bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–07–06
23 papers selected by
Kelsey Fisher-Wellman, Wake Forest University



  1. Nat Commun. 2025 Jul 01. 16(1): 5314
      Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear. Here, we uncover a mitochondrial morphology dedicated to respiratory growth of Saccharomyces cerevisiae, which we refer to as "Ringo". The Ringo morphology is characterized by stable constrictions of mitochondrial tubules. Ringo constrictions are mediated by the yeast dynamin Dnm1 and, unlike mitochondrial fission, occur in the absence of contacts with the endoplasmic reticulum. Our data show that blocking formation of the Ringo morphology correlates with decreased respiration, decreased expression of OXPHOS subunits and perturbed mitochondrial DNA distribution. These results open important perspectives about the link between mitochondrial form and function.
    DOI:  https://doi.org/10.1038/s41467-025-60658-9
  2. Nat Commun. 2025 Jul 01. 16(1): 5435
      Mutations in mitochondrial DNA (mtDNA) accumulate during aging and contribute to age-related conditions. High mtDNA copy number masks newly emerged recessive mutations; however, phenotypes develop when cellular levels of a mutant mtDNA rise above a critical threshold. The process driving this increase is unknown. Single-cell DNA sequencing of mouse and human hepatocytes detected increases in abundance of mutant alleles in sequences governing mtDNA replication. These alleles provided a replication advantage (drive) leading to accumulation of the affected genome along with a wide variety of associated passenger mutations, some of which are detrimental. The most prevalent human mtDNA disease variant, the 3243A>G allele, behaved as a driver, suggesting that drive underlies prevalence. We conclude that replicative drive amplifies linked mtDNA mutations to a threshold at which phenotypes are seen thereby promoting age-associated erosion of the mtDNA and influencing the transmission and progression of mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60477-y
  3. Nat Commun. 2025 Jul 01. 16(1): 5563
      Although glycolysis is traditionally considered a cytosolic reaction, here we show that glycolytic enzymes propagate as self-organized waves on the membrane/cortex of human cells. Altering these waves led to corresponding changes in glycolytic activity, ATP production, and dynamic cell behaviors, impacting energy-intensive processes such as macropinocytosis and protein synthesis. Mitochondria were absent from the waves, and inhibiting oxidative phosphorylation (OXPHOS) had minimal effect on ATP levels or cellular dynamics. Synthetic membrane recruitment of individual glycolytic enzymes increased cell motility and co-recruited additional enzymes, suggesting assembly of glycolytic multi-enzyme complexes in the waves. Remarkably, wave activity and glycolytic ATP levels increased in parallel across human mammary epithelial and other cancer cell lines with higher metastatic potential. Cells with stronger wave activity relied more on glycolysis than on OXPHOS for ATP. These results reveal a distinct subcellular compartment for enriched local glycolysis at the cell periphery and suggest a mechanism that coordinates energy production with cellular state, potentially explaining the Warburg effect.
    DOI:  https://doi.org/10.1038/s41467-025-60596-6
  4. Trends Cancer. 2025 Jul 02. pii: S2405-8033(25)00153-0. [Epub ahead of print]
      Sublethal apoptotic stress causing the permeabilization of some mitochondria coupled with cytosolic mitochondrial DNA (mtDNA) accumulation is known to promote cellular senescence. Lai et al. have recently demonstrated that this may be accompanied by mtDNA release within extracellular vesicles that promote local immunosuppression via myeloid-derived suppressor cells.
    Keywords:  NF-κB; PD-L1; SASP; STING; VDAC; prostate cancer
    DOI:  https://doi.org/10.1016/j.trecan.2025.06.010
  5. Sci Adv. 2025 Jul 04. 11(27): eadx4562
      The guanosine triphosphatase (GTPase) activity of the mitochondrial dynamin-related protein Optic Atrophy 1 (OPA1) regulates cristae remodeling, cytochrome c release, and apoptosis. Elevated OPA1 levels in multiple cancers correlate with reduced therapy sensitivity and poor survival, calling for specific OPA1 GTPase inhibitors. A high-throughput screening of ~10,000 compounds identified MYLS22, a heterocyclic N-pyrazole derivative as a reversible, noncompetitive OPA1 GTPase inhibitor. MYLS22 engaged with OPA1 in vitro and in cells where it induced cristae remodeling and mitochondrial fragmentation contingent on intactness of its predicted OPA1 binding site. MYLS22 enhanced proapoptotic cytochrome c release and sensitized breast adenocarcinoma cells to anti-Bcl-2 therapy, without toxicity on noncancer cells. By MYLS22 structure-activity relationship studies, we obtained Opa1 inhibitor 0 (Opitor-0) that inhibited OPA1, promoted cytochrome c release, and restored anti-Bcl-2 therapy sensitivity more efficiently than MYLS22. These chemical probes validate OPA1 as a therapeutic target to increase cancer cell apoptosis at the mitochondrial level.
