bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–08–03
25 papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.
  2. Mitochondrial metabolism: Critical mechanisms underpinning normal hematopoietic stem cell and acute myeloid leukemia stem cell function.
  3. De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.
  4. Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.
  5. ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
  6. Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.
  7. Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.
  8. Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
  9. Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry.
  10. Rewiring cancer metabolism: oncogenic signaling pathways and targeted therapeutics.
  11. Rab14 promotes Parkin mediated mitophagy.
  12. PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP.
  13. Bioenergetic profiles and respiratory control in mitochondrial physiology: Precision analysis of oxidative phosphorylation.
  14. In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
  15. Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
  16. Oligomer-based functions of mitochondrial porin.
  17. Mitochondrial pyruvate dehydrogenase phosphatase metabolism disorder in malignant tumors.
  18. Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.
  19. The source of dietary fat influences anti-tumour immunity in obese mice.
  20. ACLY inhibition promotes tumour immunity and suppresses liver cancer.
  21. Hypoxia-Induced Creatine Uptake Reprograms Metabolism to Antagonize PARP1-Mediated Cell Death and Facilitate Tumor Progression in Hepatocellular Carcinoma.
  22. Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death.
  23. SLC39A13 Regulates Heart Function via Mitochondrial Iron Homeostasis Maintenance.
  24. Cardiolipin acyl chain composition tailors the conformation of mammalian ATP synthase dimers.
  25. PDK1-dependent metabolic reprogramming regulates stemness and tumorigenicity of osteosarcoma stem cells through ATF3.
  1. Blood. 2025 Aug 01. pii: blood.2024027822. [Epub ahead of print]
    Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.
    Cornelius Pauli, Michael Kienhöfer, Maximilian Felix Blank, Oguzhan Begik, Christian Rohde, Sarah Mn Zimmermann, Laura Werner, Daniel Heid, Fu Xu, Katharina Weidenauer, Sylvain Delaunay, Nadja Krall, Katrin Trunk, Duoduo Zhao, Fengbiao Zhou, Laia Llovera, Ollivier Alexane, Anke Heit-Mondrzyk, Uwe Platzbecker, Claudia D Baldus, Hubert Serve, Martin Bornhäuser, Cathrine B Vågbø, Salvador Aznar Benitah, Jeroen Krijgsveld, Eva Maria Novoa, Carsten Müller-Tidow, Michaela Frye.
      Dysregulated RNA modifications contribute to cancer progression and therapy resistance, yet the underlying mechanism often remains unknown. Here, we perform CRISPR-based synthetic lethality screens to systematically explore the role of RNA modifications in mediating resistance to anti-leukaemic drugs. We identify the TRMT5-mediated formation of N1-methylguanosine (m1G) in the tRNA anticodon loop as essential for mediating drug tolerance to cytarabine and venetoclax in acute myeloid leukemia (AML). TRMT5 methylates nearly all mitochondrial and nuclear tRNAs with a guanosine at position 37, but its role in promoting drug tolerance specifically depends on its mitochondrial function. TRMT5 is essential for the dynamic upregulation of mitochondrial mRNA translation and oxidative phosphorylation (OXPHOS), which are critical for sustaining drug tolerance in leukemia cells. This mitochondrial dependency correlates with therapy outcomes in leukemia patients: lower expression of electron transport chain genes is linked to poorer outcomes in a cohort of nearly 100 AML patients undergoing first induction therapy. Finally, we demonstrate that targeted depletion of TRMT5 protein using a conditional degron, in conjunction with cytarabine and venetoclax treatment, synergistically induces cell death in drug-tolerant AML cells. Thus, our study reveals TRMT5 as promising drug target for therapy-resistant leukemia.
    DOI:  https://doi.org/10.1182/blood.2024027822
  2. Gene. 2025 Jul 25. pii: S0378-1119(25)00474-3. [Epub ahead of print]966 149685
    Mitochondrial metabolism: Critical mechanisms underpinning normal hematopoietic stem cell and acute myeloid leukemia stem cell function.
    Huasong Yu, Lin Yan.
      AML (Acute myeloid leukemia) is an aggressive cancer of the blood and bone marrow characterized by the excessive proliferation of immature white blood cells, that disrupt normal hematopoiesis. LSCs (Leukemic stem cells) represent a subpopulation of AML cells with stem cell-like properties that drive AML initiation, progression, and relapse by evading conventional therapies and sustaining leukemic growth. Despite advances in understanding AML biology, particularly their metabolic alternations, remain poorly understood. Indeed, recent studies have shown that mitochondrial metabolism plays a pivotal role in the regulation of both normal HSCs (hematopoietic stem cells) and LSCs. In this review, we delve into the mitochondrial metabolic characteristics of normal HSCs to provide comprehensive background knowledge. Subsequently, we thoroughly analyze how the distinctive metabolic features of LSCs, highlighting the impact of these differences on cell function and survival. We also investigate the unique mechanisms of drug resistance in LSCs, explaining how these mechanisms enhance the survival of LSCs in the face of conventional treatments. Finally, we discuss emerging therapeutic strategies targeting the mitochondrial metabolism of LSCs in AML, and we discuss prospective therapeutic strategies and future research directions.
    Keywords:  Acute myeloid leukemia; Hematopoietic stem cell; Leukemia stem cell; Metabolism; Mitochondria; Mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.gene.2025.149685
  3. Nat Commun. 2025 Jul 30. 16(1): 6987
    De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.
