bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–07–05
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
  2. Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.
  3. Complex I drives glutamine-dependent TCA cycle to support viability of MYChigh breast cancer cells.
  4. Hierarchical lineage tracing reveals diverse pathways of cytarabine resistance.
  5. Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
  6. Deleterious mitochondrial heteroplasmy drives high-risk clonal hematopoiesis and hematological malignancy.
  7. Gravitational and mechanical forces shape mitochondrial translation.
  8. HsClpP-Engaging Selective Mitochondrial Pan-PDK Degraders for Cancer Therapy.
  9. Inhibition of PRMT5 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptotic cell death.
  10. Mitochondrial calcium regulates lipid metabolism by modulating tethering of mitochondria to lipid droplets.
  11. Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC.
  12. Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.
  13. Small molecule activators of the mitochondrial protease ClpP induce senescence in triple-negative breast cancer cells and sensitize cells to the Bcl-2 inhibitor venetoclax.
  14. A carboxylate switch point controls long-range energy transduction in respiratory Complex I.
  15. When mitochondria lose their fold: matrix proteostasis and stress signaling.
  1. Res Sq. 2026 Jun 17. pii: rs.3.rs-10007862. [Epub ahead of print]
    Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
    Daniel Pelaez, Samantha McLaughlin, Kendall Knechtel, Zelia Correa, J William Harbour.
      Cancer cells alter their metabolism to support growth and survival, most notably by fermenting glucose to lactate even in the presence of oxygen, a phenomenon known as the Warburg effect. Although this metabolic state has been recognized for decades, its bioenergetic advantages remain unclear, as fermentation produces less net ATP than mitochondrial respiration. How aerobic fermentation contributes to cellular energy balance therefore remains unresolved. Here, we show that extracellular acidification generated by lactate export creates a proton gradient across the plasma membrane that is harnessed by ectopic ATP synthases to drive intracellular ATP production. We find that ATP synthase and proton-shuttling components of the mitochondrial respiratory chain translocate to the plasma membrane in cancer cells and are preferentially oriented to exploit this gradient, linking a hallmark of aerobic fermentation directly to energy supplementation. This work provides a mechanistic resolution to the apparent energetic inefficiency of the Warburg paradigm and identifies a previously unrecognized pathway for energy complementation in cancer.
    DOI:  https://doi.org/10.21203/rs.3.rs-10007862/v1
  2. Sci Adv. 2026 Jul 03. 12(27): eaee5417
    Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.
    Celia de la Calle Arregui, Anderson R Frank, Kelvin Mun, Jiwoong Kim, Kuntal Majmudar, Justin A Bishop, Cheryl Lewis, Yang Xie, David G McFadden.
      Oncocytic (Hürthle cell) carcinoma of the thyroid (OCT) is characterized by widespread loss of heterozygosity (LOH), mitochondrial accumulation, and recurrent mitochondrial DNA mutations leading to impairment of complex I. Here, we establish and characterize a novel OCT cell line, UT946, which displays severe mitochondrial electron transport chain dysfunction and a Warburg metabolic phenotype. Using a series of cytoplasmic hybrids, we establish that the complex I defect in UT946 stems from a nuclear-encoded loss-of-function mutation in the complex I subunit NDUFS1. To our surprise, the mutation in NDUFS1 was inherited as a recessive germline allele that underwent LOH in the tumor to expose functional loss of complex I. A reanalysis of 91 OCT tumor genomes revealed that LOH-driven exposure of recessive germline mutations in complex I subunits was a recurrent mechanism underlying complex I inactivation in OCT. These findings unveil a previously unidentified germline-driven mechanism of complex I loss and metabolic reprogramming in cancer and provide further evidence of the selective pressure for complex I impairment in OCT.
    DOI:  https://doi.org/10.1126/sciadv.aee5417
  3. Cell Rep. 2026 Jul 02. pii: S2211-1247(26)00707-2. [Epub ahead of print]45(7): 117629
    Complex I drives glutamine-dependent TCA cycle to support viability of MYChigh breast cancer cells.
