bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–10–26
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.
  2. Fragments of a Story: Could Mitochondrial DNA Fragmentomics Upend Lung Cancer Early Diagnosis?
  3. Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia.
  4. Targeting mitochondrial structure and dynamics for therapeutic intervention in cancer.
  5. Targeting MCL-1 to Overcome Therapeutic Resistance and Improve Cancer Mortality.
  6. ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance.
  7. The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
  8. Large transient assemblies of Apaf1 constitute the apoptosome in cells.
  9. Organellar pH as an emerging vulnerability to exploit in cancer.
  10. Mitochondrial one-carbon metabolism is required for TGF-β-induced glycine synthesis and fibrotic responses.
  11. Between ROS and a hard place: telomere damage as a driver of T cell exhaustion.
  12. The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness.
  13. Longitudinal serum metabolomics predicts therapeutic outcome in acute myeloid leukemia.
  14. Structural dynamics of the mitochondrial ADP/ATP carrier support an asymmetric transport mechanism.
  15. Impact of Exercise on Clonal Hematopoiesis.
  1. Cell Death Dis. 2025 Oct 21. 16(1): 750
    The combination of venetoclax with dimethyl fumarate synergistically induces apoptosis in AML cells by disrupting mitochondrial integrity through ROS accumulation.
    Shin-Ichiro Kawaguchi, Kazuya Sato, Junko Izawa, Norihito Takayama, Hiroko Hayakawa, Kaoru Tominaga, Hitoshi Endo, Tom Kouki, Nobuhiko Ohno, Yoshinobu Kanda.
      Leukemia cells are consistently subjected to higher oxidative stress than normal cells. To mitigate reactive oxygen species (ROS) overload, which can trigger various forms of cell death, leukemia cells employ a robust antioxidant defense system and maintain redox homeostasis. Recent evidence suggests that dimethyl fumarate (DMF), a derivative of fumarate, inactivates the antioxidant glutathione (GSH), thereby inducing oxidative stress and metabolic dysfunction, eventually leading to cell death in cancer cells. In this study, we observed that DMF decreases the GSH/oxidated GSH ratio and increases intracellular ROS levels, the extent of which is closely correlated with cell death, in acute myeloid leukemia (AML) cell lines. DMF reduced the mitochondrial membrane potential and oxidative phosphorylation (OXPHOS), effects that were almost fully restored by the antioxidant N-acetylcysteine, suggesting that these responses are ROS-dependent. Electron microscopy and inhibition assays revealed that apoptosis, rather than necroptosis or ferroptosis, is the predominant form of cell death of AML cells following DMF treatment. Notably, the combination of DMF and the BCL-2 selective BH3-mimetic venetoclax induced marked cell death in AML cells, including venetoclax-refractory　BCL-2 low expressing U937 and acquired venetoclax-resistant MOLM-14 cells. This combination also caused greater mitochondrial depolarization and a more profound reduction in OXPHOS activity than either agent alone. Collectively, our findings indicate that DMF exerts potent anti-leukemia activity in AML cells and sensitizes cells to venetoclax treatment by synergistically disrupting mitochondrial integrity through ROS accumulation.
    DOI:  https://doi.org/10.1038/s41419-025-08040-x
  2. Am J Respir Crit Care Med. 2025 Oct 22.
    Fragments of a Story: Could Mitochondrial DNA Fragmentomics Upend Lung Cancer Early Diagnosis?
    Edwin Ostrin.
      
    Keywords:  biomarkers; lung cancer; mitochondria; mtDNA
    DOI:  https://doi.org/10.1164/rccm.202508-1874ED
  3. Mol Metab. 2025 Oct 19. pii: S2212-8778(25)00182-6. [Epub ahead of print] 102275
    Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia.
    Fernando M Ponce-Garcia, Yasmin R Jenkins, Victoria D Assmann, Silpita Paul, Nitesh D Sharma, Catherine Moore, Eric H Ma, Paraskevi Diamanti, Marc Hennequart, Julianna Blagih, Le Le, Benjamin J Jenkins, Sophie Rouvray, James G Cronin, Russell G Jones, Marc Mansour, Allison Blair, Christina Halsey, Ksenia Matlawska-Wasowska, Daniel Herranz, Emma E Vincent, Nicholas Jones.
