bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–03–01
twenty-one papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. A metabolism-specific drug-repurposing screen reveals itraconazole as a potent OXPHOS inhibitor in acute myeloid leukemia.
  2. Reversible dissociation of mitochondrial Complex V balances anabolic and energy-generating needs in cancer.
  3. Targeting UGCG sensitizes AML cells to venetoclax through RAB32-mediated endoplasmic reticulum-mitochondria communication.
  4. Protein-induced membrane strain drives supercomplex formation.
  5. Marrow leptin-LEPR signaling rewires mitochondrial oxidative metabolism to confer chemoresistance in acute myeloid leukemia.
  6. Targeting ABCD1 inhibits peroxisomal fatty acid oxidation to selectively eliminate acute myeloid leukemia cells.
  7. Aspartate availability drives differential engagement of the malate-aspartate shuttle.
  8. Electrical acceleration of the glycerophosphate shuttle by the VDAC1,2-hexokinase complexes of mitochondria.
  9. A novel potent and selective GCN2 inhibitor, APL-4098, has anti-leukemic activity through dysregulation of mitochondrial function.
  10. Dual-action mitochondria-targeted prodrugs that both deplete mitochondrial glutathione and deliver a toxic payload to the matrix.
  11. The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.
  12. Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
  13. Specific SLC25 carriers regulate mitochondrial protein synthesis.
  14. Systemic hypoxia suppresses solid tumor growth.
  15. Phenotypic CRISPR screens identify NLRX1 as an essential activator of the human mitochondrial permeability transition.
  16. A gated hydrophobic funnel within BAX binds bioactive lipids to potentiate pro-apoptotic function.
  17. PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation.
  18. When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase.
  19. A mammalian, glutaminase-free asparaginase enhances venetoclax activity in preclinical AML models with chromosome 7 deletion.
  20. Hot Mitochondria and the Second Law of Thermodynamics.
  21. Optineurin enhances the chemoresistance by activating mitophagy in acute myeloid leukemia with NPM1 mutation.
  1. Blood. 2026 Feb 24. pii: blood.2024027853. [Epub ahead of print]
    A metabolism-specific drug-repurposing screen reveals itraconazole as a potent OXPHOS inhibitor in acute myeloid leukemia.
    Ekaterini Himonas, Lucie de Beauchamp, Désirée Zerbst, Eudoxie Desmares-Romain, Daniele Sarnello, Eric R Kalkman, Kevin M Rattigan, Daniel James, Engy Shokry, Mhairi Copland, Emmanuel Griessinger, Christian Récher, Véronique Mansat-De Mas, Francois Vergez, David Sumpton, Aaron D Schimmer, Mark D Minden, Eyal Gottlieb, Emma Shanks, Jean-Emmanuel Sarry, Vignir Helgason.
      Targeting mitochondrial oxidative phosphorylation (OXPHOS) enhances the effects of standard chemotherapy and overcomes treatment resistance in pre-clinical models of acute myeloid leukaemia (AML). So far, the few clinically available OXPHOS inhibitors have shown adverse effects or limited potency in clinical trials, therefore, identification of safe and effective drugs that can target mitochondrial metabolism in AML is critical. Here, we performed a high-throughput drug-repurposing screen, designed to identify clinically applicable OXPHOS-specific inhibitors through nutrient sensing. We uncover itraconazole, an FDA-approved antifungal compound, as a potent OXPHOS inhibitor in AML cells. Mechanistically, through stable isotope-assisted metabolomics and functional studies, we reveal that CYP51A1, which is part of the cytochrome P450 family and the prime target of azole antifungals, is involved in mitochondrial respiration and ETC complex I activity in AML cells. Critically, we demonstrate that itraconazole and related azole antifungals interfere with tricarboxylic acid cycle activity and inhibit OXPHOS through the inhibition of electron transport chain complex I activity. Over-expression of yeast NADH dehydrogenase-1 (NDI1) restored mitochondrial NADH oxidation and complex I activity upon itraconazole treatment. Using patient-derived cells and pre-clinical xenograft models, we demonstrate that itraconazole targets therapy-resistant leukaemic stem cells (LSCs) when used in combination with cytarabine, highlighting the repurposing potential for itraconazole as a clinically safe and effective therapeutic option for AML LSC eradication.
    DOI:  https://doi.org/10.1182/blood.2024027853
  2. iScience. 2026 Mar 20. 29(3): 114889
    Reversible dissociation of mitochondrial Complex V balances anabolic and energy-generating needs in cancer.
    Huabo Wang, Jie Lu, Colin Henchy, Steven J Mullett, Adam C Richert, Eric S Goetzman, Ahmet Toksoz, Leonardo Hale, Brandon B Wang, Nelli Mnatsakanyan, Edward V Prochownik.
