no targeted therapies exist for PTEN-deficient tumors. Here, we identify a critical druggable mechanism where PTEN-loss induces PI3Kβ phosphorylation for tumorigenesis. Using BioID interactome, we uncovered phosphorylation-dependent PI3Kβ-EPHA2 interaction in PTEN-null cells, driven by p-PI3KβY962. PTEN functions as a tyrosine phosphatase that normally dephosphorylates p-PI3KβY962. In PTEN-deficient contexts, enhanced p-PI3KβY962 forms a complex with EPHA2 and SRC, where both kinases contribute to PI3Kβ phosphorylation, activating oncogenic pERK/c-MYC and pAKT pathways. We developed a selective p-PI3KβY962 antibody detecting p-PI3KβY962 in PTEN-deficient tumors across preclinical models and clinical tumor specimens. Disrupting p-PI3KβY962 suppressed tumor growth in multiple PTEN-null models. Dasatinib, an FDA-approved SRC/EPHA2 inhibitor, effectively reduced p-PI3KβY962 and inhibited tumor progression in PTEN-null but not PTEN-WT tumors. These findings establish p-PI3KβY962 as a druggable target and biomarker for developing targeted therapy in PTEN-deficient cancers beyond conventional PI3K kinase inhibition.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1126
  12. Int J Mol Sci. 2025 Oct 28. pii: 10474. [Epub ahead of print]26(21):
    Cellular cAMP Content and Mitochondrial Profile Define Different Subtypes of Ovarian Cancer Cells.
    Daniela De Benedictis, Aasia Bibi, Luigi Leonardo Palese, Antonella Cormio, Clara Musicco, Vera Loizzi, Gennaro Cormio, Ali Abdelhameed, Domenico De Rasmo, Anna Signorile.
      Ovarian cancer (OC) is an aggressive and lethal gynecologic cancer due to its asymptomatic nature resulting in a late diagnosis. OC encompasses distinct histological subtypes, with serous OC representing the most common and aggressive form. However, within the same histological OC subtype, additional heterogeneity has been found in terms of genetic mutations and metabolic profiles probably contributing to treatment response. In cancer, metabolic reprogramming strongly involves mitochondria. Mitochondrial function can be regulated by the cAMP pathway, and its deregulation has been reported in various cancers including OC. Here we analyzed two serous OC cell lines, OC316 and OV56, and eleven human OC tissues. OC316 cell lines showed elevated cAMP level with respect to OV56. The high cAMP levels were associated with activation of thecAMP/PKA/CREB/PGC-1α axis resulting in increased mitochondrial biogenesis, respiratory chain activity, modulation of mitochondrial dynamics and apoptosis resistance. Accordingly, principal component analysis (PCA) of the twenty-three biochemical parameters, in eleven human OC tissues, classified OC into two groups showing different cAMP levels associated with distinct mitochondrial profiles. This analysis highlights a cAMP-dependent stratification revealing two mitochondrial subpopulations within serous OC. These findings indicate that the molecular heterogeneity of OC poses a challenge for understanding disease mechanisms and developing effective targeted therapies.
    Keywords:  cAMP; mitochondria; ovarian cancer
    DOI:  https://doi.org/10.3390/ijms262110474
  13. Nature. 2025 Nov 12.
    Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
    Yifan Zhang, Xiao Shen, Yuan Shen, Chao Wang, Chengping Yu, Jiangxue Han, Siyi Cao, Lin Qian, Miaolian Ma, Shijing Huang, Wenyu Wen, Miao Yin, Qun-Ying Lei.
      Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA-NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.
    DOI:  https://doi.org/10.1038/s41586-025-09745-x
  14. J Hematol Oncol. 2025 Nov 14. 18(1): 102
    Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort.
    Jorge Cortes, Antonio Curti, Pierre Fenaux, Brian A Jonas, Jürgen Krauter, Pau Montesinos, Christian Récher, David C Taussig, Eunice S Wang, Justin Watts, Andrew Wei, Karen Wl Yee, Hua Tian, Aaron Sheppard, Christophe Marzac, Stephane de Botton.
       BACKGROUND: Olutasidenib is an oral, selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, phase 2, open-label, multicenter trial.
    METHODS: Results from the pre-planned interim analysis were previously published (data cut-off [DCO]: June 2021). In this final-follow up analysis, we report an additional 2 years of efficacy and safety data (DCO: June 2023).
    RESULTS: At study completion, the overall population included 153 patients (median age, 71 years); 66% had received ≥ 2 prior treatment regimens, and 39% with a hypomethylating agent. Among the 147 efficacy-evaluable patients, 51 achieved complete remission (CR) or CR with partial hematologic recovery (CRh), resulting in a CR/CRh rate of 35% (P < 0.001; 95% CI, 27-43), with 32% of responders achieving CR. The median time to CR/CRh was 1.9 months (range, 0.9-5.6 months). Among responders, 33% achieved CR/CRh within 2-4 months and 12% required ≥ 4 months. The overall response rate (ORR) was 48% (n = 71; 95% CI, 40-56.7). Median duration of CR/CRh was 25.3 months (95% CI, 13.5-not reached), and median overall survival (OS) was 11.5 months (95% CI, 8.3-15.5). Patients with 1-2 prior regimens had a higher CR/CRh rate (41%) and longer median OS (13 months) than those with ≥ 3 prior regimens (CR/CRh: 24%; median OS: 8.9 months). CR/CRh rates were higher among patients with R132C (42%) and R132L/G/S mutations (33%) compared with those harboring R132H mutations (17%). Response rates decreased with increasing numbers of co-mutations. Few new adverse events (AEs) and no treatment discontinuations due to AEs occurred beyond Year 3.