    DOI:  https://doi.org/10.1126/sciadv.adx4562
  6. Cell Death Dis. 2025 Jul 01. 16(1): 468
      The dependence of cancer cells on mitochondrial metabolism has been revealed in various cancer types. However, the mechanisms underlying this metabolic remodeling remain largely unclear. Solute carrier family 44 member 4 (SLC44A2) is a mitochondrial membrane-localized transmembrane protein belonging to the choline transporter-like protein family. Recently, it was reported that deletion of SLC44A2 impairs adhesion and increases proliferation in cultured lung mesenchymal cells. This finding implies that SLC44A2 may play a role in the malignant phenotypes of human cancers. However, the effects of SLC44A2 on malignant phenotypes and mitochondrial metabolism in human cancers remain unexplored. In the present investigation, we observed a significant reduction in SLC44A2 expression in colorectal cancer (CRC), and low SLC44A2 expression was closely associated with poorer survival of CRC patients. Functional assays demonstrated that SLC44A2 suppressed CRC growth and metastasis both in vitro and in vivo. Mechanistically, SLC44A2 inhibits mitochondrial fatty acid oxidation, thereby reducing energy supply and increase ROS stress. This effect is achieved by promoting mitochondrial E3 ubiquitin ligase 1 (MUL1)-regulated degradation of carnitine palmitoyltransferase 2 (CPT2) via enhancing the interaction between MUL1 and CPT2, without increasing MUL1 expression, which ultimately contributes to the proliferation and metastasis of CRC. Together, SLC44A2 functions as a critical tumor suppressor in CRC and potential therapeutic target in the treatment of this malignancy.
    DOI:  https://doi.org/10.1038/s41419-025-07781-z
  7. Elife. 2025 Jun 30. pii: RP104461. [Epub ahead of print]14
      Somatic mitochondrial DNA (mtDNA) mutations are implicated as important drivers of ageing and age-related diseases. Their pathological effect can be counteracted by increasing the absolute amount of wild-type mtDNA via moderately upregulating TFAM, a protein important for mtDNA packaging and expression. However, strong TFAM overexpression can also have detrimental effects as it results in mtDNA hypercompaction and subsequent impairment of mtDNA gene expression. Here, we have experimentally addressed the propensity of moderate TFAM modulation to improve the premature ageing phenotypes of mtDNA mutator mice, carrying random mtDNA mutations. Surprisingly, we detect tissue-specific endogenous compensatory mechanisms acting in mtDNA mutator mice, which largely affect the outcome of TFAM modulation. Accordingly, moderate overexpression of TFAM can have negative and beneficial effects in different tissues of mtDNA mutator mice. We see a similar behavior for TFAM reduction, which improves brown adipocyte tissue homeostasis, while other tissues are unaffected. Our findings highlight that the regulation of mtDNA copy number and gene expression is complex and causes tissue-specific effects that should be considered when modulating TFAM levels. Additionally, we suggest that TFAM is not the sole determinant of mtDNA copy number in situations where oxidative phosphorylation (OXPHOS) is compromised, but other important players must be involved.
    Keywords:  biochemistry; chemical biology; genetics; genomics; mitochondrial DNA; mouse; mtDNA copy number; mtDNA mutations; tissue specificity
    DOI:  https://doi.org/10.7554/eLife.104461
  8. Cancer Med. 2025 Jul;14(13): e71005
       BACKGROUND: Peroxiredoxin 6 (PRDX6) scavenges reactive oxygen species (ROS) and plays a key role in antioxidant defense. Although PRDX6 is involved in various cancers, its role in breast cancer (BRCA) remains unclear.
    METHODS: Cell proliferation was assessed using CCK-8, EdU staining, and colony formation assays. Migration and invasion were evaluated via wound-healing and transwell assays. ROS levels and mitochondrial membrane potential were measured by fluorescence microscopy or flow cytometry. Oxidative phosphorylation (OXPHOS) activity was determined by ATP production and NAD+/NADH ratio. Mitochondria were visualized by TEM, and mitochondrial complex subunits were detected by quantitative real-time PCR and Western blotting. In vivo effects were evaluated using a xenograft tumor model.