    Johanna M Anttila, Mariel Savelius, Linda Id, Daniel Nicorici, Juhi Somani, Antti O Hiltunen, Pauliina M Munne, Aino Peura, Martina Peltonen, July Aung, Ryan Awadhpersad, Ellisiv Nyhamar, Bina Prajapati, Hanna Ala-Hongisto, Prson Gautam, Mika J Välimäki, Topi A Tervonen, Karina Šapovalovaitė, Raman Devarajan, María Victoria Ruiz Pérez, Minna Mutka, Panu Kovanen, Laura Niinikoski, Tuomo Meretoja, Johanna Mattson, Päivi Heikkilä, Krister Wennerberg, Marie Arsenian-Henriksson, Jukka Westermarck, Tero Aittokallio, Andrei Goga, Christopher B Jackson, Anni I Nieminen, Juha Klefström.
      In many cancers, stably elevated MYC levels drive sustained activation of anabolic programs and the cell cycle, creating opportunities for the synthetic-lethal targeting of MYChigh tumors. Enhanced mitochondrial respiration is a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains the TCA cycle by regenerating NAD+ through complex I-mediated oxidation of NADH, supporting the anabolic demand of MYC-driven cells. Metabolic carbon tracing reveals that MYC shifts the TCA cycle carbon source from glucose to glutamine. Inhibition of the glutamine-fueled TCA cycle using NAD+-depleting complex I inhibitors promotes MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYChigh tumors, combined inhibition of complex I and glutaminolysis produces persistent suppression of tumor growth. Altogether, the elevated respiration of MYChigh cells supports a glutamine carbon-enriched TCA cycle that meets anabolic demand, rendering MYChigh tumors selectively vulnerable to mitochondrial respiration and glutaminolysis inhibitors.
    Keywords:  CP: cancer; CP: metabolism; MYC; TCA cycle; breast cancer; cancer; complex I; glutamine; metabolism; mitochondria; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.celrep.2026.117629
  4. Nat Commun. 2026 Jun 30.
    Hierarchical lineage tracing reveals diverse pathways of cytarabine resistance.
    Rachel Saxe, Hannah Stuart, Abigail C Marshall, Fahiima Abdullahi, Zoë Chen, Francesco Emiliani, Aaron McKenna.
      Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of resistance mechanisms as we lack technologies to map cancer evolution under the selective pressure of treatment. To address this, we present a hierarchical, dynamic lineage-tracing method, FLARE (Following Lineage Adaptation and Resistance Evolution). We use FLARE to track the progression of acute myeloid leukemia (AML) cell lines treated with Cytarabine (AraC), a front-line treatment in AML, both in vitro and in vivo. We map distinct cellular lineages in both murine and human AML cell lines that are predisposed to AraC resistance. Using FLARE, we identify treatment-naïve populations responsible for seeding resistance that are characterized by upregulation of stemness markers and a cell adhesion-associated AraC-resistant lineage signature. We find that expression of this signature in pediatric AML is associated with the expansion of HSC-like malignant cells at relapse and significantly shorter overall survival. These findings underscore the role of pre-existing lineage states in driving relapse and establish FLARE as a platform for uncovering the evolving, heritable transcriptional programs that underlie tumor evolution.
    DOI:  https://doi.org/10.1038/s41467-026-74989-8
  5. J Biol Chem. 2026 Jun 29. pii: S0021-9258(26)02178-2. [Epub ahead of print] 113306
    Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
    Kailash Venkatraman, Daniel Milshteyn, Carolina Sarto, Elida Kocharian, Cailyn M Sakurai, Aaron M Armando, Adrian M Wong, Edward A Dennis, Xi Fang, Christopher T Lee, Itay Budin.
      Cardiolipin (CL) is a four-acyl chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-acyl chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of IMM structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.
    Keywords:  Barth syndrome; Cardiolipin; Lipid saturation; Mitochondria; Tafazzin
    DOI:  https://doi.org/10.1016/j.jbc.2026.113306
  6. medRxiv. 2026 Jun 24. pii: 2026.06.22.26356227. [Epub ahead of print]
    Deleterious mitochondrial heteroplasmy drives high-risk clonal hematopoiesis and hematological malignancy.
    Dan E Arking, Tryggvi McDonald, Wen Shi, Daniela Puiu, Jeremy V Arking, Sergiu Pasca, Yun Soo Hong, Lukasz Gondek.