      Cancer cell metabolic re-programming provides the additional energy and anabolic precursors necessary to sustain unregulated proliferation. This is partially mediated by the Warburg effect, which generates ATP while oxidizing glucose to a subset of these anabolites. Concurrently, mitochondrial mass and ATP generation via oxidative phosphorylation decline in most tumors. This raises the question of how increased glycolysis-derived anabolites can be balanced with those supplied by the TCA cycle. Using primary murine liver cancers and their derivative cell lines, we show that this can be explained by the dissociation of mitochondrial Complex V (CV or ATP synthase) into its component and functionally independent Fo and F1 domains. This occurs as a result of marked declines in MT-ATP6, a CV subunit that stabilizes Fo-F1 assembly. Serving as a proton pore, free Fo maintains a normal mitochondrial membrane potential without generating ATP, thus allowing the TCA cycle, electron transport chain, and anaplerotic reactions to function at high levels. Concurrently, free F1 functions in reverse as an ATPase to limit excess ATP accumulation. The uncoupling of TCA-cycle-derived anabolic substrate production from membrane hyperpolarization and ATP overproduction by a smaller population of highly efficient mitochondria allows TCA-cycle-generated anabolic precursors to match those generated via glycolysis.
    Keywords:  Biochemistry; Cancer; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.114889
  3. Cell Rep. 2026 Feb 23. pii: S2211-1247(26)00099-9. [Epub ahead of print]45(3): 117021
    Targeting UGCG sensitizes AML cells to venetoclax through RAB32-mediated endoplasmic reticulum-mitochondria communication.
    Xiaofan Sun, Yue Li, Danqi Pan, Caiping Wu, Weihao Xiao, Ganlu Feng, Nianhui Yang, Yizhen Li, Wei Xiong, Min Dai, Zhirou Zhang, Lei Hua, Liye Zhong, Guopan Yu, Suxia Geng, Chengxin Deng, Chengwei Luo, Ping Wu, Xin Du, Juan Du, Hui Zeng.
      Uridine diphosphate (UDP)-glucose ceramide glucosyltransferase (UGCG) is an enzyme that glycosylates ceramide and blunts its pro-apoptotic activity in cancer cells. Targeting UGCG sensitizes solid cancer cells to chemotherapy. However, whether targeting UGCG can sensitize acute myeloid leukemia (AML) cells to venetoclax remains unclear. Here, we found that the inhibition of UGCG genetically or with its inhibitor eliglustat efficiently suppressed growth and promoted apoptosis in AML cells. Moreover, eliglustat in combination with venetoclax increased apoptosis, reduced AML cell viability, and inhibited AML effectively both for primary AML cells and xenograft models. Mechanistically, the combination induced ceramide accumulation, which activated the endoplasmic reticulum (ER) stress-GRP78/PERK/CHOP axis. Interestingly, combinatory treatment activated RAB32, which led to mitochondrial fission through ER-mitochondria communication and DRP1 activation. These findings demonstrate that targeting UGCG in combination with venetoclax is an alternative combinatory strategy to treat AML and provide insights into ceramide-mediated cell death in anti-cancer therapies.
    Keywords:  CP: cancer; DRP1; RAB32; UGCG; acute myeloid leukemia; ceramide accumulation; endoplasmic reticulum stress; venetoclax
    DOI:  https://doi.org/10.1016/j.celrep.2026.117021
  4. Elife. 2026 Feb 23. pii: RP102104. [Epub ahead of print]13
    Protein-induced membrane strain drives supercomplex formation.
    Maximilian C Pöverlein, Alexander Jussupow, Hyunho Kim, Ville R I Kaila.
      Mitochondrial membranes harbor the electron transport chain (ETC) that powers oxidative phosphorylation (OXPHOS) and drives the synthesis of ATP. Yet, under physiological conditions, the OXPHOS proteins operate as higher-order supercomplex (SC) assemblies, although their functional role remains poorly understood and much debated. By combining large-scale atomistic and coarse-grained molecular simulations with analysis of cryo-electron microscopic data and statistical as well as kinetic models, we show here that the formation of the mammalian I/III2 supercomplex reduces the molecular strain of inner mitochondrial membranes by altering the local membrane thickness and leading to an accumulation of both cardiolipin and quinone around specific regions of the SC. We find that the SC assembly also affects the global motion of the individual ETC proteins with possible functional consequences. On a general level, our findings suggest that molecular crowding and strain effects provide a thermodynamic driving force for the SC formation, with a possible flux enhancement in crowded biological membranes under constrained respiratory conditions.
    Keywords:  bioenergetics; molecular biophysics; molecular dynamics; protein–membrane interactions; respiratory complexes; structural biology; supercomplexes
    DOI:  https://doi.org/10.7554/eLife.102104
  5. Cell Death Dis. 2026 Feb 23.
    Marrow leptin-LEPR signaling rewires mitochondrial oxidative metabolism to confer chemoresistance in acute myeloid leukemia.