    RESULTS: Although PRDX6 was downregulated in BRCA overall, it showed elevated expression in aggressive subtypes and advanced-stage tumors, correlating with poor prognosis. Overexpression of PRDX6 enhanced BRCA cell proliferation, migration, and invasion. PRDX6 reduced ROS levels, upregulated mitochondrial transcription factor A (TFAM) expression, and promoted mitochondrial complex subunit expression and OXPHOS. Inhibition of TFAM led to a decrease in the expression of some of the mitochondrial complex subunits, which reversed the pro-carcinogenic phenotype of the tumor. PRDX6 also promoted tumor growth in vivo.
    CONCLUSION: PRDX6 maintains intracellular homeostasis by reducing ROS and promotes mitochondrial biogenesis and OXPHOS through TFAM-dependent and -independent pathways, driving BRCA progression.
    Keywords:  PRDX6; breast cancer; mitochondria; oxidative phosphorylation (OXPHOS); tumorigenesis
    DOI:  https://doi.org/10.1002/cam4.71005
  9. Cell Rep. 2025 Jul 02. pii: S2211-1247(25)00708-9. [Epub ahead of print]44(7): 115937
      Cuproptosis, a copper-induced form of regulated cell death, holds therapeutic promise in cancer but remains mechanistically unclear. We developed Mito-TPCA, a mitochondrial thermal proximity coaggregation strategy combining enzyme-catalyzed proteome labeling with thermal profiling, to map mitochondrial protein-protein interaction dynamics during cuproptosis. This approach revealed that copper disrupts the association of pyruvate dehydrogenase kinases (PDKs) with the pyruvate dehydrogenase (PDH) complex by targeting lipoyl domains, triggering PDH dephosphorylation and aberrant activation. We demonstrate that this PDH activation is a key driver of cuproptosis and contributes to the heightened susceptibility of cancer cells. These findings establish PDH dephosphorylation/activation as a central mechanism of cuproptosis and a potential anti-cancer therapeutic target. Mito-TPCA offers a versatile platform to study mitochondrial protein complex dynamics in live cells.
    Keywords:  CP: Metabolism; CP: Molecular biology; cancer cell susceptibility; cuproptosis; mitochondrial thermal proteome; proximity labeling; pyruvate dehydrogenase aberrant activation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115937
  10. Blood. 2025 Jul 03. pii: blood.2025028935. [Epub ahead of print]
      TP53-Y220C is a recurrent hotspot mutation in cancers and leukemias. It is observed predominantly in acute myeloid leukemia (AML)/myelodysplastic syndromes among hematological malignancies and is associated with poor outcome. The mutation creates a structural pocket in the p53 protein. PC14586 (rezatapopt) is a small molecule designed to bind to this pocket and thus restore a p53-wild type (p53-WT) conformation. We demonstrate that PC14586 converts p53-Y220C into a p53-WT conformation and activates p53 transcriptional targets, but surprisingly induces limited/no apoptosis in TP53-Y220C AML. Mechanistically, MDM2 induced by PC14586-activated conformational p53-WT and the nuclear exporter XPO1 reduce the transcriptional activities of p53, which are fully restored by inhibition of MDM2 and/or XPO1. Importantly, p53-WT protein can bind to BCL-2, competing with BAX in the BH3 binding pocket of BCL-2 and also binds to BCL-xL and MCL-1. However, such binding by PC14586-activated conformational p53-WT is not detected. Pharmacological inhibition of the BCL-2/BAX interaction with venetoclax fully compensates for this deficiency, induces massive cell death in AML cells and stem/progenitor cells in vitro and prolongs survival of TP53-Y220C AML xenografts in vivo. Collectively, we identified transcription-dependent and -independent mechanisms that limit the apoptogenic activities of reactivated conformational p53-WT and suggest approaches to optimize apoptosis induction in TP53-mutant leukemia. A clinical trial of PC14586 in TP53-Y220C AML/myelodysplastic syndromes has recently been initiated (NCT06616636).