    CONCLUSION: These 5-year data support the durable efficacy and manageable safety profile of olutasidenib in R/R mIDH1 AML, including heavily pretreated patients. Findings highlight the potential role of olutasidenib in earlier lines of treatment, and support sustaining therapy for at least 6 months to allow for a clinical response. Further research is warranted to optimize treatment sequencing and patient selection.
    TRIAL REGISTRATION: NCT02719574.
    Keywords:  Mutant IDH1 inhibitor; Olutasidenib; Relapsed/refractory AML; Targeted therapy
    DOI:  https://doi.org/10.1186/s13045-025-01751-w
  15. Cell Metab. 2025 Nov 12. pii: S1550-4131(25)00440-1. [Epub ahead of print]
    Therapeutic remodeling of the ceramide backbone prevents kidney injury.
    Rebekah J Nicholson, Luis Cedeño-Rosario, J Alan Maschek, Trevor Lonergan, Jonathan G Van Vranken, Angela R S Kruse, Chris J Stubben, Liping Wang, Deborah Stuart, Queren A Alcantara, Monica P Revelo, Kate Rutter, Mayette Pahulu, Jacob Taloa, Xuanchen Wu, Juwan Kim, Juna Kim, Isaac Hall, Amanda J Clark, Samir Parikh, Jeffrey Spraggins, Donna Romero, Jeremy T Blitzer, Steven P Gygi, Jared Rutter, William L Holland, Nirupama Ramkumar, Scott A Summers.
      Perturbation of proximal tubule (PT) lipid metabolism fuels the pathological features of acute kidney injury (AKI). We found that AKI induced biosynthesis of lipotoxic ceramides within PTs in humans and mice and that urine ceramides predicted disease severity in children and adults. Mechanistic studies in primary PTs, which included a thermal proteomic profiling screen for ceramide effectors, revealed that ceramides altered assembly of the mitochondrial contact site and cristae-organizing system (MICOS) and respiratory supercomplexes, leading to acute disruption of cristae architecture, mitochondrial morphology, and respiration. These ceramide actions were dependent on the presence of the 4,5-trans double bond inserted by dihydroceramide desaturase 1 (DES1). Genetically ablating DES1 preserved mitochondrial integrity and prevented kidney injury in mice following bilateral ischemia reperfusion. Moreover, novel DES1 inhibitors that are attractive clinical drug candidates phenocopied the DES1 knockouts. These studies describe a new, therapeutically tractable mechanism underlying PT mitochondrial damage in AKI.
    Keywords:  ETC; MICOS; acute kidney injury; ceramides; cristae; lipid metabolism; lipidomics; metabolism; mitochondria; proximal tubule; sphingolipids
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.006
  16. Bioorg Chem. 2025 Nov 07. pii: S0045-2068(25)01104-6. [Epub ahead of print]167 109224
    Reversing the Warburg effect: Discovery of potent pyruvate dehydrogenase kinase inhibitors for inhibiting tumor growth.
    Meiyan Tang, Yiyang Li, Pengju Ye, Yanliu Peng, Yijia Tang, Zhe Wang, Hongxiang Xiao, Li-Li Wang, Xiaoyong Lei, Zhizhong Xie, Xiaoyan Yang, Guotao Tang, Xiangping Deng.
      Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in tumors, driving cancer progression by promoting the Warburg effect. Consequently, PDK1 inhibition represents a promising anticancer strategy, though potent low-toxicity inhibitors remain scarce. In this study, 20 new derivatives were designed and synthesized through further structural optimization of the dichloroacetate (DCA) derivatives, and their inhibitory effects on PDK1 and anticancer activities were systematically evaluated. Compound D16 emerged as the lead candidate, demonstrating potent PDK1 inhibition (53.20 % at 1 μM), significant suppression of cancer cells proliferation (A549 IC50 = 0.86 μM) and migration. Notably, D16 reverses the Warburg effect, shifting cellular energy metabolism from glycolysis toward oxidative phosphorylation, evidenced by increased acetyl-CoA, reduced lactate, elevated ROS, and induced apoptosis. Importantly, low-dose D16 (20 mg/kg) robustly inhibited tumor growth in vivo without systemic toxicity. These findings establish D16 as a potent PDK1 inhibitor that shifts tumor metabolism, offering a promising therapeutic approach for cancer treatment.
    Keywords:  Anticancer; Pyruvate dehydrogenase kinase 1; Warburg effect
    DOI:  https://doi.org/10.1016/j.bioorg.2025.109224
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