      Mitochondrial DNA (mtDNA) heteroplasmy, the coexistence of multiple mtDNA variants within cells, accumulates with age and is associated with hematological malignancies and mortality. However, whether predicted deleterious heteroplasmies causally contribute to cancer or merely represent passenger mutations remains unresolved. Here, leveraging ∼36,000 first-degree relative pairs from the UK Biobank and All of Us Research Program cohorts, we deconvolute overall heteroplasmy metrics into those that are shared across family members (representing inherited variants) and those that are not (representing de novo variants) to establish a Mendelian randomization framework for assessing causality. We show that shared heteroplasmies exhibit strong purifying selection, with reduced predicted deleteriousness compared to not shared variants, and that 90% of an individual's deleterious heteroplasmy burden is somatically acquired. Critically, shared deleterious heteroplasmy burden, fixed at conception and thus temporally upstream of potential confounders, is significantly associated with hematological malignancies (RR=2.81, 95% CI 1.29-6.13), with effect sizes concordant with the not shared heteroplasmy burden. Furthermore, shared deleterious heteroplasmy specifically associates with high-risk clonal hematopoiesis of indeterminate potential (CHIP), particularly spliceosome mutations, suggesting mitochondrial dysfunction promotes clonal expansion of specific CHIP subtypes. Finally, we identify ultra-rare individual mtDNA variants associated with hematological malignancies, a hallmark of driver mutations. These findings establish mtDNA heteroplasmies, including inherited variants, as causal contributors to hematological malignancy risk and demonstrate that most disease-relevant burden is acquired during life, identifying potential opportunities for prevention and therapeutic intervention in individuals at elevated risk for hematological cancer, particularly of myeloid origin.
    DOI:  https://doi.org/10.64898/2026.06.22.26356227
  7. Nat Commun. 2026 Jun 30. pii: 5552. [Epub ahead of print]17(1):
    Gravitational and mechanical forces shape mitochondrial translation.
    Taisei Wakigawa, Yusuke Kimura, Mari Mito, Toshiya Tsubaki, Muhoon Lee, Koki Nakamura, Abdul Haseeb Khan, Hironori Saito, Tohru Yamamori, Tomokazu Yamazaki, Akira Higashibata, Tatsuhisa Tsuboi, Yusuke Hirabayashi, Nono Takeuchi-Tomita, Taku Saito, Atsushi Higashitani, Yuichi Shichino, Shintaro Iwasaki.
      Life on Earth has evolved in a form suitable for the gravitational force. Although the pivotal role of gravity in gene expression has been suggested, the molecular details remain unclear. Here, we show that mitochondria utilize gravity to activate protein synthesis within the organelle. Genome-wide ribosome profiling reveals reduced mitochondrial translation in mammalian cells and Caenorhabditis elegans under microgravity. We found that attenuation of cell adhesion through laminin-integrin interactions caused the phenotype. Mitochondrial translation is activated by a signal relayed by FAK, RAC1, PAK1, BAD, and Bcl-2 family proteins in the cytosol, and the mitochondrial fatty acid synthesis (mtFAS) pathway in the matrix. Consumption of mitochondrial malonyl-CoA by mtFAS reduces the malonylation of the translational machinery and accelerates the rates of translational initiation and elongation. Physiologically, this system operates in mechano-response of skeletal muscles. Our work provides mechanistic insights into how cells convert gravitational and mechanical forces into translation in mitochondria.
    DOI:  https://doi.org/10.1038/s41467-026-74493-z
  8. J Med Chem. 2026 Jul 02.
    HsClpP-Engaging Selective Mitochondrial Pan-PDK Degraders for Cancer Therapy.
    Ying Yang, Haipeng Zhang, Min Yang, Jiaming Ou, Zhenzhen Dai, Mingyang Xu, Haibo Yan, Xiaobing Liu, Yun He, Aiming Yang, Shao-Lin Zhang.
      Selective degradation of mitochondrial proteins remains a significant challenge due to the unique compartmentalization and proteostasis mechanisms of this organelle. Here, we report A1, a mitochondria-targeted small-molecule degrader that selectively eliminates pyruvate dehydrogenase kinases (PDKs) by recruiting the mitochondrial protease HsClpP, achieving nanomolar degradation potency (DC50 ≈ 10 nM). Mechanistically, A1 induces efficient pan-PDK degradation, thereby rewiring mitochondrial metabolism toward enhanced oxidative phosphorylation. This metabolic shift promotes the accumulation of reactive oxygen species (ROS), leading to opening of the mitochondrial permeability transition pore (mPTP) and activation of the intrinsic mitochondrial apoptosis. Notably, A1 also elicits hallmark features of immunogenic cell death (ICD), including calreticulin exposure and HMGB1 release, thereby stimulating antitumor immune responses. Consistent with these findings, A1 markedly suppresses both primary and distal tumor growth, with selective PDK degradation in tumor tissues and no observable systemic toxicity. Collectively, these results establish mitochondria-targeted degradation of metabolic enzymes as a promising therapeutic strategy for cancer.