    Huan Zhang, Naiara Santana-Codina, Qijia Yu, Clara Poupault, Claudia Campos, Xingping Qin, Nicole Sindoni, Marina Ciscar, Aparna Padhye, Miljan Kuljanin, Junning Wang, Matthew J Dorman, Peter Bross, Andrew J Aguirre, Stephanie K Dougan, Kristopher A Sarosiek, Joseph D Mancias.
      Oncogenic KRAS induces metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC) characterized, in part, by dependency on de novo pyrimidine biosynthesis. Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, delays pancreatic tumor growth; however, limited monotherapy efficacy suggests that compensatory pathways may drive resistance. Here, we use an integrated metabolomic, proteomic and in vitro and in vivo DHODH inhibitor-anchored genetic screening approach to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination therapy strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Co-targeting DHODH and BCL-XL synergistically induces apoptosis in PDAC cells and patient-derived organoids. The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC.
    DOI:  https://doi.org/10.1038/s41467-025-61242-x
  4. Blood. 2025 Aug 01. pii: blood.2024028079. [Epub ahead of print]
    Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.
    Abhishek K Singh, Angelo D'Alessandro, Ashley Wellendorf, Daniel Gonzalez-Nieto, Matthew Kofron, Monika Dzieciatkowska, Leo Mejia, Luis Barrio, Marie-Dominique Filippi, Jose A Cancelas.
      Hematopoietic stem cells (HSC) exhibit a distinctive antioxidant profile during steady-state and stress hematopoiesis. HSC and multipotential progenitors (HSC/MPP) are metabolically coupled to bone marrow (BM) mesenchymal stromal cells through mitochondrial transfer, a process dependent on hematopoietic connexin 43 (Cx43) and low AMP-activated protein kinase (AMPK) activity. However, the mechanism by which Cx43 preserves mitochondrial functionality in HSC remains elusive. Here, through integrated transcriptomic, proteomic, metabolomic, phenotypic, and functional analyses of HSC and their isolated mitochondria, we identified that Cx43 is present on inner and outer mitochondrial membranes of HSC/MPP, where it primarily regulates mitochondrial metabolism and ATP synthesis by preserving the mitochondrial cristae, activation of mitochondrial AMPK and 2-oxoglutarate dehydrogenase (OGDH)-a rate liming enzyme in TCA cycle and electron transfer chain. During replicative stress, Cx43 deficient HSC/MPP fail to adapt metabolically, accumulate mitochondrial Ca2+, increase mitochondrial AMPK activity, mitochondrial fission, mitophagy, and production of reactive oxygen species, thereby limiting HSC/MPP regeneration potential. Disruption of hyper mitochondrial fragmentation and mitophagy by Drp1 dominant negative mutant (Drp1K38A) or restoration of mitochondrial function through ex vivo heteroplasmy prevent the harmful effects of Cx43 deficiency on mitochondrial metabolism and restore HSC activity in serial transplantation experiments. Re-expression analysis of Cx43 structure function mutants indicate that Cx43 hemichannels are sufficient to reset HSC mitochondrial metabolism, dynamics, Ca2+ levels, and regeneration capacity. This report defines the cell-autonomous mechanism of action behind the role of Cx43 in HSC activity and opens a venue to translational applications in transplantation.
    DOI:  https://doi.org/10.1182/blood.2024028079
  5. Cell Death Discov. 2025 Jul 29. 11(1): 349
    ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
    Mudassar Ali, Anjali, Koyeli Mapa.
      Mitochondria, the double membrane-bound organelles of endosymbiotic origin, are crucial centers for cellular energy production and several essential metabolic pathways. Recent studies reveal that mitochondria become dysfunctional following numerous cellular stresses, and during pathologies, demanding an extensive investigation of mitochondrial turnover mechanisms. Apart from the specific response pathways to tackle different stresses, mitophagy, or degradation of mitochondria by autophagy, is a critical quality control mechanism that clears irreversibly damaged mitochondria. Mitophagy is majorly executed either by receptor-mediated or PINK1-Parkin-dependent pathways. Here, we show that the human orthologue of yeast Vms1, ANKZF1, participates in PINK1-Parkin-mediated mitophagy. We show that ANKZF1 is extensively recruited to damaged mitochondria along with Parkin during mitochondrial proteotoxic stress induced by the expression of a single misfolded/aggregated protein or during uncoupler-induced membrane depolarization. Importantly, ANKZF1 recruitment to damaged mitochondria is significantly enhanced in the presence of Parkin, and ANKZF1 physically interacts with Parkin and LC3 during mitochondrial proteotoxic or depolarization stress. ANKZF1 harbors six putative LC3-interacting regions (LIRs), LIR4 present at residues 333-336, is particularly important for ANKZF1-LC3 interaction. Furthermore, we show that ANKZF1 knockout cells are compromised in clearing stress-damaged mitochondria by mitophagy, indicating an important role of ANKZF1 in mitochondrial turnover during stress. In summary, we show a new role of ANKZF1 in eliminating the stress-damaged mitochondria, reiterating the mito-protective role of Vms1/ANKZF1 during mitochondrial stresses. PINK1/Parkin signaling leads to polyubiquitination of outer mitochondrial membrane (OMM) proteins on stressed mitochondria. ANKZF1 functions as an adaptor protein, binding to polyubiquitinated OMM proteins via UBA domain and autophagosome receptor LC3 via LIR motif.
    DOI:  https://doi.org/10.1038/s41420-025-02638-y
  6. Nat Commun. 2025 Jul 28. 16(1): 6923
    Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.