      T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondrial metabolism in T-ALL is an attractive therapeutic avenue. Related to this, canagliflozin (cana), is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase, but its potential anti-leukaemic effects remain unexplored. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and apoptosis. These anti-leukaemic effects driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and mitochondrial metabolism, and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing its anti-leukaemic effects. Collectively, our study reveals a cana-driven metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102275
  4. PLoS Biol. 2025 Oct;23(10): e3003453
    Targeting mitochondrial structure and dynamics for therapeutic intervention in cancer.
    Wakiko Iwata, Nora Haggerty, Hiromi Sesaki, Miho Iijima.
      Mitochondrial division and fusion are critical regulators of cancer cell metabolism, proliferation, survival, metastasis, and drug resistance. Division promotes tumor development by reprogramming energy metabolism, whereas its inhibition can suppress tumor growth and metastasis. The mechanochemical GTPase DRP1, a key mediator of mitochondrial division, has emerged as a promising therapeutic target. Mitochondrial cristae also contribute to cancer progression by modulating metabolic reprogramming and oncogenic signaling. Targeting these processes may stimulate anti-tumor innate immune responses through the release of mitochondrial DNA into the cytoplasm. A deeper understanding of tumor-specific mitochondrial membrane structures and dynamics could therefore reveal novel intervention strategies and guide precision cancer therapies.
    DOI:  https://doi.org/10.1371/journal.pbio.3003453
  5. Health Sci Rep. 2025 Oct;8(10): e71390
    Targeting MCL-1 to Overcome Therapeutic Resistance and Improve Cancer Mortality.
    Md Mohiuddin.
       Background: Myeloid cell leukemia-1 protein (MCL-1) is a major anti-apoptotic member of the Bcl-2 family and is typically overexpressed in a broad range of malignancies, including non-small-cell lung cancer, multiple myeloma, acute myeloid leukemia, and various solid tumors. By sequestering pro-apoptotic effectors, MCL-1 maintains mitochondrial stability and supports the tumor cell survival during stress, driving disease progression, therapeutic resistance, and ultimately, poor patient outcomes. In the last 10 years, the development of selective small-molecule inhibitors of MCL-1 has opened doors to enable the targeting of this mechanism of apoptosis avoidance.
    Discussion: This perspective summarizes the current knowledge regarding the dual roles of MCL-1 in apoptosis and mitochondrial homeostasis regulation. The structural foundations for the design of MCL-1 inhibitors are revisited, the pharmacological profiles of the leading drugs (S63845, AZD5991, AMG 176) in advanced clinical development are summarized, and emerging strategies, such as combination therapies with inhibitors of anti-apoptotic proteins such as BCL-2, PROTAC strategies designed to degrade MCL-1, and reversible-binding chemotypes to maximize MCL-1 inhibition and minimize toxicity, are reviewed. The non-apoptotic roles of MCL-1 in immune modulation and metabolism adaptation are also reviewed, along with the development of analytical methods to refine the patient selection process (e.g., BH3 profiling and transcriptomic signatures). The overexpression of MCL-1 is associated with worse patient survival in ACC, CESC, ESCA, HNSC, LGG, and UVM cancers.
    Conclusion: MCL-1 is an exciting anti-cancer target, and its inhibition may sensitize treatment-resistant tumors to cell death and enhance patient survival. The key to clinical success will be to carefully develop more intensive dosing regimens, rationally combine agents, and develop trial designs that prioritize the evaluation of new agents that maximize antitumor activity without the risk of off-target toxicities. Continued translational research and adaptive clinical trials are critical to fully realize the therapeutic potential of MCL-1 inhibition across various cancer contexts.
    Keywords:  BCL‐2; BH3 mimetics; MCL‐1; PROTACs; apoptosis
    DOI:  https://doi.org/10.1002/hsr2.71390
  6. Cell Death Dis. 2025 Oct 21. 16(1): 741
    ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance.
    Teresa T Liu, Mia J Carrarini, Livianna K Myklebust, Kegan O Skalitzky, Nathalie El-Khoury, Ian J Sipula, Alexander Chang, Vishal Soman, Ailing Liu, Nnamdi Ihejirika, Uma R Chandran, Michael J Jurczak, William A Ricke, Donald B DeFranco, Laura E Pascal.