    Xinai Liao, Wei Dai, Xiaolin Xu, Danni Cai, Maoqing Tan, Zukai Wang, Yanrong Huang, Diyu Hou, Jingru Liu, Liuhuan Wang, Jin Wang, Xiaoting Wang, Shuxia Zhang, Xinjian Lin, Huifang Huang.
      Leptin is abundant within marrow adipose tissue, yet its impact on acute myeloid leukemia (AML) therapy response is undefined. Here, we report that elevated bone-marrow leptin and blast-cell leptin-receptor (LEPR) levels strongly associate with poor cytarabine (Ara-C) clearance and reduced survival in newly diagnosed AML patients. Mechanistic and functional validation in human AML lines, primary blasts, and two syngeneic mouse models (MLL-AF9, AML1-ETO9a) shows that exogenous leptin markedly blunts Ara-C cytotoxicity, whereas the high-affinity LEPR antagonist Allo-aca restores chemosensitivity without altering baseline leukemia growth. Leptin up-regulates LEPR and triggers JAK2/STAT3 signaling that boosts mitochondrial complex Ⅰ activity, oxidative phosphorylation, and mitochondrial reactive oxygen species (mtROS); the resulting mtROS surge activates a compensatory antioxidant program that shields blasts from drug-induced oxidative damage. These data identify an adipokine-driven metabolic circuit governing AML chemoresistance and reveal LEPR blockade as a tractable strategy to improve outcomes, underscoring adipose-tumor crosstalk as a general therapeutic vulnerability.
    DOI:  https://doi.org/10.1038/s41419-026-08528-0
  6. Blood. 2026 Feb 26. pii: blood.2025031202. [Epub ahead of print]
    Targeting ABCD1 inhibits peroxisomal fatty acid oxidation to selectively eliminate acute myeloid leukemia cells.
    Ekaterina N Parfenova, Nikolina Vrdoljak, Drake Mosca, Juan J Aristizabal-Henao, Michael A Kiebish, Mark D Minden, Paul A Spagnuolo.
      Altered lipid metabolism enables growth of acute myeloid leukemia (AML) cells. While mitochondrial lipid oxidation is well characterized, the contribution of peroxisomal fatty acid oxidation (pFAO) is unclear. In this study, we demonstrate that AML cells upregulate the peroxisomal very-long-chain fatty acid (VLCFA) transporter ABCD1 and increase endogenous levels of pFAO relative to healthy hematopoietic cells. Genetic silencing or pharmacological inhibition of ABCD1, with eicosenol, impairs pFAO causing accumulation of VLCFAs and selective AML cell death in vitro and in vivo. Loss of ABCD1 disrupts peroxisomal fatty acid import and lipid homeostasis in AML, while normal progenitors remain viable by upregulating glycolysis. In murine models, ABCD1 inhibition with eicosenol reduces leukemia burden and prolongs survival without toxicity. These findings identify ABCD1 as a regulator of pFAO and a novel anti-AML therapeutic target.
    DOI:  https://doi.org/10.1182/blood.2025031202
  7. Mol Cell. 2026 Feb 26. pii: S1097-2765(26)00099-7. [Epub ahead of print]
    Aspartate availability drives differential engagement of the malate-aspartate shuttle.
    Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner, Lydia W S Finley.
      The malate-aspartate shuttle is a major electron shuttle that transfers reducing equivalents from the cytosol to the mitochondria, where they can be safely deposited onto the electron transport chain. Nevertheless, many proliferating cells discard reducing equivalents in the form of lactate, raising the question of what factors limit electron shuttle use. Here, we show that aspartate availability determines engagement of the malate-aspartate shuttle. In proliferating cells, increasing aspartate availability enhances use of the malate-aspartate shuttle and increases metabolism of glucose-derived pyruvate in mitochondria, a process that requires regeneration of oxidized electron carriers in the cytosol. During differentiation, elevated flux through the malate-aspartate shuttle cells enables cells to fuel mitochondrial networks from glucose-derived carbon. Engineering aspartate demand reverses this metabolic signature of differentiated cells. Together, these results demonstrate that cell-state-specific demand for aspartate is sufficient to determine use of the malate-aspartate shuttle and drives changing mitochondrial substrate preferences during differentiation.
    Keywords:  GOT1; GOT2; TCA cycle; Warburg effect; aspartate; differentiation; electron shuttles; malate-aspartate shuttle; metabolism; proliferation
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.004
  8. Biochim Biophys Acta Bioenerg. 2026 Feb 25. pii: S0005-2728(26)00006-X. [Epub ahead of print] 149586
    Electrical acceleration of the glycerophosphate shuttle by the VDAC1,2-hexokinase complexes of mitochondria.
    Victor V Lemeshko.