    Andrew Roe, Catríona M Dowling, Cian D'Arcy, Daniel Alencar Rodrigues, Yu Wang, Matthew Hiller, Carl Keogh, Kate E R Hollinshead, Massimiliano Garre, Brenton Cavanagh, Kieran Wynne, Tianyan Liu, Zhixing Chen, Emma Kerr, Marie McIlroy, Jochen H M Prehn, Ingmar Schoen, Tríona Ní Chonghaile.
      Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negative breast cancer cells, HDAC6 inhibition or knockdown results in alterations to mitochondrial cristae structure, as detected by live-cell super-resolution STED nanoscopy and electron microscopy, along with the release of mitochondrial DNA. Mass-spectrometry immunoprecipitation reveals multiple mitochondrial HDAC6-interactors, with FH emerging as a top hit. Super-resolution 3D-STORM shows HDAC6 interactions with FH in mitochondrial networks, which increases after perturbation of HDAC6 activity with BAS-2. Treatment with BAS-2 leads to fumarate accumulation by 13C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism.
    DOI:  https://doi.org/10.1038/s41467-025-61897-6
  7. Cancer Discov. 2025 Jul 31.
    Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.
    Hsi-Wen Yeh, Nicole Lauren DelGaudio, Beste Uygur, Alon Millet, Artem Khan, Gokhan Unlu, Michael Xiao, Rebecca C Timson, Caifan Li, Kerem Ozcan, Karl W Smith, Luiza Martins Nascentes Melo, Gabriele Allies, Olca Basturk, Albert Sickmann, Erol C Bayraktar, Richard Possemato, Alpaslan Tasdogan, Kivanc Birsoy.
      Cancer cells require substantial metabolic adaptations to metastasize to distant organs, but the metabolites essential for successful colonization remain poorly defined. Here, we used a mitochondrial metabolomics approach to compare primary and metastatic breast cancer cells. This analysis revealed accumulation of mitochondrial glutathione (GSH) during lung metastasis, driven by elevated expression of SLC25A39, a mitochondrial GSH transporter. Loss of SLC25A39 impairs metastatic colonization in genetic screens, cell line models, and patient-derived xenografts, without affecting primary tumor growth. Mitochondrial GSH import is specifically required during early colonization and functions independently of its canonical antioxidant role. CRISPR activation screens identified ATF4, a stress-induced transcription factor, as a bypass mechanism that restores metastatic potential in SLC25A39-deficient cells. Mechanistically, SLC25A39 is required for optimal ATF4 activation during metastasis and under hypoxia, linking mitochondrial GSH availability to integrated stress response signaling. These findings identify mitochondrial GSH as a necessary and limiting metabolite for metastatic progression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1556
  8. Mol Biol Cell. 2025 Jul 30. mbcE25010033
    Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
    Sara Wong, Katherine R Bertram, Sai Sangeetha Balasubramaniam, Nidhi Raghuram, Thomas Knight, J Alan Maschek, James E Cox, Adam L Hughes.
      Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
    DOI:  https://doi.org/10.1091/mbc.E25-01-0033
  9. Nature. 2025 Jul 30.
    Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry.
    Debasish Paul, Derek L Bolhuis, Hualong Yan, Sudipto Das, Xia Xu, Christina C Abbate, Lisa M M Jenkins, Michael J Emanuele, Thorkell Andresson, Jing Huang, John G Albeck, Nicholas G Brown, Steven D Cappell.
      Mammalian cells entering the cell cycle favour glycolysis to rapidly generate ATP and produce the biosynthetic intermediates that are required for rapid biomass accumulation1. Simultaneously, the ubiquitin-ligase anaphase-promoting complex/cyclosome and its coactivator CDH1 (APC/CCDH1) remains active, allowing origin licensing and blocking premature DNA replication. Paradoxically, glycolysis is reduced by APC/CCDH1 through the degradation of key glycolytic enzymes2, raising the question of how cells coordinate these mutually exclusive events to ensure proper cell division. Here we show that cells resolve this paradox by transiently inactivating the APC/C during cell cycle entry, which allows a transient metabolic shift favouring glycolysis. After mitogen stimulation, rapid mTOR-mediated phosphorylation of the APC/C adapter protein CDH1 at the amino terminus causes it to partially dissociate from the APC/C. This partial inactivation of the APC/C leads to the accumulation of PFKFB3, a rate-limiting enzyme for glycolysis, promoting a metabolic shift towards glycolysis. Delayed accumulation of phosphatase activity later removes CDH1 phosphorylation, restoring full APC/C activity, and shifting cells back to favouring oxidative phosphorylation. Thus, cells coordinate the simultaneous demands of cell cycle progression and metabolism through an incoherent feedforward loop, which transiently inhibits APC/C activity to generate a pulse of glycolysis that is required for mammalian cell cycle entry.
    DOI:  https://doi.org/10.1038/s41586-025-09328-w
  10. Sci China Life Sci. 2025 Jul 25.
    Rewiring cancer metabolism: oncogenic signaling pathways and targeted therapeutics.
    Siying Lyu, Nina Gildor, Qing Zhang, Chengheng Liao.
      Metabolic reprogramming is a hallmark of cancer, playing a critical role in tumorigenesis by supporting cancer cell survival, proliferation, metastasis, and immune evasion. Oncogenic signaling pathways regulate key metabolic processes by orchestrating gene expression and enhancing metabolic enzyme activity, ensuring cancer cells meet their bioenergetic and biosynthetic demands. Here, we highlight the roles of major oncogenic metabolic signaling pathways, including phosphoinositide 3-kinase (PI3K)/AKT, Myc, p53, and hypoxia-inducible factor (HIF), in driving metabolic rewiring. We provide a conceptual framework to understand why metabolic reprogramming occurs in tumor cells, how metabolic alterations contribute to tumorigenesis, metastasis, and immune evasion, and the therapeutic implications of targeting these metabolic vulnerabilities in cancer.