      Declining mitochondrial function is an established feature of aging and contributes to most aging-related diseases through its impact on various pathologies such as chronic inflammation, fibrosis and cellular senescence. Our recent work suggests that benign prostatic hyperplasia, which is an aging-related disease frequently associated with inflammation, fibrosis and senescence, is characterized by a decline in mitochondrial function. Here, we utilize glycolytic restriction and pharmacologic inhibition of the mitochondrial electron transfer chain complex I to promote mitochondrial dysfunction and identify the cellular processes impacted by declining mitochondrial function in benign prostate stromal cells. Using this model, we show that mitochondrial dysfunction induced alterations in cell-cell and cell-matrix adhesion, elevated fibronectin expression, resistance to anoikis and stress-induced premature senescence (SIPS). We also showed that ablation of ZC3H4, a transcription termination factor implicated in anoikis-resistance and reduced in BPH relative to normal prostates, phenocopied various phenotypes in the human BHPrS1 prostate stromal cell line that resulted from inhibition of complex I. Furthermore, ZC3H4 ablation resulted in the elevation of mitochondrial superoxide (mtROS) and mitochondrial membrane potential, altered mitochondrial morphology and NAD+/NADH ratio, and reduced CI function in BHPrS1 cells. Thus, ZC3H4 loss promotes mitochondrial dysfunction to drive pathophysiologic changes in the stromal compartment that are features of the aging prostate.
    DOI:  https://doi.org/10.1038/s41419-025-08027-8
  7. Blood. 2025 Oct 20. pii: blood.2024026749. [Epub ahead of print]
    The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
    Kentson Lam, Yoon Joon Kim, Evelyn Li-Ting Tan, Carlo Miguel Ong, Andrea Zoey Liu, Fanny Jiahua Zhou, Mary Jean Sunshine, Bernadette Chua, Silvia Vicenzi, Katelyn Zhining Chen, Helena Yu, Pierce Ford, Jie-Hua Zhou, Yuning Hong, Eric J Bennett, Leslie A Crews, Edward D Ball, Robert Signer.
      Oncogenic growth places great strain and dependence on protein homeostasis (proteostasis). This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers at tolerable doses, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and increased autophagic flux to preserve proteostasis. Genetic inactivation of HSF1 sensitized AML cells to proteasome inhibition, marked by accumulation of unfolded protein, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival and significant slowing of disease progression and extension of survival in vivo. Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed human AML cells, and significantly reduced AML burden and extended survival in vivo. Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and colony formation, and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, compared to normal hematopoietic stem/progenitor cells. Combined autophagy/proteasome inhibition activated a terminal integrated stress response, which was surprisingly driven by Protein kinase R (PKR). These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.
    DOI:  https://doi.org/10.1182/blood.2024026749
  8. Nat Commun. 2025 Oct 24. 16(1): 9429
    Large transient assemblies of Apaf1 constitute the apoptosome in cells.
    Alicia C Borgeaud, Iva Ganeva, Calvin Klein, Amandine Stooss, Daniela Ross-Kaschitza, Liyang Wu, Joel S Riley, Stephen W G Tait, Thomas Lemmin, Thomas Kaufmann, Wanda Kukulski.
      Upon cell death signals, the apoptotic protease-activating factor Apaf1 and cytochrome c interact to form the apoptosome complex. The apoptosome is crucial for mitochondrial apoptosis, as it activates caspases that dismantle the cell. However, the in vivo assembly mechanism and appearance of the apoptosome remain unclear. We show that upon onset of apoptosis, Apaf1 molecules accumulate into multiple foci per cell. Disassembly of the foci correlates with cell survival. Structurally, Apaf1 foci resemble organelle-sized, cloud-like assemblies. They form through specific interactions with cytochrome c, contain caspase-9, and depend on procaspase-9 expression for their formation. We propose that Apaf1 foci correspond to the apoptosome in cells. Transientness and ultrastructure of Apaf1 foci suggest that the dynamic spatiotemporal organisation of apoptosome components regulates progression of apoptosis.
    DOI:  https://doi.org/10.1038/s41467-025-64478-9
  9. Trends Cancer. 2025 Oct 23. pii: S2405-8033(25)00234-1. [Epub ahead of print]
    Organellar pH as an emerging vulnerability to exploit in cancer.