    DOI:  https://doi.org/10.1182/blood.2025028935
  11. Biochim Biophys Acta Bioenerg. 2025 Jun 29. pii: S0005-2728(25)00032-5. [Epub ahead of print] 149566
      Acetogenins isolated from the Annonaceae plant family are potent inhibitors of mitochondrial NADH-ubiquinone (UQ) oxidoreductase (complex I). Since acetogenins have a markedly different chemical framework from other complex I inhibitors, studying their inhibitory action offers valuable insights into the mechanism of complex I inhibition. A cryo-EM structure of mouse complex I with a bound ~35 Å-long acetogenin derivative suggested that acetogenins bind along the full length of the predicted UQ-accessing tunnel, with their γ-lactone ring orientating toward the iron‑sulfur cluster N2. However, this binding mode does not fully explain the structure-activity relationships of various acetogenin derivatives. To further elucidate their inhibition mechanism, we conducted photoaffinity labeling experiments in bovine heart SMPs using a photoreactive acetogenin derivative DLA-1, containing a small photolabile diazirine near the γ-lactone ring. DLA-1 labeled both the complex I subunits 49-kDa and ND1, which define the architecture of "top" and "bottom" regions of the canonical UQ-accessing tunnel, respectively. Proteomic analysis revealed that the labeled sites in ND1 are not within the tunnel's interior, whereas in the case of 49-kDa subunit, part of the tunnel's inner region is labeled. To investigate the molecular basis of acetogenin binding, we performed atomistic molecular dynamics simulations of DLA-1 and a natural-type acetogenin analog in the UQ-accessing tunnel. The simulation data indicate that DLA-1 is relatively rigid yet adopts multiple conformations and interacts with several regions in the tunnel including the residues identified by photoaffinity labeling. Based on these results, we discuss the binding modes of acetogenin analogs to complex I.
    Keywords:  Acetogenin; MD simulations; Mitochondria; Photoaffinity labeling; Respiratory complex I
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149566
  12. Leukemia. 2025 Jun 30.
      Metabolic reprogramming is a key focus of targeted therapies in acute myeloid leukemia (AML). The mitochondrial sirtuin SIRT5 removes succinyl groups from specific lysines and impacts cell metabolism, but its role in AML tumorigenesis has not been extensively explored. A recent study highlighted that SIRT5 regulates AML cell activity by modulating glutamine metabolism, but its molecular targets in AML remain unclear. This study aims to identify the substrates of SIRT5 in AML. It was found that a total of 83 proteins with 121 lysine (K) residues showed increased succinylation after SIRT5 knockdown, as determined by succinylome analysis of MOLM-13 cells. SIRT5 was validated to interact with HADHA, a key molecule in the fatty acid oxidation pathway. Knockdown of SIRT5 resulted in hypersuccinylation and reduced enzymatic activity of HADHA. Mimetic mutations of lysine indicated that SIRT5 desuccinylates HADHA at K644. Inhibiting SIRT5 or HADHA increased sensitivity to venetoclax (VEN) in both VEN-sensitive and VEN-resistant cell lines. SIRT5 knockdown enhanced VEN-mediated suppression of mitochondrial metabolism and improved the survival of AML-transplanted NSG mice when combined with VEN. This study reveals the role of SIRT5 in AML metabolic regulation and provides valuable insights for developing SIRT5-targeted drugs and combination therapies with metabolic inhibitors.
    DOI:  https://doi.org/10.1038/s41375-025-02673-9
  13. Front Immunol. 2025 ;16 1560104
      Assays to monitor metabolic parameters of immune cells at a single cell level provide efficient means to study immunometabolism. We show here that staining intensity of mitochondria targeting probes in T cells is dramatically influenced by P-glycoprotein/P-gp expression, a xenobiotic efflux pump that extrudes these fluorescent dyes. Discrepancies between MitoTracker Green FM/MTG signals and multiple dye-independent measurements are seen in CD4 T and CD8 T cell subsets and are corrected by P-gp inhibition (PSC833) during MTG staining. We further investigate invariant Natural Killer T (iNKT) cells, which express the highest level of P-glycoprotein among T cells. Using mtDNA abundance, mitochondrial volume, respiration and proteomics, we establish that iNKT cells have higher mitochondrial content and activity than CD4 T cells, opposite to what MTG signals reveal. A similar phenomenon is also seen in human PBMCs, and with TMRE, a dye indicator of mitochondrial membrane potential. Collectively, these data argue that P-glycoprotein expression is a significant confounding factor when analyzing T cells using mitochondrial specific dyes. Complementary methods are necessary to reliably assess mitochondrial features in T cells.