    Keywords:  cancer metabolism; cell proliferation; immune evasion; metastasis; oncogenic signaling pathways; target therapy
    DOI:  https://doi.org/10.1007/s11427-025-2979-3
  11. Mol Biol Cell. 2025 Jul 30. mbcE25060271
    Rab14 promotes Parkin mediated mitophagy.
    Samina Momtaz, Marco Padilla-Rodriguez, Paola Cruz Flores, Natalia Rulli, Nam Yong Lee, Jean M Wilson.
      Mitochondrial degradation by mitophagy is essential to maintain cell metabolism; dysregulation can result in the accumulation of damaged mitochondria. While the Rab family of small GTPase proteins are involved with vesicular trafficking in the endocytic and biosynthetic pathways, Rab-GTPases also have a role in mitochondrial integrity. However, a role for Rab14, a trans-Golgi network (TGN)-endosomal Rab-GTPase in mitophagy has not been described. In cells knocked down for Rab14, mitochondria acquire an elongated morphology and increased levels of mitochondrial proteins, whereas overexpression of Rab14 decreased these proteins. Furthermore, mito-Keima assays show increased mitophagy upon Rab14 overexpression. Rab14-induced mitophagy is dependent on Parkin expression, as well as TBK1 and PI3K activity, placing it in the Parkin-dependent mitophagy pathway. 3D-reconstruction shows contact site formation between Rab14 and mitochondria, and inhibition of the TGN kinase PI(4)KIIIβ decreases Rab14-mitochondria contact sites and prevents Rab14-mediated mitophagy, suggesting that TGN-derived Rab14 vesicles mediate mitophagy. These results suggest that Rab14 promotes mitophagy and plays an essential role in modulating cellular metabolism. [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-06-0271
  12. Elife. 2025 Jul 30. pii: RP101244. [Epub ahead of print]13
    PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP.
    Jiongke Wang, Yujie Shi, Ying Wang, Yingqiang Shen, Huan Liu, Silu Sun, Yimei Wang, Xikun Zhou, Yu Zhou, Xin Zeng, Jing Li, Qianming Chen.
      Proteasome activator 28γ (PA28γ) plays a critical role in malignant progression of various tumors, however, its role and regulation are not well understood. Here, using oral squamous cell carcinoma (OSCC) as the main research model, and combining co-immunoprecipitation (Co-IP), proximity ligation assays (PLA), AlphaFold 3-based molecular docking, and truncation constructs, we discovered that PA28γ interacted with complement 1q binding protein (C1QBP). This interaction is dependent on the C1QBP N-terminus (aa 1-167) rather than the known functional domain. Point mutation in C1QBP (T76A/G78N) disrupting predicted hydrogen bonding with PA28γ-D177 significantly reduced their binding. Notably, we found that PA28γ enhances C1QBP protein stability in OSCC. Functionally, PA28γ and C1QBP co-localized in mitochondria, promoting fusion (via upregulation of OPA1, MFN1/2), respiratory complex expression, oxidative phosphorylation (OXPHOS), ATP production, and ROS generation. Crucially, PA28γ-enhanced OSCC cell migration, invasion, and proliferation in vitro were dependent on C1QBP. In vivo, orthotopic OSCC models showed Pa28γ overexpression increased tumor growth and elevated C1qbp levels, correlating with elevated ATP and ROS. Using transgenic Psme3-/- mice and subcutaneous tumor grafts, we confirmed that silencing of Pa28γ suppresses tumor growth, reduces C1qbp levels, and dampens mitochondrial metabolism-specifically in knockout hosts. Clinically, PA28γ and C1QBP expression were positively correlated during oral carcinogenesis and in metastatic OSCC tissues across cohorts. High co-expression predicted poor prognosis in OSCC patients. Thus, PA28γ stabilizes C1QBP via N-terminal interaction to drive mitochondrial OXPHOS and tumor progression, highlighting its potential as a therapeutic target.
    Keywords:  C1QBP; PA28γ; cancer biology; human; mitochondria; mouse; oral squamous cell carcinoma; oxidative phosphorylation; protein‒protein interactions
    DOI:  https://doi.org/10.7554/eLife.101244
  13. Exp Physiol. 2025 Aug 01.
    Bioenergetic profiles and respiratory control in mitochondrial physiology: Precision analysis of oxidative phosphorylation.
    Alba Timón-Gómez, Carolina Doerrier, Zuzana Sumbalová, Luiz F Garcia-Souza, Eleonora Baglivo, Luiza H D Cardoso, Erich Gnaiger.
