bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–10–04
seventeen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Acanthamoeba ATP synthase structure reveals the TCA cycle is tethered to OXPHOS.
  2. Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition.
  3. A selective inhibitor reveals roles for LONP1 in mitochondrial proteostasis and OXPHOS dependencies.
  4. Hypoxia? NNoT a PROblem!
  5. ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesis and fatty acid oxidation in colorectal cancer.
  6. Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in GNAS (Gαs) mutant pancreas cancer.
  7. Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
  8. Targeting ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia.
  9. Mitochondrial rewiring supports survival of triple negative breast cancer cells after ionizing radiation.
  10. TFAM loss drives oxaliplatin resistance by linking mtDNA release to STING-TBK1-mediated lysophagy.
  11. Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
  12. The Protective Effect of Venetoclax on the Calcium-Induced Mitochondrial Pore and ROS Production as a New Possible Factor Contributing to Drug Resistance.
  13. Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age.
  14. Loss of TCA cycle turning promotes stem cell function.
  15. Glucosylceramide synthase is required for C6-ceramide nanoliposome-induced organelle stress and cell death.
  16. CC-486 plus venetoclax: another step toward oral AML therapy.
  17. Very Long Chain Fatty Acid Synthesis is a Targetable Dependency in RAS Pathway Mutant Leukemia.
  1. Cell. 2026 Oct 01. pii: S0092-8674(26)01068-8. [Epub ahead of print]189(20): 6307-6324.e7
    Acanthamoeba ATP synthase structure reveals the TCA cycle is tethered to OXPHOS.
    MitoCarta Tree of Life Consortium
      Oxidative phosphorylation (OXPHOS) is a key metabolic process that couples redox energy to ATP production. While some core OXPHOS complex subunits are found across all domains of life, many have diverged or expanded across evolution-as seen in the protozoan pathogen Acanthamoeba castellanii. By integrating cryo-electron microscopy of unenriched mitochondrial lysate with mass spectrometry proteomics, we resolved the structures of endogenous mitochondrial ATP synthase (complex V), Hsp60, and respiratory complex III from Acanthamoeba. We capture Acanthamoeba ATP synthase in an IF1-inhibited state and reveal how Acanthamoeba-specific subunits and extensions stabilize the molecular machine, which includes a β subunit extension that interfaces with the peripheral stalk. Additionally, we characterize an active malate dehydrogenase (MDH) dimer structurally integrated within the ATP synthase peripheral stalk, thus revealing a direct protein tether between OXPHOS and the tricarboxylic acid cycle. Together, these findings provide structural insight into lineage-specific adaptations in Acanthamoeba that may tune protozoan metabolism.
    Keywords:  ATP synthase; Acanthamoeba; complex V; cryo-EM; crystallography; malate dehydrogenase; mitochondria; oxidative phosphorylation; respiratory complexes; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.cell.2026.08.057
  2. Cancer Res. 2026 Sep 28.
    Impaired Mevalonate-Dependent NAD⁺ Regeneration Suppresses Serine Biosynthesis and Enhances Sensitivity to PHGDH Inhibition.
    Thi Thinh Nguyen, Jane Ding, Mohit Bansal, Sunil Sudarshan, Han-Fei Ding.
      The mevalonate pathway generates sterols and isoprenoids essential for membrane biosynthesis and signaling. Increased activity of the mevalonate pathway is a common feature of cancer and has emerged as a potential therapeutic vulnerability. Here, we showed that the mevalonate pathway sustains de novo serine biosynthesis and aspartate production by maintaining NAD⁺ regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impaired oxidative phosphorylation, lowered the NAD⁺/NADH ratio, suppressed serine and aspartate biosynthesis, and activated the GCN2-eIF2α-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limited purine and pyrimidine biosynthesis. Genetic and pharmacological disruption of ubiquinone synthesis recapitulated the metabolic defects, whereas expression of the bacterial NADH oxidase LbNOX restored the NAD⁺/NADH ratio and reversed the metabolic and growth defects induced by statin treatment. Importantly, impairment of NAD⁺ regeneration reduced PHGDH-dependent de novo serine synthesis, thereby sensitizing neuroblastoma cells to PHGDH inhibition. Accordingly, simvastatin enhanced the anti-proliferative effects of the PHGDH inhibitor NCT-503 in vitro and exhibited elevated anti-tumor activity in combination with NCT-503 in neuroblastoma xenograft models. Together, these findings establish ubiquinone-dependent NAD⁺ regeneration as a key mechanism linking the mevalonate pathway to amino acid and nucleotide biosynthesis and provide a mechanistic rationale for combined targeting of the mevalonate pathway and serine biosynthesis in cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1063
  3. Life Sci Alliance. 2026 Dec;pii: e202503535. [Epub ahead of print]9(12):
    A selective inhibitor reveals roles for LONP1 in mitochondrial proteostasis and OXPHOS dependencies.