    Keywords:  P-glycolprotein; T cells; TMRE; mitochondria; mitotracker; oxidative phosphorilation
    DOI:  https://doi.org/10.3389/fimmu.2025.1560104
  14. Discov Oncol. 2025 Jul 02. 16(1): 1253
      Mitochondrial pyruvate carrier (MPC), composed of MPC1 and MPC2, plays a pivotal role in regulating cancer metabolism. While previous studies have implicated MPC1 in tumor progression, the specific function of MPC2 in renal cell carcinoma (RCC) remains largely unclear. In this study, we found that reduced MPC2 expression was significantly associated with advanced TNM stage and poor patient prognosis. Functional assays demonstrated that MPC2 suppresses RCC cell proliferation both in vitro and in vivo. Additionally, concurrent low expression of MPC2 and MPC1 was correlated with significantly shorter overall survival, suggesting their combined prognostic value. Gene set enrichment analysis indicated that both MPC1 and MPC2 are negatively associated with the Bmi1 signaling pathway. Mechanistically, inhibition of the MPC complex-either genetically or pharmacologically-led to increased Bmi1 protein levels by reducing its ubiquitin-mediated degradation. These findings identify the MPC complex as a potential tumor suppressor and prognostic biomarker set in RCC, functioning in part through modulation of Bmi1 stability.
    Keywords:  Bmi1; MPC1; MPC2; RCC; Ubiquitination
    DOI:  https://doi.org/10.1007/s12672-025-03053-6
  15. Proc Natl Acad Sci U S A. 2024 Aug 13. 121(33): e2401996121
      Upstream frameshift 1 (UPF1) is an RNA helicase involved in a number of mRNA regulatory processes including nonsense-mediated decay. Mutations in the UPF1 locus that reduce its expression have been associated with adenosquamous carcinoma of the pancreas, a particularly aggressive form of the disease. To determine the effect of Upf1 suppression in a murine model of pancreatic adenocarcinoma, we silenced with shRNA Upf1 in cells derived from an autochthonous tumor in an LSL-KrasG12D/+; Trp53R172H/+; Pdx-1Cre/+ mouse (KPC) and orthotopically implanted these cells in the pancreas of C57BL/6 mice. Tumors derived from Upf1-deficient cells were markedly larger than those derived from control cells, a difference observed only in immunocompetent mice. The immune infiltrate of Upf1-deficient tumors was enriched in myeloid-derived suppressor cells (MDSCs) and depleted of CD8+ cells compared to control KPC tumors. Upf1-deficient KPC cells secreted inflammatory cytokines including G-CSF and CXCL2, known to recruit MDSCs. Cytokine secretion from Upf1-deficient KPC cells was induced by increased levels of mitochondrial reactive oxygen species (ROS), which in turn were due to an increase in complex I activity in the electron transport chain. Thus, Upf1 helicase deficiency leads to increased mitochondrial complex I activity which produces ROS that signals for cytokine release that drives immune suppression and enhanced tumor growth.
    Keywords:  UPF1; complex I; mitochondrial ROS; myeloid-derived suppressor cells; tumor microenvironment
    DOI:  https://doi.org/10.1073/pnas.2401996121
  16. Nat Rev Mol Cell Biol. 2025 Jul 03.
      Mitochondria contain about 1,000-1,500 different proteins, most of which are encoded by the nuclear genome and synthesized in the cytosol, although a handful are specified by the mitochondrial DNA and translated within mitochondria. The coordinated transport of nucleus-encoded proteins into mitochondria, followed by their proper folding, assembly and/or integration into mitochondrial membranes, is central to mitochondrial biogenesis. In this Review, we describe the pathways and machineries for protein transport across and insertion into the inner and outer mitochondrial membranes, as well as the targeting and sorting signals, and energy requirements for these processes. These machineries include the TOM and SAM complexes in the outer membrane and the TIM complexes in the inner membrane, and some components in the intermembrane space. We emphasize recent developments in our understanding of the protein structures of the transport machineries and discuss mechanisms for the shift of protein localization and correction of mislocalization.
    DOI:  https://doi.org/10.1038/s41580-025-00865-w
  17. Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00510-6. [Epub ahead of print]85(13): 2457-2459
      In this issue of Molecular Cell, Chen et al.1 identify a novel arginine-sensing system, composed of the cytosolic proteins BAG2 and SAMD4B, which promotes cancer cell survival during arginine deficiency.