      Glycerophosphate shuttle, an important crossroad between oxidative phosphorylation system, glycolysis and lipid metabolism, consists of the rate-limiting mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) and the cytosolic dehydrogenase (GPD1). GPD2 level is relatively high in islet beta-cells, spermatozoa and neurons, required abruptly rapid periodic ATP consumption, as well as in rapidly growing normal tissues during neonatal period and many cancers. According to the computational model developed in the present work, the glycerophosphate shuttle should be significantly activated by the outer membrane potential (OMP) generated by the VDAC1,2-hexokinase complexes of mitochondrial outer membrane. This is due to the capture of cytosolic glycerol-3-phosphate2- into the mitochondrial intermembrane space by the positive OMP, thus increasing its local concentration near GPD2. The predicted acceleration is most significant at relatively high Km of GPD2 for glycerol-3-phosphate2- and strongly modulated by the VDAC's voltage-gating properties. In general, OMP generated by the VDAC1,2-hexokinase complexes might play a crucial role in the above-mentioned crossroad, converting it into the "electrical metabolic crossroad". The suggested electrical deviation of glycolysis towards the mitochondrial GPD2, as a tool for the metabolic shift to an accelerated aerobic glycolysis without an inhibition of mitochondrial respiration, highlights this metabolic switching as one of the possible options of the Warburg effect.
    Keywords:  Glycerophosphate shuttle; Glycolysis; Hexokinase; Mitochondria; Outer membrane potential; VDAC
    DOI:  https://doi.org/10.1016/j.bbabio.2026.149586
  9. Clin Cancer Res. 2026 Feb 23.
    A novel potent and selective GCN2 inhibitor, APL-4098, has anti-leukemic activity through dysregulation of mitochondrial function.
    Monica Román-Trufero, Gavin Whitlock, Claire Seydoux, Kevin Blighe, Bianca Perfler, Armin Zebisch, Richard Butt, Matthew J Fuchter, Holger W Auner, Nadine Clemo.
       PURPOSE: GCN2, one of the four kinases that activate the Integrated Stress Response to maintain proteostasis, has been shown to support cancer cell growth and survival in multiple preclinical cancer models. Acute myeloid leukemia (AML) is an aggressive hematological malignancy with dismal prognosis and high relapse rates that is marked by a dependency on finely tuned proteostasis. Here, we investigate the anti-leukemic potential of a new small-molecule GCN2 inhibitor, APL-4098.
    EXPERIMENTAL DESIGN: selectivity and potency of APL-4098 were assessed using biochemical and cell-based assays. Anti-leukemic effects were evaluated ex vivo in primary patient-derived AML and in vivo using cell line-derived (CDX) and patient-derived (PDX) xenograft models. Synergy of APL-4098 and venetoclax was examined in the PDX. RNA sequencing and metabolic assays were used to explore APL-4098 mechanism of action.
    RESULTS: APL-4098 exhibited nanomolar-range potency against and high selectivity for GCN2. APL-4098 showed strong anti-proliferative activity ex vivo across two independent cohorts of primary AML patient cells, including cytotoxic effects on the leukemia stem cells (LSCs) and in vivo, achieving 98% tumor growth inhibition in an AML CDX. In a PDX, APL-4098 preferentially depleted the LSC-enriched compartment and, in combination with venetoclax, reduced leukemia burden by over 98%. Transcriptomic and metabolic analyses revealed APL-4098 compromises mitochondrial function and elicits the mitochondrial unfolded protein response.
    CONCLUSIONS: APL-4098 is a novel, potent and selective GCN2 inhibitor with strong preclinical efficacy against AML cells, including LSCs. Our findings support APL-4098 as a promising candidate for AML treatment.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-1444
  10. Eur J Med Chem. 2026 Feb 20. pii: S0223-5234(26)00151-0. [Epub ahead of print]308 118706
    Dual-action mitochondria-targeted prodrugs that both deplete mitochondrial glutathione and deliver a toxic payload to the matrix.
    Patrick A Cardwell, Alva M Casey, Suvagata Roy Chowdhury, Eloïse Marques, Chak Shun Yu, Rebecca L Taig, Stuart T Caldwell, Julien Prudent, Michael P Murphy, Richard C Hartley.
      Mitochondrial glutathione (mGSH) protects the organelle and the cell against reactive oxygen species (ROS), electrophilic metabolites and xenobiotics. Many cancers upregulate GSH to confer resistance against cell death by ferroptosis and anticancer drugs, so mGSH depletion is a potential anticancer strategy. We previously developed MitoCDNB, a mitochondria-targeted molecule that selectively depletes mGSH and disrupts mitochondrial thiol redox homeostasis. However, mGSH depletion by MitoCDNB required catalysis by glutathione-S-transferases (GSTs). Here, we develop a dual-action prodrug scaffold to deplete mGSH independently of GSTs and simultaneously release a payload to increase oxidative stress. The scaffold has four components: a triphenylphosphonium (TPP) group for targeting to the mitochondria, a GSH-reactive electrophilic dinitroaryl ring bearing a sulfonamide leaving group for depleting mGSH, an ethylenediamine-derived self-immolative linker and a phenolic payload. The rates of nucleophilic aromatic substitution (SNAr) of the sulfonamide by GSH and the cyclisation of the released linker-payload intermediate were measured and the kinetics successfully modelled as consecutive reactions. Under physiological levels of GSH (10 mM) and matrix pH (8.0), our best linker releases a 7-hydroxycoumarin reporter with a half-life of 2.5 min at 30 °C. We used the scaffold for cellular and mitochondrial uptake of a compound that depletes mGSH and releases the redox-cycling pro-oxidant, menadiol/menadione, in the mitochondrial matrix. The combination of mGSH depletion with enhanced mitochondrial ROS production showed synergistic cytotoxicity towards cancer cells, paving the way for the development of dual-action mitochondria-targeted prodrugs as potential cancer therapeutics.