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c00879
  9. Blood Neoplasia. 2026 Aug;3(3): 100249
    Inhibition of PRMT5 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptotic cell death.
    Fen Zhu, Jing Wang, Christine E Ryan, Liam Hackett, Jeremy Zhang, Stephanie Chamberlain, Johnson Ung, Stephen J F Chong, Matthew S Davids.
      Protein arginine methyltransferase 5 (PRMT5), a type II arginine methyltransferase, is overexpressed in several aggressive B-cell malignancies and facilitates cancer cell proliferation. JNJ-64619178, a selective small-molecule inhibitor targeting PRMT5, has previously shown promising preclinical activity across a range of hematological malignancies; however, the clinical activity of JNJ-64619178 monotherapy is limited despite strong target engagement. Therefore, we sought to identify rational combination partners for JNJ-64619178 to achieve improved activity in B-cell malignancies. Using dynamic Bcl-2 homology 3 (BH3) profiling, a functional assay to evaluate the net increase in proapoptotic signaling in response to drugs, we found that JNJ-64619178 increased overall proximity to apoptotic cell death (mitochondrial apoptotic priming) and dependence on B-cell leukemia/lymphoma (BCL)-2 for survival (BCL-2 dependence), particularly in diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cell lines. In other B-cell non-Hodgkin lymphoma (B-NHL) cell lines that are primarily MCL-1 dependent and less BCL-2 dependent, JNJ-64619178 increased mitochondrial apoptotic priming without shifting anti-apoptotic dependence from MCL-1 to BCL-2. Co-targeting PRMT5 and BCL-2 synergistically induced apoptosis in DLBCL and MCL cell lines that displayed at least partial BCL-2 dependence at baseline, but not in less BCL-2-dependent B-NHL cell lines. Interestingly, JNJ-64619178 upregulated death receptor 4 (DR4) and death receptor 5 (DR5) expression on the cell membrane of B-NHL cell lines, thereby sensitizing them, including the less BCL-2-dependent cell lines, to recombinant TRAIL-induced extrinsic apoptotic cell death. These findings highlight a role of PRMT5 in regulating both intrinsic and extrinsic apoptosis and suggest potential combination partners with PRMT5 inhibitors for potential clinical application in B-NHL.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100249
  10. EMBO J. 2026 Jul 03.
    Mitochondrial calcium regulates lipid metabolism by modulating tethering of mitochondria to lipid droplets.
    Rebeca Acin-Perez, Essam A Assali, Michaela Veliova, Jennifer Ngo, Alexandra J Brownstein, Francisco Villalobos, Anton Petcherski, Pablo Hernansanz-Agustin, Doyeon Kim-Vasquez, Shili Xu, Mikayla Tamboline, Raquel Maria Silva, Alexander Upcher, Cynthia Shu, Daniel E Ferriss, Marc Liesa, Jose Antonio Enriquez, Israel Sekler, Orian S Shirihai.
      Adrenergic stimulation of brown adipocytes induces a robust detachment of mitochondria from lipid droplets (LD), which is followed by lipolysis and lipid catabolism. However, the signals inducing mitochondria attachment or detachment, and their role in lipid metabolism, remain unknown. Here, we reconstituted mitochondria-LD interaction in brown adipocyte tissue (BAT) ex vivo. We find that removal of mitochondria from lipid droplets permits higher lipolytic activity of recombinant lipases. Testing the effect of thermogenic secondary messengers and metabolites on attachment and detachment identified elevated mitochondrial matrix calcium as a potent inducer of detachment. Further, deletion of the mitochondrial sodium/calcium exchanger, NCLX, resulted in reduced attachment and increased detachment, while activation of NCLX increased attachment. We find that elevated matrix calcium causes detachment by inducing architectural transformation of peridroplet mitochondria (PDM) from their typical LD-surface-bound crescent shape into a round shape. PDE2A inhibition activates NCLX and increases PDM content in BAT in vitro and in vivo. We conclude that a surge in mitochondrial matrix calcium ions serves as a potent signal to induce mitochondrial detachment from lipid droplets, thereby facilitating lipolysis.