      Oxidative phosphorylation (OXPHOS) is fundamental to mitochondrial function. Respirometry with living cells provides limited information compared to precision OXPHOS analysis with mitochondrial preparations, including isolated mitochondria, tissue homogenates, permeabilized tissues, and permeabilized cells. We studied mouse mitochondria from brain, a glucose-dependent tissue, and from heart, which relies highly on fatty acid oxidation (FAO). HEK 293T cells were analysed as a widely used experimental model. Human peripheral blood mononuclear cells (PBMCs) and platelets were obtained from non-invasive liquid biopsies, considering their potential as mitochondrial biomarkers. Twenty respiratory states were interrogated applying two substrate-uncoupler-inhibitor titration (SUIT) reference protocols in parallel. Convergent electron transfer (ET) into the coenzyme Q junction increased OXPHOS and ET capacities compared to separately stimulated pathways. In mouse heart and human PBMCs, OXPHOS capacities were identical to ET capacities in every pathway state. While this equivalence applied to the NADH-linked pathway in platelets, ET capacity exceeded OXPHOS capacity supported by NADH-linked substrates plus succinate. Surprisingly, mouse brain exhibited the highest excess ET capacity in the NADH-linked pathway. In contrast, ET capacity of different batches of HEK 293T cells varied at constant OXPHOS capacity. Precision OXPHOS analysis enables attribution of respiratory performance to nutrient-specific pathways. In studies ranging from exercise physiology to mitochondrial diseases, metabolic adjustments must be distinguished from functional defects. Bioenergetic profiles obtained by precision OXPHOS analysis gain perspective in the context of comparative mitochondrial physiology.
    Keywords:  OXPHOS; coupling control; electron transfer system (ETS); high‐resolution respirometry (HRR); pathway control; substrate‐uncoupler‐inhibitor‐titration (SUIT) protocol
    DOI:  https://doi.org/10.1113/EP092792
  14. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2511890122
    In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
    Kevin Rose, Eric Herrmann, Eve Kakudji, Javier Lizarrondo, A Yasemin Celebi, Florian Wilfling, Samantha C Lewis, James H Hurley.
      Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN. Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals. Phagophores were visualized, with bridge-like lipid transporter densities connected to mitophagic phagophores. A subpopulation of ATP synthases relocalized from cristae to the inner boundary membrane. The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by subtomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation being enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.
    Keywords:  autophagy; cryo-ET; mitochondria; mitophagy; prohibitin
    DOI:  https://doi.org/10.1073/pnas.2511890122
  15. Commun Biol. 2025 Jul 29. 8(1): 1122
    Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
    Pin-Chao Liao, Tzu-Ying Lin, Catherine A Tsang, Chen-Jing Huang, Katherine Filpo, Istvan Boldogh, Liza A Pon.
      The mitochondria-associated degradation pathway (MAD) mediates removal and elimination of damaged, unfolded mitochondrial proteins by the ubiquitin-proteasome system (UPS). Previous studies revealed that MAD is critical for mitochondrial protein quality control and that MAD function extends beyond mitochondrial outer membrane (MOM) to proteins within the organelle. Here, we reconstitute retrotranslocation of MAD substrates from the mitochondrial matrix across mitochondrial inner and outer membranes in cell-free systems. This retrotranslocation is ATP-dependent but membrane potential-independent. We also identify a role for the TOM complex, the protein import channel in the MOM, in this process. Inhibition of protein translocation across the Tom40p channel reduces the retrotranslocation of MAD substrates. Our studies support the model that the TOM complex is a bidirectional protein channel in the MOM: it mediates retrotranslocation of damaged mitochondrial proteins across the MOM in the MAD pathway for mitochondrial protein quality control in addition to its function in import of proteins into the organelle.
    DOI:  https://doi.org/10.1038/s42003-025-08549-z
  16. Nat Commun. 2025 Jul 25. 16(1): 6854
    Oligomer-based functions of mitochondrial porin.
    Hironori Takeda, Saori Shinoda, Chiho Goto, Akihisa Tsutsumi, Haruka Sakaue, Chunming Zhang, Takashi Hirashima, Yuta Konishi, Haruka Ono, Yu Yamamori, Kentaro Tomii, Hiroya Shiino, Yasushi Tamura, Solène Zuttion, Bruno Senger, Sylvie Friant, Hubert D Becker, Yuhei Araiso, Nanako Kobayashi, Noriyuki Kodera, Masahide Kikkawa, Toshiya Endo.
      Porin, or the voltage-dependent anion channel (VDAC), is a primary β-barrel channel in the mitochondrial outer membrane. It transports small metabolites and ions through its β-barrel pore and plays key roles in apoptosis and inflammatory response. Here we report the cryo-electron microscopy structure of yeast porin (Por1) in its hexameric form at 3.2 Å resolution. This structure allows us to introduce various mutations at the protomer interfaces, uncovering three critical functions of Por1 assembly beyond transport. Por1 binds unassembled Tom22, a subunit of the mitochondrial protein import gate (the TOM complex), to facilitate protein import into the intermembrane space, maintains proper mitochondrial lipid composition in the outer membrane through lipid scramblase activity, and contributes to the retention and regulated loss of mitochondrial DNA, in cooperation with nucleases identified through screening enabled by the obtained Por1 mutant.
    DOI:  https://doi.org/10.1038/s41467-025-62021-4
  17. Oncol Res. 2025 ;33(8): 1861-1874
    Mitochondrial pyruvate dehydrogenase phosphatase metabolism disorder in malignant tumors.
    Yufeng Wang, Huifeng Dang, Qianqian Wang, Shuxiao Wu, Lei Han, X U Luo, Yingxia Tian, Hailin Tang.
      This review focuses on the metabolic issues related to mitochondrial pyruvate dehydrogenase phosphatase (PDP) in malignant tumors and its potential mechanisms. Recent research on tumor metabolic mechanisms has shown that PDP dysregulation is closely linked to metabolic reprogramming in tumor cells, and potentially promotes tumor. Research has comprehensively explored the structural-functional characteristics of PDP, its metabolic regulatory mechanisms, and its role in various types of malignant tumors. Nevertheless, several questions still exist regarding its potential mechanisms within acetylation, phosphorylation, hypoxia, immune infiltration, mitochondrial metabolism, drug resistance, oxidative phosphorylation, and tumor prognosis. This article intends to summarize the latest research, examine PDP's potential as a therapeutic target, and propose future research directions to enhance cancer treatment strategies.