    Keywords:  Cancer; Glutathione; Mitochondria; Oxidative stress; Prodrug; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.ejmech.2026.118706
  11. PLoS One. 2026 ;21(2): e0329048
    The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.
    Hernán A Tirado, Nithya Balasundaram, Jean Jacobs, Fleur Leguay, Lotfi Laaouimir, Nick van Gastel.
      Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic stem and progenitor cells characterized by profound metabolic dysregulation. Pyrimidine biosynthesis has emerged as a critical metabolic dependency in AML, but clinical translation has been hampered by unacceptable toxicity of current pyrimidine synthesis inhibitors. Since aspartate is an essential nutrient for pyrimidine biosynthesis, we investigated the role of aspartate import via the excitatory amino acid transporter 1 (EAAT1) in AML. We found that EAAT1 is broadly expressed across AML cell lines and patient samples, with enrichment in M4 and M5 subtypes and increasing levels following chemotherapy treatment. Pharmacological inhibition of EAAT1 impaired AML cell viability in vitro, but metabolomic profiling and nutrient rescue experiments showed that these effects were independent of intracellular aspartate levels. Moreover, AML cells cultured in aspartate-free medium maintained proliferation and did not become more sensitive to chemotherapy. EAAT1 inhibition in mice increased bone marrow plasma aspartate levels, confirming inhibition of cellular aspartate uptake, but did not affect growth or chemosensitivity of MLL-AF9-expressing AML cells in vivo. These findings suggest that AML cells possess several complementary mechanisms to support their aspartate requirements and that EAAT1 inhibition does not impair AML growth or response to chemotherapy.
    DOI:  https://doi.org/10.1371/journal.pone.0329048
  12. Nat Struct Mol Biol. 2026 Feb 27.
    Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
    Lara Kroczek, Hendrik Nolte, Yvonne Lasarzewski, Ishita Agrawal, Thibaut Molinié, Daniel Curbelo Piñero, Kathrin Lemke, Elena Rugarli, Thomas Langer.
      Mitochondria dynamically adapt to cellular stress to ensure cell survival. The stress-regulated mitochondrial peptidase OMA1 orchestrates these adaptive responses, which limit mitochondrial fusion and promote mitochondrial stress signaling and metabolic rewiring. Here, we show that cellular stress adaptation involves OMA1-mediated regulation of mitochondrial protein import and OXPHOS biogenesis. OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response. Our results demonstrate stress-dependent changes in mitochondrial protein import as part of the OMA1-mediated mitochondrial stress response and highlight the interdependence of proteostasis regulation between different organelles.
    DOI:  https://doi.org/10.1038/s41594-026-01756-0
  13. Sci Adv. 2026 Feb 27. 12(9): eaeb0049
    Specific SLC25 carriers regulate mitochondrial protein synthesis.
    Danielle L Rudler, Laetitia A Hughes, Martin S King, Jessica Baker, Richard G Lee, Andrianto P Gandadireja, Anisha Sunil, Samuel V Fagan, Blake Payne, Nicola Gray, Tim McCubbin, Edmund R S Kunji, Oliver Rackham, Aleksandra Filipovska.
      A genome-wide knockout screen identified members of the SLC25 family of mitochondrial carrier proteins as important regulators of the rate of de novo mitochondrial protein synthesis. To elucidate this relationship, we generated human cell knockouts for SLC25A25, SLC25A44, SLC25A45, and SLC25A48, which have been shown to exchange adenosine triphosphate-magnesium (ATP-Mg) and phosphate, branched-chain amino acids, methylated basic amino acids, and choline, respectively. Multiomic and functional analyses identified that these four carriers are crucial for mitochondrial translation, biogenesis and function of the oxidative phosphorylation system, as well as mitochondrial morphology. Thermostability screens showed that SLC25A48 is specifically stabilized by choline, and changes in the mitochondrial metabolome and lipidome indicated defects in choline biosynthetic pathways and remodeling of mitochondrial membranes, both consistent with SLC25A48 being a choline transporter. These results highlight the essential roles of specific SLC25 transporters in maintaining mitochondrial structure and function and show that impaired transport of branched-chain amino acids, methylated basic amino acids, ATP-Mg, and choline affects mitochondrial translation.