    Zsolt Szilagyi, Pauline Michon, Carlos Pardo-Hernández, Mãdãlina Sãcultanu, Javier Miralles Fusté, Andrew M Griffin, Paul S Charifson, Cindy Phan, Yonghong Shi, Gunther Kern, Gabriel Martinez Botella, Thomas A Keating, Bertil Macao, Nils-Göran Larsson, Maria Falkenberg, Jeremy Green, Claes M Gustafsson.
      Lon protease 1 (LONP1) is a conserved hexameric protease implicated in mitochondrial disorders and cancer progression. In this study, we present PZL-26, a potent and selective small-molecule inhibitor that targets LONP1 without affecting the proteasome, leading to selective accumulation of mitochondrial proteins. Using PZL-26 in a whole-genome CRISPR-Cas9 screen, we identified genes essential for cell survival under protease inhibition, supporting a role for LONP1 in key mitochondrial processes, including complex I biogenesis, mitochondrial transcription, and translation. Our CRISPR screen results are consistent with proteomics analysis, with both approaches converging on the same mitochondrial pathways and highlighting functional interactions between LONP1 and other mitochondrial proteases, including potential compensatory mechanisms. These findings establish PZL-26 as an effective tool for exploring LONP1 function and pave the way for future therapeutic strategies targeting LONP1 in mitochondrial diseases and cancer.
    DOI:  https://doi.org/10.26508/lsa.202503535
  4. Mol Cell. 2026 Oct 01. pii: S1097-2765(26)00627-1. [Epub ahead of print]86(19): 3862-3863
    Hypoxia? NNoT a PROblem!
    Ningning Liang, Costas A Lyssiotis, Daniel R Wahl.
      Glioma cells experience profound metabolic stress in hypoxic tumor regions, where mitochondrial respiration is constrained and redox balance becomes difficult to maintain. A recent study by Vettore and colleagues1 in Molecular Cell identifies nicotinamide nucleotide transhydrogenase as a key mitochondrial enzyme that connects NADH oxidation to NADPH production, thereby supporting proline synthesis and growth under hypoxia. This work highlights how distinct redox pools are coordinated in cancer cells and suggests that NNT-dependent metabolism may represent a vulnerability in hypoxic tumors.
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.007
  5. bioRxiv. 2026 Sep 25. pii: 2026.09.24.753323. [Epub ahead of print]
    ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesis and fatty acid oxidation in colorectal cancer.
    Zhiping Feng, Thomas E Bearrood, Sydney L Campbell, Adrianne M Kinsey, Nedas Matulionis, Che-Hong Chen, Takuya Seike, Logan Leak, A Kaan Tarhan, Scott J Dixon, Daria Mochly-Rosen, Heather R Christofk, James K Chen.
      Metabolic reprogramming is a hallmark of cancer cells, and stem-like populations often upregulate aldehyde dehydrogenases (ALDHs). Functional studies have established essential roles for individual ALDH isoforms in tumor initiation, progression, and metastasis; however, the mechanisms by which these enzymes promote malignancy remain poorly understood. Here we show that aldehyde dehydrogenase 1B1 (ALDH1B1), a mitochondrial enzyme highly expressed in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), generates γ-butyrobetaine (GBB) and γ-aminobutyric acid (GABA) in CRC cells. The biosynthesis of both aminocarboxylic acids has been attributed to the cytosolic enzyme ALDH9A1, and we demonstrate that mitochondrial GBB and GABA are functionally distinct from the cytosolic pools of these metabolites. We further demonstrate that mitochondrial GBB can function as an antiport substrate of carnitine-acylcarnitine translocase (CACT), the transporter that mediates fatty acid uptake into the mitochondrial inner matrix. This activity complements the role of cytosolic GBB as the biosynthetic precursor to carnitine. Accordingly, ALDH1B1 can markedly enhance mitochondrial fatty acid oxidation (FAO), a catabolic process that has been linked to CRC and PDAC stemness, progression, and metastasis. Our findings reveal an unexpected role for ALDH1B1 in carnitine metabolism, GABA biosynthesis, and FAO and illustrate how the compartmental reprogramming of metabolic pathways can promote tumor growth.