    Cheska Marie Galapate, Cosimo Commisso.
      Cancer cells undergo metabolic reprogramming to sustain their energy demands, and favor glycolysis despite the presence of functional mitochondria. This metabolic shift leads to the rapid production of lactate and protons. If not managed, this accumulation of acidic byproducts would lower the intracellular pH (pHi). To counteract this, cancer cells employ diverse mechanisms to extrude excess protons through membrane transporters, and also sequester them within acidic organelles. Consequently, an alkaline pHi provides cancer cells with a survival advantage by promoting their proliferation, migration, and resistance to cell death. Given the role of organellar acidification in sustaining this altered pH balance, targeting this process represents a potential therapeutic vulnerability in cancer. We explore the mechanisms by which cancer cells maintain pH homeostasis, with a particular focus on organellar pH and its impact on tumor progression. In addition, we assess inhibitors of the key transporters involved in organellar acidification and discuss their therapeutic potential in cancer.
    Keywords:  cancer metabolism; organelle acidification; pH homeostasis
    DOI:  https://doi.org/10.1016/j.trecan.2025.09.006
  10. Nat Commun. 2025 Oct 20. 16(1): 9250
    Mitochondrial one-carbon metabolism is required for TGF-β-induced glycine synthesis and fibrotic responses.
    Angelo Y Meliton, Kun Woo D Shin, Rengül Cetin-Atalay, M Volkan Atalay, Yufeng Tian, Jennifer C Houpy Szafran, Takugo Cho, Kaitlyn A Sun, Parker S Woods, Obada R Shamaa, Bohao Chen, Nickolai O Dulin, Aliya N Husain, Alexander Muir, Hardik Shah, Gökhan M Mutlu, Robert B Hamanaka.
      TGF-β-dependent activation of lung fibroblasts is a hallmark of Idiopathic Pulmonary Fibrosis (IPF) which results in excessive collagen deposition and progressive scarring. Collagen production by lung fibroblasts is supported by de novo synthesis of glycine, the most abundant amino acid in collagen protein. SHMT2 produces glycine by transferring a one-carbon (1 C) unit from serine to tetrahydrofolate (THF), producing 5,10-methylene-THF (meTHF). meTHF is then converted back to THF in the mitochondrial 1 C pathway. It is unknown how 1 C metabolism contributes to collagen protein production and fibrosis. Here, we demonstrate that TGF-β induces the expression of mitochondrial 1 C pathway enzymes, including MTHFD2, in human lung fibroblasts. MTHFD2 was required for TGF-β-induced cellular glycine accumulation and collagen protein production in lung fibroblasts. Pharmacologic inhibition of MTHFD2 ameliorated fibrotic responses after intratracheal bleomycin instillation in vivo. Our findings suggest that mitochondrial 1 C metabolism is a therapeutic target for IPF and other fibrotic diseases.
    DOI:  https://doi.org/10.1038/s41467-025-64320-2
  11. Cancer Res. 2025 Oct 20.
    Between ROS and a hard place: telomere damage as a driver of T cell exhaustion.
    Tanmana Mitra, Santosha A Vardhana.
      In recent years, accumulation of mitochondrial reactive oxygen species (ROS) has been shown to limit the proliferative capacity and intratumoral persistence of CD8+ T cells, but the molecular mechanisms by which ROS produce functional defects in exhausted CD8+ T cells remain incompletely understood. Using a series of elegant genetic tools, Rivadeneira and colleagues demonstrate that accumulation of mitochondrial reactive oxygen species (ROS) is sufficient to directly compromise telomere integrity. The authors induced singlet oxygen within specific subcellular compartments in T cells, achieving precise temporal and spatial control over ROS production. Genetically driven mitochondrial ROS accumulation reproduced hallmarks of intratumoral T cell dysfunction while also producing marked telomere fragility. Consistent with these findings, tumor-infiltrating CD8+ T cells from patients with melanoma and head and neck cancers exhibited substantial accumulation of DNA damage at telomeres compared with healthy donor or autologous peripheral T cells. Moreover, restricting ROS generation specifically to telomeres was sufficient to reproduce T cell dysfunction, while targeting the antioxidant enzyme GPX1 to telomeres reduced DNA damage and enhanced T cell effector functions, leading to improved tumor control. These findings reveal telomeres as key mediators of redox stress-driven T cell dysfunction and suggest that interventions aimed at protecting chromosome ends may represent a novel strategy to enhance antitumor immunity.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4716
  12. Redox Biol. 2025 Oct 08. pii: S2213-2317(25)00397-0. [Epub ahead of print]87 103884
    The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness.