    Keywords:  Malignant tumors; Metabolism; Mitochondria; Pyruvate dehydrogenase phosphatase (PDP)
    DOI:  https://doi.org/10.32604/or.2025.063716
  18. Nat Metab. 2025 Jul 29.
    Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.
    Aparna D Rao, Ling Cai, Marelize Snyman, Rachel E Walsdorf, Xiangyi Li, Sophia N Wix, Gabrielle Gard, Ariel B Brown, Juliana Kim, Joao Santos Patricio, Sarah Muh, Misty Martin Sandoval, Lauren G Zacharias, Kristen A Heimdal, Wen Gu, Jade Homsi, Brittny Tillman, Rohit Sharma, Travis W Vandergriff, Ashley Solmonson, Brandon Faubert, Thomas P Mathews, Sean J Morrison, Ralph J DeBerardinis, Jennifer G Gill.
      Patient-derived xenografts (PDXs) are frequently used as preclinical models, but their recapitulation of tumour metabolism in patients has not been closely examined. We developed a parallel workflow to analyse [U-13C]glucose tracing and metabolomics data from patient melanomas and matched PDXs. Melanomas from patients have substantial TCA cycle labelling, similar to levels in human brain tumours. Although levels of TCA cycle labelling in PDXs were similar to those in the original patient tumours, PDXs had higher labelling in glycolytic metabolites. Through metabolomics, we observed consistent alterations of 100 metabolites among PDXs and patient tumours that reflected species-specific differences in diet, host physiology and microbiota. Despite these differences, most of nearly 200 PDXs retained a 'metabolic fingerprint' largely durable over six passages and often traceable back to the patient tumour of origin. This study identifies both high- and low-fidelity metabolites in the PDX model system, providing a resource for cancer metabolism researchers.
    DOI:  https://doi.org/10.1038/s42255-025-01338-2
  19. Nat Metab. 2025 Jul 25.
    The source of dietary fat influences anti-tumour immunity in obese mice.
    Britta Kunkemoeller, Hannah Prendeville, Claire McIntyre, Ayantu Temesgen, Rόisín M Loftus, Conghui Yao, Lydia Dyck, Linda V Sinclair, Christina Rollings, Aaron Douglas, Gerard Pernes, Kathleen A J Mitchelson, Cathal Harmon, Mathilde Raverdeau, Ross Ward, Harry Kane, Jaclyn Kline, Katie L O'Brien, Martin Brennan, Frances Smith, Brenneth Stevens, Helen M Roche, Ed C Lavelle, David K Finlay, Doreen A Cantrell, Edward T Chouchani, Susan Kaech, Evanna L Mills, Marcia Haigis, Lydia Lynch.
      Obesity increases the risk of many cancers and impairs the anti-tumour immune response. However, little is known about whether the source or composition of dietary fat affects tumour growth or anti-tumour immunity in obesity. Here, we show that high-fat diets (HFDs) derived from lard, beef tallow or butter accelerate tumour growth in a syngeneic model of melanoma, but HFDs based on coconut oil, palm oil or olive oil do not, despite equivalent obesity. Using butter-based and palm oil-based HFDs as examples, we find that these dietary fat sources differentially regulate natural killer and CD8 T cell infiltration and function within the tumour microenvironment, governed by distinct effects on the plasma metabolome and intracellular metabolism. We identify diet-related lipid intermediates, namely long-chain acylcarnitine species, as immunosuppressive metabolites enriched in mice fed butter compared to palm oil HFD. Together, these results highlight the significance of diet in maintaining a healthy immune system and suggest that modifying dietary fat may improve cancer outcomes in obesity.
    DOI:  https://doi.org/10.1038/s42255-025-01330-w
  20. Nature. 2025 Jul 30.
    ACLY inhibition promotes tumour immunity and suppresses liver cancer.
    Jaya Gautam, Jianhan Wu, James S V Lally, Jamie D McNicol, Russta Fayyazi, Elham Ahmadi, Daniela Carmen Oniciu, Spencer Heaton, Roger S Newton, Sonia Rehal, Dipankar Bhattacharya, Fiorella Di Pastena, Binh Nguyen, Celina M Valvano, Logan K Townsend, Suhrid Banskota, Battsetseg Batchuluun, Maria Joy Therese Jabile, Alice Payne, Junfeng Lu, Eric M Desjardins, Naoto Kubota, Evangelia E Tsakiridis, Bejal Mistry, Alex Aganostopoulos, Vanessa Houde, Ann Dansercoer, Koen H G Verschueren, Savvas N Savvides, Joanne A Hammill, Ksenia Bezverbnaya, Paola Muti, Theodoros Tsakiridis, Wenting Dai, Lei Jiang, Yujin Hoshida, Mark Larché, Jonathan L Bramson, Scott L Friedman, Kenneth Verstraete, Dongdong Wang, Gregory R Steinberg.