    DOI:  https://doi.org/10.64898/2026.09.24.753323
  6. Sci Adv. 2026 Oct 02. 12(40): eaeh7186
    Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in GNAS (Gαs) mutant pancreas cancer.
    Grant A Hagedorn, Jackson C Spieser, Noriko Hirai, Yuki Sato, Jake Valentine, Hanson Jiang, Wang Wang, Maria F Czyzyk-Krzeska, Krushna C Patra.
      Maintenance of fissed mitochondria is viewed as a defining feature of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant cancers. However, regulation of this process by accompanying comutations or environmental factors is not clearly defined. Here, by analyzing a subset of pancreatic cancer lesions driven by concurrent KrasG12D and GNAS complex locus gene (GNASR201C/H) mutations, we found that despite the presence of mutant Kras, hyperactive GnasR201C maintains mitochondria predominantly in a fused state, which is necessary for tumor growth. Multiplex proteomics, super-resolution microscopy, loss- and gain-of-function studies, coupled with metabolite rescue experiments, revealed that GnasR201C-regulated branched-chain amino acid (BCAA) pathway is a previously unidentified regulator of mitochondrial morphology. Mechanistically, the BCAA pathway, the associated tricarboxylic acid cycle, and aspartate metabolism converge on nicotinamide adenine dinucleotide (NADH-NAD+) metabolites to promote mitochondrial elongation. NAD+ availability is crucial for mitochondrial fusion, as facilitating NAD+ generation through alternative means promotes fusion. Collectively, we unraveled a new mechanism that drives mitochondrial fusion and showed that the combination of oncogenic signaling and metabolism can maintain distinct mitochondrial morphology within genetic subsets of KRAS-mutant pancreatic cancer.
    DOI:  https://doi.org/10.1126/sciadv.aeh7186
  7. Science. 2026 Oct;394(6819): eadz4797
    Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
    Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Adam Chatoff, Andrea Andress Huacachino, Hannah J Richter, Meghna Birla, Sabina Chubanava, Yann Deleye, Rini Arianti, David Tandio, Sarah E Utzon, Zafir Kaiser, Yachen Shen, Ditte Neess, Hannes Embring, Dilip Menon, Olivia J Conway, Frederike Sass, Fabian Finger, Lidia Argemi-Muntadas, Tao Ma, Elahu G Sustarsic, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucińska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew P Gillum, Terry D Hinds, Raymond E Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Endre Kristóf, Susanne Mandrup, Brice Emanuelli, Nathaniel W Snyder, Daniel J Fazakerley, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.
      Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator-activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl-coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.
    DOI:  https://doi.org/10.1126/science.adz4797
  8. Cancer Res. 2026 Sep 28.
    Targeting ClpP Rewires the Metabolic-Immune Axis in Acute Myeloid Leukemia.
    Xinrong Xiang, Baozhu Luo, Lei Zhao, Jing Sui, Yi Wu, Jiasheng Huang, Song Liu, Hexian Li, Fangfang Wang, Mengran Chen, Ying Qu, Aiping Tong, Chong Chen, Yu Wu, Youfu Luo.