    DOI:  https://doi.org/10.1126/sciadv.aeb0049
  14. bioRxiv. 2026 Feb 10. pii: 2026.02.09.704975. [Epub ahead of print]
    Systemic hypoxia suppresses solid tumor growth.
    Ayush D Midha, Brandon T L Chew, Benedict M H Choi, Jung Min Suh, Chris Carpenter, Alan H Baik, Tej A Joshi, Skyler Y Blume, Augustinus G Haribowo, Pedro Ruivo, Will R Flanigan, Ankur Garg, Daniel D Zhang, Vishvak Subramanyam, Rebecca Shuere, Youngho Seo, Henry VanBrocklin, Hani Goodarzi, Isha H Jain.
      Local hypoxia is a hallmark of solid tumors and a negative prognostic factor in the progression and treatment of cancer. Here, we showed that systemic hypoxia, in contrast to localized tumor hypoxia, decreases tumor growth in vivo across multiple cancer types and preclinical models. The reduced tumor growth in systemic hypoxia was not explained by hypoglycemia, hypoinsulinemia, or HIF activation. Instead, metabolite profiling in tumors and tumor interstitial fluid revealed extensive perturbations in purine-related metabolites. Stable isotope tracing demonstrated that systemic hypoxia caused tumors to suppress de novo purine synthesis. Furthermore, tumors did not develop resistance to systemic hypoxia therapy, and when used in combination with chemotherapy or immunotherapy, systemic hypoxia dramatically suppressed tumor growth. Finally, we showed that systemic hypoxia can be achieved pharmacologically with the small molecule HypoxyStat. These findings challenge the long-held paradigm of hypoxia as a negative prognostic factor in cancer progression, and they suggest a potential therapeutic role for systemic hypoxia in suppressing solid tumor growth.
    DOI:  https://doi.org/10.64898/2026.02.09.704975
  15. Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2535298123
    Phenotypic CRISPR screens identify NLRX1 as an essential activator of the human mitochondrial permeability transition.
    William C Valinsky, Robert P Ray, Kathy S Schaefer, Jonathan B Grimm, Carla Nicolini, Luke D Lavis, David E Clapham.
      The mitochondrial permeability transition (mPT) is an evolutionarily conserved destructive process that permeabilizes the inner mitochondrial membrane in response to calcium overload. The molecular mechanism underlying the mPT is not established. To unambiguously identify essential proteins, we designed two phenotypic assays for mitochondrial calcium overload and applied them to FACS-based CRISPR screening in human cells, ultimately evaluating 19,113 genes. The first screen studied mitochondrial membrane potential (MMP) collapse in response to calcium overload. Top-ranked genes were the essential proteins of the mitochondrial calcium uniporter complex, MCU and EMRE, reflecting that the calcium-induced MMP collapse results from mitochondrial calcium entry and not the mPT. The second screen measured the permeability of the inner mitochondrial membrane. Here, the fluorescent interaction of a membrane impermeant ~600 Da dye and a mitochondrial-targeted HaloTag protein was studied under mPT activating conditions; calcium overload and the thiol-reactive molecule phenylarsine oxide. With secondary validation, we identified four protein-encoding genes that delayed or prevented the mPT under knockout: NF2, REST, BPTF, and NRLX1. Knockout of the nonmitochondrial proteins BPTF, NF2, or REST increased mitochondrial calcium retention capacity (CRC). However, calcium release or sensitivity to cyclosporin A (CsA) persisted, indicative of mPT sensitizers. Only knockout of the mitochondrial matrix protein, NLRX1, increased CRC, abolished calcium release, and was CsA-insensitive. This top-ranked hit of the mitochondrial permeability screen meets the definition of an essential mPT activator. Integral membrane proteins, including all previously proposed mPT candidates, were not essential activators.
    Keywords:  MCU; NLRX1; calcium; mitochondria; permeability transition
    DOI:  https://doi.org/10.1073/pnas.2535298123
  16. Nat Commun. 2026 Feb 25.
    A gated hydrophobic funnel within BAX binds bioactive lipids to potentiate pro-apoptotic function.
    Jesse D Gelles, Yiyang Chen, Mark P A Luna-Vargas, Ariele Viacava Follis, Md Abdullah Al Noman, Md Kabir, Stella G Bayiokos, Jarvier N Mohammed, Tara M Sebastian, Ngoc Dung Pham, Yi Shi, Jian Jin, Richard W Kriwacki, Jerry Edward Chipuk.