    Christine Zarges, Hanna Fieler, Robin Alexander Rothemann, Simon Poepsel, Lucas T Jae, Jan Riemer.
      The mitochondrial disulphide relay is the key machinery for import and oxidative protein folding in the mitochondrial intermembrane space. Among IMS proteins with unknown function, we identified FAM136A as a new substrate of the mitochondrial disulphide relay. We demonstrate a transient interaction between FAM136A and MIA40, and that MIA40 introduces four disulphide bonds in two twin-CX3C motifs of FAM136A. Consequently, IMS import of FAM136A requires these cysteines and its steady state levels in intact cells are strongly dependent on MIA40 and AIFM1 levels. Furthermore, we show that FAM136A forms non-covalent homodimers as a mature protein. Acute deletion of FAM136A curtails cellular proliferation capacity and elicits a robust induction of the integrated stress response, coincident with the aggregation and/or depletion of selected IMS proteins including HAX1 and CLPB. Together, this establishes FAM136A as a pivotal component of the IMS proteostasis network, with implications for overall cellular function and health.
    Keywords:  FAM136A; Integrated stress response; MIA40; Oxidative protein folding
    DOI:  https://doi.org/10.1016/j.redox.2025.103884
  13. Transl Oncol. 2025 Oct 19. pii: S1936-5233(25)00298-0. [Epub ahead of print]62 102567
    Longitudinal serum metabolomics predicts therapeutic outcome in acute myeloid leukemia.
    Qing Cai, Wanying Liu, Changjian Yan, Jiazheng Li, Yan Huang, Xiang Li, Qinwen Yang, Xiaoyu Wei, Huilin Yang, Guanbin Zhang, Ting Yang, Yanxin Chen, Jianda Hu.
      Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with approximately 50 % of patients failing to achieve remission during initial treatment and progressing to refractory AML. Metabolomics, a technology directly linked to clinical phenotypes, offers more precise susceptibility biomarkers compared to genomics and epigenetics. Our study compares metabolic samples collected at multiple time points pre- and after-chemotherapy, performs longitudinal integrated analysis to characterize dynamic alterations, and assesses the temporal impacts of therapeutic responses. Four metabolites-pseudouridine, O-phospho-L‑serine, l-aspartate, and 2-deoxy-d-ribose 1-phosphate-were significantly elevated in AML patients, mechanistically linking dysregulated nucleotide biosynthesis and adaptive amino acid metabolic reprogramming to leukemogenic proliferation.Longitudinal sampling during AML treatment revealed temporal metabolic changes, identifying key metabolites and pathways associated with therapeutic responses.By integrating pre- and after-treatment metabolic index with clinical indicators, we developed predictive models for treatment outcomes. The pre-treatment metabolic model (AUC=0.9143, 95 % CI 0.816-1) and the after-treatment metabolic index (AUC=0.9136, 95 % CI 0.83-1) both demonstrated excellent predictive performance for AML therapeutic outcomes. In conclusion, our findings underscore the potential of targeting glycolipid synthesis and amino acid metabolism to improve clinical outcomes. The dynamic metabolic reprogramming landscape serves as a robust indicator of AML treatment efficacy, offering novel directions for precision therapy in AML.
    Keywords:  Acute myeloid leukemia; Dynamic analysis; Metabolic model; Metabolomics
    DOI:  https://doi.org/10.1016/j.tranon.2025.102567
  14. Int J Biol Macromol. 2025 Oct 19. pii: S0141-8130(25)08905-6. [Epub ahead of print] 148348
    Structural dynamics of the mitochondrial ADP/ATP carrier support an asymmetric transport mechanism.
    Yunna Li, Qiuzi Yi, Yabing Cai, Yuchen Zhang, Jianchun Kong, Pingping Jiang, Xiaohui Cang.