      Acute myeloid leukemia (AML) critically depends on oxidative phosphorylation (OXPHOS). Mitochondrial targeted therapies are advancing into clinical trials, but metabolic vulnerabilities have been primarily explored from a tumor-intrinsic perspective. Leukemic cells can actively reshape an immunosuppressive tumor microenvironment through metabolic competition, highlighting the importance of evaluating the impact of mitochondrial targeted therapies on antitumor immunity. Here, we showed that elevated expression of the mitochondrial caseinolytic protease P (ClpP) is associated with advanced AML. Development of IMP125, a potent ClpP agonist, enabled dual targeting of AML to elicit robust anti-leukemic activity. In addition to direct cytotoxicity, IMP125 induced immunometabolic reprogramming of AML models. Owing to differential ClpP expression, IMP125 preferentially suppressed mitochondrial respiration and oxygen consumption in AML cells while exerting minimal direct effects on T-cell respiration. By reducing AML oxygen consumption and metabolic demand, IMP125 alleviated hypoxia and metabolic competition within the leukemic niche. In this remodeled microenvironment, T cells exhibited recovery of OXPHOS, effector function, and memory-associated features, consistent with an indirect mechanism mediated through metabolic suppression in AML cells. The anti-leukemic efficacy of IMP125 was dependent on T cells and was synergistically enhanced by PD-1 blockade. Collectively, this work reframes ClpP agonism from a tumor-intrinsic therapy to a strategy that actively induces metabolic-immune rewiring, bridging ClpP-targeted and immunotherapeutic approaches for mitochondrial-dependent AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0477
  9. bioRxiv. 2026 Sep 07. pii: 2026.09.03.748963. [Epub ahead of print]
    Mitochondrial rewiring supports survival of triple negative breast cancer cells after ionizing radiation.
    Steven W Wall, Karen Wang, Allison Greer, Mokryun L Baek, Audra Lane, Mariah J Berner, Jonathan T Lei, Ángel A Garcés, Sofia Khoury, Emily G Caggiano, Matthew D Meyer, Sarah Latka, Hugo Villanueva, Emil Schüler, Cullen M Taniguchi, Rutulkumar Patel, Gloria V Echeverria.
      Triple negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Conventional treatments include neoadjuvant chemo-immunotherapy followed by surgical resection and may include further adjuvant immunotherapy and/or radiotherapy of the tumor bed and lymph nodes. Nonetheless, TNBC patients with residual disease have rapid metastatic recurrence. While the roles of metabolic and mitochondrial adaptations in chemotherapeutic resistance have been the subject of many studies, their importance in the context of ionizing radiation (IR) therapy remains poorly understood. We established longitudinal in vitro models of post-IR human TNBC, characterized by cellular regression to a residual phenotypic state, then eventual cell repopulation. This was accompanied by plastic adoption of unique metabolic, proteomic, and morphologic features that largely reverted when cells regrew. Following IR, residual cells exhibited extensive mitochondrial rewiring, including elevated mitochondrial content, oxidative phosphorylation (oxphos) rates, cristae structures, and metabolite levels. Concomitantly, levels of the short protein isoform of the mitochondrial inner membrane protein optic atrophy 1 (OPA1) were significantly elevated in residual cells, and OPA1 knockout ablated mitochondrial adaptations induced by IR. OPA1 genetic or pharmacologic perturbations led to improved cellular responses to IR. Metabolomic and proteomic analyses of radio-residual cells uncovered a coordinated program of antioxidant and redox capacity elevation with mitochondrial metabolism, which was corroborated by analyses of external datasets. Together, these findings provide evidence that TNBC cells surviving radiotherapy adopt an OPA1-dependent program of mitochondrial reorganization that supports their survival and regrowth, thereby positioning OPA1 as a therapeutic dependency that could improve radiotherapy efficacy in TNBC.
    DOI:  https://doi.org/10.64898/2026.09.03.748963
  10. Oncogene. 2026 Oct 02.
    TFAM loss drives oxaliplatin resistance by linking mtDNA release to STING-TBK1-mediated lysophagy.
    Xiao-Xuan Wang, Xin-Han Wang, Zi-Hong Fan, Xiao-Feng Ding, Jian-Rui Zhong, Bing-Ming Zhu, Jie Lyu, Su-Jie Wang, Qing-Yu He, Yang Wang, Jing Zhang.