    DOI:  https://doi.org/10.1038/s44318-026-00827-8
  11. Nature. 2026 Jul 01.
    Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC.
    Yiming Peng-Winkler, Xiao-Zheng Liu, Sanne M L Verheul, Charlotte Girondel, Sebastian Igelmann, Sara Marie Rotter, Michail Doukas, Ming Liu, Anke Vandekeere, Mélanie Planque, Juan Fernández-García, Sébastien Tabariès, Marta Buetas-Arcas, Sandra Martínez-Martín, Florian Döbbe, Margherita Demicco, Ines Vermeire, Janine Theile, Johannes Ceuppens, Jonas Haesevoets, Emma Tobarra-López, Dorien Broekaert, Johannes Georg Bode, Tom Luedde, Peter Vermeulen, Daniele V F Tauriello, Raquel Perez-Lopez, Steve Stegen, Laura Soucek, Tiago De Oliveira, Lena-Christin Conradi, Peter M Siegel, Cornelis Verhoef, Sarah-Maria Fendt.
      Patients with colorectal cancer (CRC) frequently develop liver metastases1-3. The prognosis of these patients is skewed by the histopathological heterogeneity of their liver metastases4,5. Patients with 'replacement' metastases have a 5-year overall survival of less than 44.2%, compared with 73.4% in patients with 'encapsulated' (previously known as desmoplastic) metastases5; yet there are currently no approved therapies targeting replacement liver metastases. Here we show that treatment-naive patients with CRC with liver steatosis have an increased occurrence of replacement metastases compared with patients without steatosis. Mechanistically, we find that steatosis-promoted fatty acid oxidation increases formation of replacement metastases by increasing MYC stability through acetylation. In turn, MYC activates proline synthesis, fuelling collagen production, enabling growth of replacement metastases. Targeting MYC, P5CS or COL1A1 suppresses the occurrence and growth of replacement metastases in patient-derived organoids, mouse or patient-derived xenograft models. Spatial metabolite and protein analyses of liver metastases from patients with CRC further support this mechanism. In conclusion, we provide a mechanistic understanding of the emergence of liver metastases with poor prognosis in treatment-naive patients with CRC, identifying potential targets for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41586-026-10686-2
  12. Nat Commun. 2026 Jul 01.
    Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.
    Abhisha Sawant Dessai, Nadya A Elhalawany, Tao Dai, Justine J Jacobi, Christian Prechtl, Alphonse N Dimeck, Sierra R Morton, Mark D Long, Prashant K Singh, Nagireddy Putluri, Mariana Lopes, Song Liu, Dominic J Smiraglia, Katerina V Gurova, Peder J Lund, Leah A Gates, Sung Yun Jung, Subhamoy Dasgupta.
      Mitochondria remain at the core of cell metabolism, whereas the nucleus integrates cellular and environmental signals to activate genes. However, the mechanisms that directly link cellular metabolism to gene regulation are not well understood. Here we show, a metabolic pathway in the nucleus controls acetylation of histones by nuclear localization of mitochondrial enzymes aconitase (ACO2) and isocitrate dehydrogenase (IDH2). Metabolic tracing studies show that IDH2 and ACO2 catalyze reductive carboxylation of α-ketoglutarate to rapidly synthesize citrate to increase nuclear acetyl-CoA pool. Genetic and proteomic analyses reveal nuclear IDH2 and ACO2 form a complex with KAT2A/GCN5 for acetylation of histones to increase chromatin accessibility and activation of proliferative genes. Robust nuclear expressions of ACO2 and IDH2 drive aggressive tumors indicating the tumorigenic potential of IDH2-ACO2-KAT2A axis. Altogether, our work reveals a paradigm coupling a nuclear metabolic pathway with histone acetylation to control of gene expression that accentuates hyperproliferative phenotype in tumors.
    DOI:  https://doi.org/10.1038/s41467-026-74786-3
  13. Cell Death Dis. 2026 Jun 29.
    Small molecule activators of the mitochondrial protease ClpP induce senescence in triple-negative breast cancer cells and sensitize cells to the Bcl-2 inhibitor venetoclax.