      The mitochondrial ADP/ATP carrier (AAC) mediates ADP/ATP exchange across inner mitochondrial membrane via alternating between cytosol-open (c-) and matrix-open (m-) states. Despite the determination of crystallized structures for both states, its transport mechanism still remains unclear. One obstacle is that the structures are co-crystallized with bulky and asymmetric inhibitors. Here, we carried out molecular dynamics simulations on the m-state AAC with and without the co-crystallized nanobody and inhibitor BKA. We found that in apo AAC, the matrix side exhibits enhanced asymmetry, suggesting that the asymmetry observed in crystallized structures is not an artifact of inhibitor binding as previously proposed. Comparative analysis of apo AAC trajectories in m- and c-states reveals that transmembrane helix H2 undergoes the most drastic conformational changes, while the H4-H5 bundle shows the least change among neighboring helix pairs. Further analysis indicates that the PG -level 1 in H2 and H6 separates the carrier into two asymmetric motion units, with the smaller unit undergoing more pronounced movement. Mutagenesis experiments validate functional significance of the asymmetric distribution of highly conserved P×[D/E] × ×[K/R] and [D/E]G motifs among three repeat domains. Free energy calculations further confirm the previously reported asymmetric internal interactions in c-state AAC despite its pseudo-symmetric structure. Collectively, these results point to an asymmetric transport mechanism of AAC. Moreover, the work sheds light on the special internal three-repeat topology of the mitochondrial carrier family, and underscores the necessity of incorporating structural dynamics data when deducing transport mechanisms from static experimental structures in the two states.
    Keywords:  ADP-ATP carrier; Asymmetry; Conformational change
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148348
  15. JACC Adv. 2025 Oct 21. pii: S2772-963X(25)00689-1. [Epub ahead of print]4(11 Pt 1): 102260
    Impact of Exercise on Clonal Hematopoiesis.
    Jessica M Scott, Brandon L Tsai, Caitlin Stewart, Stefan E Eng, James R White, Kelly L Bolton, Ines Vaz-Luis, Julie Havas, Antonio Di Meglio, Anne-Laure Martin, Sandrine Boyault, Ruilin Wang, Jean Baptiste Micol, Luis A Diaz, Paul C Boutros, Lee W Jones.
       BACKGROUND: Clonal hematopoiesis (CH) is more prevalent in cancer patients and is associated with excess all-cause mortality (ACM) risk compared to patients without CH. Interventions to mitigate risk are not available.
    OBJECTIVES: The objective of the study was to investigate whether exercise reduces CH prevalence and excess ACM risk of CH in cancer patients.
    METHODS: We integrated genomic sequencing data with detailed exercise and clinical annotation from 2 retrospective studies: 3,539 patients with solid tumors from the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) and 1,142 patients with primary breast cancer from CANTO (CANcer TOxicities). Patients were classified as nonexercisers (ie, 0 metabolic equivalent of task-h/week) or exercisers (ie, >0 metabolic equivalent of task-h/week). We then conducted a remotely-supervised structured exercise therapy study in 4 patients with cancer and CH.
    RESULTS: In multivariable analysis, CH prevalence was not different between exercisers and nonexercisers in MSK-IMPACT (OR: 0.95; 95% CI: 0.8 to 1.13; adjusted Firth's logistic regression) or CANTO (OR: 1.28; 95% CI: 0.89-1.84; adjusted Firth's logistic regression). Patients with CH had a higher unadjusted hazard of ACM relative to patients without CH (HR: 1.41; 95% CI: 1.23-1.62). Relative to non-CH nonexercisers, CH-exercisers had a lower adjusted hazard of ACM (HR: 0.69; 95% CI: 0.55-0.87). In the prospective exercise study, cardiovascular risk factors were improved; no changes in peripheral blood somatic variant allele frequency were observed.
    CONCLUSIONS: Exercise was not associated with CH burden but does reduce excess ACM of CH in patients with cancer. Further research is needed to investigate the exercise-CH relationship in cancer and other populations. Trial Registration Clinical trials.gov number: NCT03996239.
    Keywords:  cancer; cardiovascular disease; clonal hematopoisis; exercise
    DOI:  https://doi.org/10.1016/j.jacadv.2025.102260
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒26 at 1:38.