      Acquired resistance to oxaliplatin (Oxa) represents a major clinical challenge in the treatment of colorectal cancer (CRC). Lysosomes are intracellular degradative organelles that enable cancer cells to adapt to metabolic and environmental stress; however, their precise regulatory roles in drug resistance remain poorly understood. Here, we report that lysosomal damage and its selective autophagic clearance (lysophagy) occur frequently in both Oxa-treated CRC cells and Oxa-resistant (OxaR) CRC cells. Through quantitative proteomics, we identified the significant downregulation of mitochondrial transcription factor A (TFAM) as a key event in Oxa-treated and OxaR cells. Mechanistically, Oxa-induced TFAM loss leads to mitochondrial DNA (mtDNA) leakage into the cytosol, which activates the STING-TBK1 signaling axis. This pathway subsequently enhances lysophagic flux, providing cancer cells with a survival advantage under Oxa stress. Crucially, pharmacological inhibition of TBK1 abrogates this adaptive lysophagy, restoring Oxa sensitivity and suppressing tumor growth in both xenograft and patient-derived organoid models. Collectively, our study reveals a novel TFAM-mtDNA-STING-TBK1 signaling axis that promotes chemoresistance through the co-option of lysophagy, highlighting TBK1 as a viable therapeutic target to overcome Oxa resistance in CRC.
    DOI:  https://doi.org/10.1038/s41388-026-03990-8
  11. Sci Adv. 2026 Oct 02. 12(40): eaei2831
    Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
    Nancy T Santiappillai, Andrew Cho, Georg Verch, Ana C Codo, Achuth Nair, Ya-Ting Wang, Allie Lipshutz, Celia Martínez de la Torre, Eric Minwei Liu, Marjan Berishaj, Alissa J Trzeciak, Zhaoquan Wang, Michelle Saoi, Waleska Saitz Rojas, Justin R Cross, Ed Reznik, Justin S A Perry, Kayvan R Keshari.
      Triple-negative breast cancer (TNBC) develops in hypoxic, nutrient-limited tumors enriched with macrophages and cell death. We show that metabolically distinct TNBCs differentially exploit macrophage-derived nutrients, influencing tumor growth and therapeutic response. Prolonged hypoxia reprogrammed mouse and human macrophages, enabling them to release metabolites that rescued the growth of select TNBC cell lines during glutamine deprivation or glutamine metabolism inhibition. Hypoxic macrophages reduced glutamine consumption, increased arginine utilization, and secreted higher levels of ornithine, an intermediate of arginine metabolism. Exogenous ornithine, but not arginine, restored the growth of responsive TNBC cells. Mechanistically, TNBC cells diverted ornithine into proline biosynthesis, supporting oxidative pentose phosphate pathway activity. In vivo, depletion of tumor-associated myeloid cells reduced tumor growth and impaired proline synthesis in glutaminase inhibitor-resistant TNBC. These findings identify hypoxia-driven metabolic cross-talk between macrophages and TNBC cells, revealing ornithine-dependent proline metabolism as a mechanism by which macrophages sustain tumor growth under nutrient stress and contribute to resistance to glutamine-targeted therapies.
    DOI:  https://doi.org/10.1126/sciadv.aei2831
  12. Front Biosci (Landmark Ed). 2026 Sep 20. 31(9): 55451
    The Protective Effect of Venetoclax on the Calcium-Induced Mitochondrial Pore and ROS Production as a New Possible Factor Contributing to Drug Resistance.
    Alexey G Kruglov, Tatiana A Fedotcheva, Nadezhda I Fedotcheva.
       OBJECTIVE: Recent data show that there are direct relationships between mitochondrial activity, cancer progression, and chemoresistance. Venetoclax (Ven) is a mitochondria-targeted chemotherapeutic drug, which facilitates apoptosis by selectively inhibiting the antiapoptotic protein Bcl-2. Ven exhibits a dual effect, affecting not only mitochondria but also the cell drug resistance system. There is also evidence indicating that cancer cells develop resistance to Ven, which is mediated by the upregulation of antiapoptotic proteins, simultaneous activation of multiple signaling pathways, an alteration in the cellular and mitochondrial metabolism, and other defensive mechanisms. The influence of Ven on the opening of the mitochondrial permeability transition pore (mPTP), a key event in the induction of mitochondria-dependent cell death, has not been previously studied.
    METHODS: The effect of Ven on calcium-induced mPTP opening, respiration, and reactive oxygen species (ROS) production was examined in isolated rat liver mitochondria, using cation-selective electrodes, as well as fluorescent and chemiluminescent methods.