      Mitochondria maintain a distinct biochemical environment that cooperates with pro-apoptotic BAX and BH3‑only proteins (e.g., BIM) to promote mitochondrial outer membrane permeabilization (MOMP), the key event to initiate physiological and pharmacological forms of apoptosis. The sphingosine-1-phosphate metabolite 2-trans-hexadecenal (2t‑hexadecenal) is a bioactive lipid that supports BAX-dependent MOMP. Using integrated structural and computational approaches, we determine that 2t‑hexadecenal binds within a distinct, dynamic region-a hydrophobic cavity formed by core-facing residues of α5, α6, and gated by α8-we now term the "BAX actuating funnel" (BAF). Complementary biochemical and biophysical techniques reveal that 2t-hexadecenal non-covalently interacts with the BAF and cooperates with BIM to stimulate intramolecular activation of monomeric BAX prior to membrane association. BAX α8 mobility and proline 168-mediated allostery are critical determinants for 2t-hexadecenal synergy with BAX and BIM, as is alkenal length to stimulate BAF function. Collectively, this work imparts detailed molecular insights into how pro-apoptotic BCL-2 proteins and bioactive lipids non-covalently cooperate to initiate the mitochondrial pathway of apoptosis with implications for biological and therapeutic regulation.
    DOI:  https://doi.org/10.1038/s41467-026-69836-9
  17. Nat Commun. 2026 Feb 23.
    PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation.
    Sangheeta Bhattacharjee, Sayan Das, Banhi Chowdhury, Benu Brata Das.
      Protein arginine methyltransferase 5 (PRMT5) catalyzes arginine methylation and regulates cellular functions such as proliferation, RNA splicing, and nuclear DNA damage response. This study uncovers that a fraction of nuclear-encoded PRMT5 localizes to the mitochondria, which is critical for maintaining mitochondrial DNA (mtDNA) homeostasis. PRMT5 knockout (PRMT5-/-) cells had reduced nucleoid counts, diminished mtDNA copy numbers, disrupted the balance of the mitochondrial fission-fusion cycle, impaired mitochondrial plasticity, and nucleoid trafficking. PRMT5-/- cells are hypersensitive to mtDNA-damaging agents, exhibit reduced mitochondrial transcripts, oxidative phosphorylation, and respiratory capacity that triggers cell death. We identify TFAM as a previously unrecognized interacting partner of PRMT5, which catalyzes symmetric dimethylation of TFAM at R82 residue, which is crucial for mtDNA binding and protection. Defective R82-methylation destabilizes TFAM, which is then degraded by LonP1. Together, we establish that PRMT5 is a mitochondrial enzyme and a key regulator of TFAM in mtDNA maintenance.
    DOI:  https://doi.org/10.1038/s41467-026-69676-7
  18. Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2535701123
    When alternative becomes essential: The role of mitochondrial glycerol-3-phosphate dehydrogenase.
    Léa Herpe, Mélanie Aminot, Nicolas Pichaud.
      Complex I is known as the primary entry point for electrons within the mitochondrial electron transport system (ETS). However, the glycerol-3-phosphate (G3P) shuttle, composed of cytosolic and mitochondrial G3P dehydrogenase (cG3PDH and mtG3PDH, respectively), transfer reducing equivalents from the cytosol to the mitochondrial matrix. The mtG3PDH feeds electrons into the ETS via FADH2 oxidation, but with theoretically lower energy conversion efficiency than complex I. It is thus believed to be an "alternative" pathway, only supporting mitochondrial respiration when complex I fails. mtG3PDH also plays an important role in reactive oxygen species (ROS) production. To investigate the role of this understudied protein in mitochondrial bioenergetics and redox homeostasis, we generated Drosophila melanogaster mutant lines for mtG3PDH (GPO1) using a CRISPR/Cas9-based approach and determined several physiological and metabolic parameters. A drastically higher mortality rate was observed among the GPO1 flies, as well as a lethargic behavior characterized by an inability to climb. These results are in accordance with an impaired mitochondrial efficiency (ATP/O) mainly due to decreased ATP production (~60% decrease) and O2 consumption (~33% decrease), rather than elevated ROS. In fact, GPO1 flies produced ~70% less ROS than controls, likely due to the reduced direct and reverse electron transfer-related ROS production from mtG3PDH. These results support an essential role of mtG3PDH in mitochondrial bioenergetic, challenging its alternative aspect, and confirming its importance in mitochondrial redox homeostasis.
    Keywords:  Drosophila; comparative physiology; glycerol-3-phosphate; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1073/pnas.2535701123
  19. Front Oncol. 2025 ;15 1606239
    A mammalian, glutaminase-free asparaginase enhances venetoclax activity in preclinical AML models with chromosome 7 deletion.
    Dhabya Majid, Zhe Wang, Amanda M Schalk, Bin Yuan, Qi Zhang Tatarata, Jessica L Root, Araceli Isabella Garza, Mhd Yousuf Yassouf, Basant T Gamal, Sammy Feri-Borgogno, Annie Hoai Nguyen, Marina Konopleva, Evelien Peeters, Ying Su, Patrick K Reville, Farhad Ravandi-Kashani, Arnon Lavie, Hussein A Abbas.