      Immunosuppressive tumour microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) (MASH-HCC)1-3. Although immune cell metabolism influences effector function, the effect of tumour metabolism on immunogenicity is less understood4. ATP citrate lyase (ACLY) links substrate availability and mitochondrial metabolism with lipid biosynthesis and gene regulation5-7. Although ACLY inhibition shows antiproliferative effects in various tumours, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways8-12. Here, using a mouse model of MASH-HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumours reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 and structural analysis by cryo-electron microscopy reveals that EVT0185-CoA directly interacts with the CoA-binding site of ACLY. Oral delivery of EVT0185 in three mouse models of MASH-HCC dramatically reduces tumour burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumour ACLY with increases in the chemokine CXCL13, tumour-infiltrating B cells and tertiary lymphoid structures. The depletion of B cells blocked the antitumour effects of ACLY inhibition. Together, these findings illustrate how targeting tumour metabolism can rewire immune function and suppress cancer progression in MASH-HCC.
    DOI:  https://doi.org/10.1038/s41586-025-09297-0
  21. Cancer Res. 2025 Jul 31.
    Hypoxia-Induced Creatine Uptake Reprograms Metabolism to Antagonize PARP1-Mediated Cell Death and Facilitate Tumor Progression in Hepatocellular Carcinoma.
    Rui-Zhe Li, Guo-Qiang Pan, Chen Xiong, Zi-Niu Ding, Tuan-Song Zhang, Lun-Jie Yan, Dongxu Wang, Xiaolu Zhang, Xiao-Feng Dong, Yu-Chuan Yan, Yu Zhou, Rui Dong, Zhao-Ru Dong, Tao Li.
      Recently, a PARP1-dependent cell-death process termed "parthanatos" that is driven by DNA damage has emerged as a crucial regulator of tissue homeostasis and tumorigenesis. Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. Here, we investigated the crosstalk between parthanatos and hypoxia. Despite causing DNA damage, hypoxia failed to induce parthanatos in hepatocellular carcinoma (HCC). The creatine transporter SLC6A8 promoted parthanatos antagonism and malignant phenotypes in hypoxic HCC cells. Hypoxia-induced creatine accumulation drove metabolic reprogramming and antagonized parthanatos. Mechanistically, creatine elevated SERPINE1 expression through MPS1-mediated Smad2/3 phosphorylation and formed a creatine/SERPINE1/HIF-1α positive feedback loop. SERPINE1 facilitated USP10-mediated deubiquitination and stabilization of PKLR by forming a SERPINE1-USP10-PKLR complex. USP10 contained a strong PAR-binding motif, and SERPINE1 reversed the attenuated deubiquitination activity of USP10 caused by the direct binding of PAR under hypoxia. The SLC6A8 inhibitor RGX-202 exerted potent antitumor activity alone and in combination with lenvatinib in patient-derived xenografts and primary HCC mouse models. Overall, this study identified intracellular creatine accumulation as a mechanism that allows hypoxic cancer cells to circumvent parthanatos and as a therapeutic target in HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0301
  22. Cancer Metab. 2025 Jul 25. 13(1): 36
    Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death.
    Yingying Yang, Ekaterina Parfenova, Nikolina Vrdoljak, Mark Minden, Jessica Luc, Andrew C Doxey, Paul A Spagnuolo.
       BACKGROUND: Acute myeloid leukemia (AML) is a devastating hematological malignancy with limited therapeutic options and poor survival outcomes. Therefore, the development of novel and selective anti-AML therapies is needed. 6-methoxydihydroavicine (6ME), a benzophenanthridine alkaloid, imparted selective AML cell death in vitro and in vivo. Mechanistically, 6ME inhibited fatty acid oxidation (FAO) by binding to and decreasing the activity of PPARδ, a transcription factor involved in FAO.
    METHODS: AML cell lines and patient-derived cells were used to assess the activity of 6ME in vitro and in vivo. Computational methods, immunoblotting, and co-IP-HPLC analysis assessed the molecular target, and cellular consequence of 6ME activity.
    RESULTS: 6ME induced cytotoxicity of AML cell lines (IC50: 1.0 ± 0.13 μM) and patient-derived cells while sparing normal hematopoietic cells. Mouse engraftment studies showed that 6ME (5 mg/kg, three times/week for 4 weeks) selectively reduced patient-derived AML cell engraftment without affecting hematopoietic cell engraftment or imparting toxicity. Mechanistically, 6ME bound to and inhibited PPARδ leading to downregulated FAO gene expression (i.e., CD36 and CPT2) and reduced fatty acid cellular uptake resulting in FAO inhibition.
    CONCLUSION: Pharmacological inhibition of PPARδ with 6ME is a novel approach to inducing selective death in AML.
    Keywords:  6-methoxydihydroavicine; Acute myeloid leukemia; Fatty acid oxidation; PPAR
    DOI:  https://doi.org/10.1186/s40170-025-00402-5
  23. Circ Res. 2025 Jul 29.
    SLC39A13 Regulates Heart Function via Mitochondrial Iron Homeostasis Maintenance.
    Huihui Li, Xiaoting Wang, Yu Zhang, Yuan Yang, Joe Z Zhang, Bing Zhou.
       BACKGROUND: Iron is a necessary trace element for multiple reactions but is toxic in excess. Its intracellular balance is delicately maintained. We previously found that the loss of SLC39A13 (ZIP13), a newly identified endoplasmic reticulum/Golgi-resident iron transporter, impacted iron homeostasis in multiple tissues. The purpose of this study is to investigate the role of ZIP13 in regulating cardiac functions and the precise mechanism of cardiac injury caused by ZIP13 deficiency.