    RESULTS: Ven was found to have a protective effect against the Ca2+-induced mPTP opening, increasing the threshold calcium concentrations and the calcium load that activate pore opening. A comparison with the known mPTP inhibitors ADP, bongkrekic acid (BA), cyclosporine A (Cs), oligomycin, used separately and in combination with Ven, showed a similarity of the effect of Ven (at a concentration of 50 µM) to the effect of BA (20 µM). The effects of both were prevented by carboxyatractyloside (CATR). Also, the protective effect of Ven, as well as that of BA, was completely eliminated by 2-thenoyltrifluoroacetone (TTFA), an inhibitor of the ubiquinone-binding site of succinate dehydrogenase complex at low concentrations (5 µM and 50 µM under the oxidation of succinate and NAD-dependent substrates, respectively). Simultaneously, Ven decreased the ROS production induced by TTFA under the same conditions.
    CONCLUSIONS: Ven shows two protective activities, namely, the inhibition of mPTP opening and the suppression of ROS production in mitochondria, which may be additional causes of the development of drug resistance. The results of the TTFA test are consistent with the data on the dependence of Ven resistance on the state of the respiratory chain.
    Keywords:  bongkrekic acid; cell respiration; drug resistance; mitochondria; mitochondrial permeability transition pore; reactive oxygen species; succinate dehydrogenase; venetoclax
    DOI:  https://doi.org/10.31083/FBL55451
  13. bioRxiv. 2026 Sep 27. pii: 2026.09.24.754271. [Epub ahead of print]
    Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age.
    Sarah Jean Shemtov, Eric Hwang, Claire S Chung, Herbert Anson, Lucy Carrillo, Sangmin Lee, Ivetta Vorobyova, Junxiang Wan, Scott R Kennedy, Amy R Vandiver, Bert M Verheijen, Whitaker Cohn, Bérénice A Benayoun, Max A Thorwald, Pinchas Cohen, Jonathan Wanagat, Jean-François Gout, Marc Vermulst.
      Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.
    DOI:  https://doi.org/10.64898/2026.09.24.754271
  14. bioRxiv. 2026 Sep 22. pii: 2026.09.21.753355. [Epub ahead of print]
    Loss of TCA cycle turning promotes stem cell function.
    Yafeng Li, Joseph Rose, Edward O Kwarteng, Xiaotong Yang, Jacob Zielke, Li Li, Zhiyu Zhao, Ji Hyung Jun, Michalis Agathocleous.
      The citric acid cycle (TCA cycle) is the common terminal pathway for the oxidation of all nutrients. Citrate oxidation to oxaloacetate produces CO 2 , and citrate synthase (CS) uses nutrient-derived acetyl groups to regenerate citrate and fuel cycle turning. However, the essentiality of cycle fueling and turning in vivo remains unclear. Here, we use hematopoiesis, the most proliferative system in the body, as a model to show that, contrary to common assumptions, TCA cycle turning is dispensable for respiration, survival, and proliferation of stem and progenitor cells in vivo and its loss promotes stem cell function. Hematopoietic-specific Cs deletion in adult mice blocked citrate cycling without reducing the frequency of hematopoietic stem (HSC) and progenitor cells. HSCs and progenitor cells adapted to TCA cycle loss by markedly increasing nutrient consumption and biosynthesis. Disruption of cycle turning increased HSC regeneration, myeloid progenitor proliferation, and myelopoiesis in vivo. HSCs without a turning TCA cycle outcompeted wild-type HSCs within the same environment. The effect of CS deletion on HSC function was not phenocopied by genetic ablation of cytosolic citrate use and was rescued by ablation of glutamine use in biosynthesis. Therefore, TCA cycle turning restrains nutrient uptake, biosynthesis, cell proliferation, and stem cell function. These results suggest an explanation for the reduction in cycle activity observed in many normal proliferating cells and cancer cells.
    DOI:  https://doi.org/10.64898/2026.09.21.753355
  15. bioRxiv. 2026 Sep 22. pii: 2026.09.21.753214. [Epub ahead of print]
    Glucosylceramide synthase is required for C6-ceramide nanoliposome-induced organelle stress and cell death.