       Introduction: Acute myeloid leukemia (AML) remains a malignancy with poor prognosis andfrequent resistance to standard therapies, underscoring the urgent need for novel treatmentstrategies. In this preclinical study, we evaluated the anti-leukemic efficacy of EBD-300, a novelmammalian-derived asparaginase lacking glutaminase activity, in combination with Venetoclax(VEN).
    Results: EBD-300 monotherapy exhibited significant activity in AML cell lines harboringchromosome 7/7q deletions, which are likely dependent on extracellular asparagine due to thepresence of only a single copy of the asparagine synthetase (ASNS) gene - the enzymeresponsible for endogenous asparagine synthesis. The combination of EBD-300 with VENdecreased the IC50 values of some VEN-resistant AML cell lines and reduced the colony-formingcapacity of primary AML patient samples. In patient-derived xenograft (PDX) mouse models,EBD-300, alone or in combination with VEN, significantly reduced leukemic burden in theperipheral blood, bone marrow, and spleen, and improved overall survival in one model.
    Discussion: Although survival benefits were observed in some, but not all, models, suggestingpotential model-specific effects, these findings collectively support a potential therapeutic roleEBD-300 in combination with VEN in AML. While weight loss was observed, EBD-300 mayrepresent a potentially safer alternative to conventional bacterial asparaginases by mitigatingthe adverse effects typically associated with the glutaminase coactivity of the bacterialasparaginases, an observation that requires further investigation.
    Keywords:  AML; AML with deletion 7; acute myeliod leukemia; asparaginase; combination treatment; leukemia; venetoclax
    DOI:  https://doi.org/10.3389/fonc.2025.1606239
  20. Res Sq. 2026 Feb 20. pii: rs.3.rs-8744427. [Epub ahead of print]
    Hot Mitochondria and the Second Law of Thermodynamics.
    Alexei Tkachenko, Belem Yoval-Sánchez, Alexander Galkin.
      Mitochondria are central hubs of cellular bioenergetics, converting chemical free energy into ATP while inevitably releasing heat during respiration. Fluorescence-based thermometry has been interpreted to show intracellular "hot spots" more than 10 °C above the bulk physiological temperature, implying that mitochondria might operate far outside conventional thermal bounds. Such claims, however, appear inconsistent with basic biophysics: the small size of mitochondria, their aqueous and highly conductive environment, and their limited power output all argue against large steady-state temperature gradients. This discrepancy has prompted renewed scrutiny of both the physical limits of intracellular heat transfer and the biological interpretation of nanoscale thermal measurements. A key open question is whether nonequilibrium biochemical processes, such as respiration-driven proton pumping, could act as nanoscale heat pumps that maintain higher local temperatures than allowed by passive diffusion alone. Here, we develop a model-independent thermodynamic analysis based solely on the Second Law of Thermodynamics to bound the maximal temperature difference that any biochemically driven mechanism can sustain across the inner mitochondrial membrane and show that even under idealized conditions the achievable temperature rise is restricted to a small fraction of a degree, effectively closing this loophole.
    DOI:  https://doi.org/10.21203/rs.3.rs-8744427/v1
  21. Free Radic Biol Med. 2026 Feb 19. pii: S0891-5849(26)00146-2. [Epub ahead of print]248 162-176
    Optineurin enhances the chemoresistance by activating mitophagy in acute myeloid leukemia with NPM1 mutation.
    Lisha Tang, Nan Wu, Qiaoling Xiao, Jing Yang, Jun Ren, Xinyi Chen, Wen Zhao, Yongcan Liu, Jiayuan Hu, Zailin Yang, Xiaoling Gao, Ling Zhang.
      Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutation is a common genetic subtype with unique pathological features. However, current therapies remain challenged by relapse and drug resistance, underscoring an urgent need for novel therapeutic strategies. In this study, we identified hyperactivated mitophagy as a critical metabolic vulnerability in NPM1-mutated AML through bioinformatics analysis and experimental validation. Mechanistically, augmented mitophagy was driven by high expression of the mitophagy receptor optineurin (OPTN), which was upregulated by cytoplasmic dislocation of CCCTC binding factor (CTCF) in cells harboring the NPM1 mutant. Functionally, OPTN-mediated mitophagy promoted leukemogenesis by maintaining mitochondrial homeostasis, thereby sustaining leukemia cell proliferation and conferring chemoresistance. Correspondingly, genetic inhibition of OPTN suppressed mitophagy, disrupted mitochondrial homeostasis, and sensitized cells to cytarabine (Ara-C), ultimately potentiating its antileukemic efficacy in a cell-derived xenograft (CDX) model. Collectively, these findings indicate that OPTN-mediated mitophagy is an oncogenic driver in NPM1-mutated AML and that, targeted inhibition of this process is a promising strategy for overcoming chemoresistance, particularly in combination with conventional chemotherapy.
    Keywords:  Acute myeloid leukemia; Chemotherapeutic sensitivity; Mitochondrial homeostasis; Mitophagy; Nucleophosmin 1; OPTN
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.049
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