    METHODS: Cardio-specific knockout of Zip13 (Zip13-CKO), tamoxifen-inducible Zip13 knockout (Zip13-iKO), and systemic (germline) Zip13 knockout mouse model were used to study the effect of Zip13 deletion on cardiac functions. These mice were analyzed for growth, cardiac systolic function, mitochondrial morphology, mitochondrial iron metabolism, and mitochondrial biogenesis and activity. We also generated cardio-specific ferroportin 1 (Fpn1-CKO) and Zip13&Fpn1 (Zip13&Fpn1-CKO) double-knockout mice to compare with Zip13-CKO mice. Mouse embryonic fibroblasts and primary cardiomyocytes were used for in vitro experiments.
    RESULTS: Zip13-CKO mice displayed severe cardiac systolic dysfunctions. The mitochondrial function and morphology were markedly abnormal in Zip13-CKO cardiomyocytes, accompanied by cytosolic iron increase and mitochondrial iron decrease. These were also confirmed in vitro with mouse embryonic fibroblasts and primary cardiomyocytes. Moreover, iron supplementation or overexpressing MFRN1 (mitoferrin 1), a mitochondrial iron importer, could substantially restore the mitochondrial iron homeostasis and function of ZIP13-deficient primary cardiomyocytes, indicating mitochondrial iron dyshomeostasis underlies the observed cardiac abnormality. The Zip13-CKO did not wholly resemble that of Fpn1-CKO, which was associated with elevated cytosolic iron, but no statistically significant change was observed in mitochondrial iron. Zip13&Fpn1-CKO mice presented a more severe heart defect than either single mutant alone, likely due to a further aggravated iron accumulation in the cytosol of cardiomyocytes.
    CONCLUSIONS: We propose that ZIP13 and FPN1 are both required to maintain cardiac functions via overlapping but different manners; FPN1 maintains the cytosolic iron by exporting iron out of the cells, while ZIP13 helps balance the iron equilibrium between the cytosol and the organellar network system, including the mitochondrion. These findings establish the critical role of ZIP13 in maintaining mitochondrial iron homeostasis and activity, enabling cardiomyocytes to perform effectively their essential roles.
    Keywords:  homeostasis; iron; mice; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326201
  24. Commun Chem. 2025 Jul 30. 8(1): 220
    Cardiolipin acyl chain composition tailors the conformation of mammalian ATP synthase dimers.
    M Makowski, V G Almendro-Vedia, I López-Montero.
      The interplay between ATP synthase dimers and the four-tailed lipid cardiolipin (CL) shapes mitochondrial cristae structure and function. In the mitochondrial disorder Barth syndrome (BTHS), cristae membranes accumulate a less unsaturated, three-tailed form of cardiolipin (MLCL). These cristae become structurally and functionally compromised through mechanisms poorly understood. We have studied through molecular dynamics simulations how BTHS lipid composition affects the conformation of the ATP synthase dimer. The wedge-shaped transmembrane region of the ATP synthase dimer attracts cardiolipins through shape complementarity. MLCL showed decreased affinity for the dimer interface than CLs of the healthy model. A more heterogeneous lipid environment with a higher elastic strain promoted a dimer conformation that would stabilize wider intracrista spaces, and hence, less efficient OXPHOS reactions in BTHS. Our results provide clues on the role played by the CL acyl chain composition in the architecture and function of mitochondria in health and BTHS.
    DOI:  https://doi.org/10.1038/s42004-025-01611-1
  25. Cell Death Dis. 2025 Jul 29. 16(1): 574
    PDK1-dependent metabolic reprogramming regulates stemness and tumorigenicity of osteosarcoma stem cells through ATF3.
    Kazuya Tokumura, Kazuya Fukasawa, Jiro Ichikawa, Koki Sadamori, Manami Hiraiwa, Eiichi Hinoi.
      Osteosarcoma stem cells (OSCs) are characterized by their self-renewal and multilineage differentiation abilities, contributing to osteosarcoma malignancy. The Warburg effect describes cancer cells' preference for glycolysis over mitochondrial oxidative phosphorylation (OXPHOS) for energy production. Unlike differentiated cancer cells, cancer stem cells exhibit unique and diverse metabolic properties depending on the context. This study investigated the metabolic reliance of OSCs and related genes through in silico analyses of clinical osteosarcoma specimens and in vitro and in vivo genetic and pharmacological analyses. Glycolysis and OXPHOS pathways were more active in OSCs than in non-OSCs at single-cell resolution. Pyruvate dehydrogenase kinase 1 (PDK1), a key enzyme balancing glycolysis and OXPHOS, was upregulated in OSCs and correlated with poor prognosis in patients with osteosarcoma. Genetic inhibition of PDK1 via RNA interference reduced OSC stemness, glycolysis, and heterotopic tumor formation. Pharmacological inhibition of PDK1 mirrored these genetic effects and repressed orthotopic tumor burden and pulmonary metastasis. Activating transcription factor 3 (ATF3) was identified through screening as a downstream factor of PDK1-regulated OSC properties. ATF3 overexpression reversed the stemness reduction caused by PDK1 deficiency through, at least in part, activating the TGF-β/Smad pathway without affecting the metabolic balance. ATF3 expression, glycolysis, and stemness were significantly induced by wild-type PDK1 overexpression but not by a kinase-dead PDK1 mutant in OSCs. Pharmacological inhibition of glycolysis counteracted the upregulation of ATF3 expression and increased stemness in OSCs by PDK1 overexpression. These findings indicate that PDK1 fine-tunes metabolic balance to govern OSC stemness and tumorigenicity through, at least in part, modulating ATF3/TGF-β/Smad pathway, suggesting a potential therapeutic approach for targeting OSCs in osteosarcoma.
    DOI:  https://doi.org/10.1038/s41419-025-07903-7
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