    Sabrina C D Daglish, Owen G Canterbury, Paul R Graves, Sarah A Carter, Sydney M Beese, Brandon L Mouery, Maggie A Hynek, Elizabeth C Moorman, Andrei J Mistreanu, Aadra P Bhatt, Nestor Tellez, Mitchell T Butler, Lucas J Aponte-Collazo, Emily M J Fennell, Laura E Herring, Scott Lyons, C Allie Mills, Hani Ashamalla, Edwin J Iwanowicz, John P Morris Iv, James E Bear, Yoshimi Endo Greer, Stanley Lipkowitz, Lee M Graves.
      ONC201 is a first-in-class, FDA-approved small molecule activator of the mitochondrial ATP-dependent caseinolytic peptidase P (ClpP). This and other related small molecules referred to as ClpP agonists, exert antiproliferative effects in several cancer cell types. We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines. Senescence was determined by increased β-galactosidase (β-gal) activity, downregulation of phosphorylated Rb, c-Myc (Myc), and lamin B1, upregulation of senescent-associated secretory phenotype (SASP), and extended cell proliferation assays. These responses were not observed in ClpP knockout cell lines, demonstrating ClpP-dependence. Proteomics analyses identified multiple events related to the development of senescence including cell cycle arrest and mitochondrial dysfunction. Flow cytometry confirmed an S-phase arrest and DNA damage was detected by Comet assay, 53BP1, phospho-S*Q, and γH2A.X immunostaining. In parallel with this, activation of the ATM pathway and phosphorylation of Chk2 was observed. We determined that ClpP agonist-induced senescence was irreversible in both in vitro and in vivo studies. Following TR-57 treatment and drug washout, cells remained growth arrested which coincided with loss of mitochondrial membrane potential and ability to produce ATP by oxidative phosphorylation. β-gal staining after TR-57 treatment and drug washout demonstrated a sustained increase in β-gal activity, indicating cells are senescent after drug washout. This response was reproduced in vivo wherein senescent 4T1-Luc cells did not develop tumors following injection into mice. Finally, the combination of a ClpP agonist with a known senolytic (venetoclax), synergistically increased the amount of cell death observed. In summary, we show that ClpP agonists stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells.
    DOI:  https://doi.org/10.1038/s41419-026-09061-w
  14. Nat Commun. 2026 Jul 01. pii: 5737. [Epub ahead of print]17(1):
    A carboxylate switch point controls long-range energy transduction in respiratory Complex I.
    Adel Beghiah, Patricia Saura, Terezia Kovalova, Franziska Hoeser, Thorsten Friedrich, Ville R I Kaila.
      Complex I is a highly intricate membrane-bound protein complex that powers the cellular energy metabolism by a long-range ( > 300 Å) proton-coupled electron transfer (PCET) reaction. Here, we investigate the highly debated coupling mechanism of Complex I by probing the charge transfer reaction along its functionally central carboxylate pathway (E-channel). By combining biophysical and site-directed mutagenesis experiments with high-resolution (2.6-2.8 Å) cryo-electron microscopy (cryo-EM) and multiscale simulations, we identify a conserved carboxylate switch point (D79NuoA) that mediates proton transfer by establishing a kinetic gate and couples the redox chemistry to proton pumping. We find that mutation of the identified site, as found in patients suffering from severe neurodegenerative disorders, drastically perturbs the charge transfer mechanism, and results in a 20% PCET activity. Our combined findings illustrate mechanistic principles of molecular gates underlying long-range charge transfer reactions, and show how disease mutations perturb the function of conserved switch points in energy transduction.
    DOI:  https://doi.org/10.1038/s41467-026-74767-6
  15. Front Physiol. 2026 ;17 1873221
    When mitochondria lose their fold: matrix proteostasis and stress signaling.
    Nils Bertram, Dejana Mokranjac.
      A dedicated network of chaperones and proteases is present in the mitochondrial matrix that orchestrates import, folding, disaggregation and eventually degradation of proteins. When this network is overwhelmed, unfolded or misfolded proteins accumulate in different types of aggregates which may either support recovery of functional proteins, initiate spatial sequestration or drive toxic aggregation. Here, we discuss mitochondrial protein aggregation and how mitochondrial proteostasis stress is communicated to the rest of the cell.
    Keywords:  Hsp70; mitochondria; mitochondria-nuclear signaling; protein aggregation; proteostasis
    DOI:  https://doi.org/10.3389/fphys.2026.1873221
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