    Luke R Vass, Ella W Smith, Jayda M Cavanaugh, Summer L Johnson, Ariana Sabzevari, Pedro Costa-Pinheiro, Jeremy J P Shaw, Thomas P Loughran, Todd E Fox.
      Sphingolipids are bioactive lipids that regulate key signaling pathways both directly as ligands and through membrane re-organization. Ceramide sits at the center of this network and is considered pro-death in many contexts, making ceramide accumulation an attractive therapeutic strategy. Given the wide-ranging regulation of cellular responses this network exerts, better understanding ceramide metabolism may promote therapeutic efficacy of sphingolipid-based therapeutics. Ceramide glycosylation, catalyzed by glucosylceramide synthase (GCS; UGCG), is in turn widely regarded as a detoxification route thus limiting efficacy of ceramide-based therapeutics. Here we show the opposite. Delivery of short-chain C6-ceramide via a ceramide nanoliposome (CNL) induced organelle stress and cell death in chronic lymphocytic leukemia (CLL) via the accumulation of glycosphingolipids (GSLs), rather than through ceramide itself. Pharmacologic and genetic blockade of GCS protected B-cell leukemia, breast carcinoma, glioblastoma, lung adenocarcinoma, and non-malignant embryonic kidney cells from CNL-induced death. Conversely, exogenous C8-glucosylceramide was sufficient to kill cells that cannot degrade it. We show that GSL accumulation drives an ordered organelle response beginning with lysosomal deacidification, endoplasmic reticulum stress, followed by mitochondrial respiratory capacity decline, each attenuated by inhibition of GSL synthesis. These effects were accompanied by MLKL phosphorylation, increased activity of the stress sensor JNK and CHOP induction, with JNK inhibition partially protecting from death. These findings invert the prevailing view of ceramide glycosylation as a resistance mechanism and identify glycosphingolipid flux as a required effector arm of ceramide-directed therapy.
    DOI:  https://doi.org/10.64898/2026.09.21.753214
  16. Blood Adv. 2026 Oct 13. 10(19): 6683-6684
    CC-486 plus venetoclax: another step toward oral AML therapy.
    Kimberly Seymour, Marina Konopleva.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2026021747
  17. Blood Cancer Discov. 2026 Sep 30.
    Very Long Chain Fatty Acid Synthesis is a Targetable Dependency in RAS Pathway Mutant Leukemia.
    Rebecca Gelfer, Maya Bagish, Merve Sahin, Kaitlyn H Ko, Maria Sirenko, Matthew Wereski, Gabriel San Miguel-Matos, Angelica C Romero-Vega, Shoron Mowla, Nathaniel B Long, Michelle Saoi, Clementina Strozek, Su-Fern Tan, Christopher A Famulare, Kevin Chen, B Bishal Paudel, Madhuri Madavaram, Zhuoning Li, Michael R Waarts, Xiaodi Wu, Justin R Cross, Wenbin Xiao, Iannis Aifantis, Tak Wah Mak, Todd E Fox, David J Feith, Elisa de Stanchina, Mara Monetti, Richard P Koche, Sheng F Cai, Ross L Levine.
      Oncogenic RAS pathway mutations are associated with therapeutic resistance in acute myeloid leukemia, and identification of therapeutic vulnerabilities has been hindered by a lack of clinically relevant models and tractable ex vivo platforms. We utilize a bone marrow endothelial cell co-culture system to perform CRISPR screens on wild-type hematopoietic cells and isogenic leukemias with and without mutant Nras. We credentialed Elovl1, a very long chain fatty acid elongase, as a dependency in RAS pathway mutant leukemia using genetic and pharmacologic approaches. Metabolic and genetic studies in primary leukemias revealed that the fitness defect from Elovl1 loss reflects a mutant-specific dependency on de novo sphingolipid biosynthesis, specifically sphingomyelin production, as Sgms1 deletion phenocopies Elovl1 loss. Sphingomyelin-mediated generation of lipid rafts, key scaffolds for multiple signaling pathways, is essential to the survival of Nras-mutant AML cells. Our work leverages a new leukemia model to identify a targetable dependency in this treatment-refractory leukemia.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-26-0274
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