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.010
  18. Cell Genom. 2025 Jun 26. pii: S2666-979X(25)00201-0. [Epub ahead of print] 100945
      The oxidative phosphorylation (OxPhos) system is central to metabolism. The more than 90 structural subunits are encoded by different chromosome categories (autosomal, X, and mtDNA). The system is envisioned as an invariant structure between cells and individuals. However, a comprehensive analysis of the 1,000 Genomes Project data reveals unexpected genetic intra-individual variability resulting from the heterozygosity of diploid autosomal genes, while diversity at the population level is generated by variability in mtDNA. We characterized the different levels of structural constriction at evolutionary and population levels for all OxPhos protein residues. To support this analysis, we developed ConScore, a conservation-based predictor of variant impact within OxPhos proteins (area under the receiver operating characteristic curve [ROC-AUC] = 0.97; area under the precision-recall curve [PR-AUC] = 0.94). Notably, for the nuclear-encoded subunits, we found mechanisms limiting individual variability as allelic imbalance or homozygosity bias. Integrating structural, functional, and genetic data, we highlight the significance of each OxPhos protein position, expanding insights into its role in speciation and disease.
    Keywords:  OxPhos; conservation score; evolutionary drivers; human variability; mitochondrial DNA; mtDNA; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.xgen.2025.100945
  19. Cell Death Discov. 2025 Jul 01. 11(1): 291
      Tumor cells balance ATP production and carbon skeleton synthesis by flexibly altering catabolic pathways to sustain their significant growth advantage. Uncouplers have shown potential for tumor suppression by converting chemical energy from catabolism into heat. However, their use may be limited due to indiscriminate metabolic interference in both tumor and normal cells, as well as the uncertainty surrounding their effects on the immune microenvironment. Herein, we found that low-dose uncoupler BAM15 promoted AMPK, AKT signaling, and the TCA cycle without increasing cell proliferation or inducing cell death in vitro, suggesting an increase in futile cycling. Intratumoral injection of 50 ng/mL BAM15 accelerated catabolic processes while inhibiting anabolic pathways, resulting in a metabolomic reshaping with increased levels of linoleic acid, C5DC, and others. These changes were shown to enhance tumor-killing effects by T cells. To reduce side effects on normal tissues and improve tumor retention, BAM15 was targeted for delivery by loading it into TCVs. This TCV-BAM15 treatment significantly increased CD8+ T cell counts and granzyme B levels. Our findings highlight a previously unrecognized therapeutic effect and signaling mechanism of low-dose BAM15 treatment in tumors. We propose that this novel strategy holds promise as a tumor immunity therapy with fewer adverse effects compared to free uncoupling drugs at high concentrations.
    DOI:  https://doi.org/10.1038/s41420-025-02584-9
  20. Commun Biol. 2025 Jul 01. 8(1): 972
      Mitochondria are implicated in many cellular functions such as energy production and apoptosis but also disease pathogenesis. To effectively perform these roles, the mitochondrial inner membrane has invaginations known as cristae that dramatically increase the surface area. This works to provide more space for membrane proteins that are essential to the roles of mitochondria. While separate components of this have been studied computationally, it remains a challenge to combine elements into an overall model. Here, we present a comprehensive model of a crista junction from a human mitochondrion and the accompanying workflow to construct it. Our coarse-grained representation of a crista shows how various experimentally determined features of organelles can be combined with molecular modelling to give insights into the interactions and dynamics of complicated biological systems. This work is presented as an initial 'living' model for this system, intended to be built upon and improved as our understanding, methodology and resources develop.
    DOI:  https://doi.org/10.1038/s42003-025-08381-5
  21. Trends Cancer. 2025 Jul 03. pii: S2405-8033(25)00144-X. [Epub ahead of print]
      Menin has emerged as a promising therapeutic target in acute myeloid leukemia (AML). The menin-MLL1 interaction promotes an oncogenic transcriptional program that drives leukemogenesis in HOX-mediated acute leukemias, including KMT2A-rearranged (KMT2Ar), nucleophosmin 1-mutated (NPM1m), and NUP98-rearranged (NUP98r) AML, prompting development of menin inhibitors for treatment of these subtypes. Successes in clinical investigation have led to recent FDA approval of revumenib for KMT2Ar AML, with numerous trials examining menin inhibitors as monotherapy and in combination with other antileukemic drugs ongoing. Although menin inhibitors represent a major advancement in AML treatment, acquired resistance is an evolving barrier to efficacy. Here, we examine the biological rationale for menin inhibition and discuss the landscape of clinical trials and resistance mechanisms associated with menin inhibitors.
    Keywords:  KMT2A; NPM1; acute myeloid leukemia; menin inhibitors
    DOI:  https://doi.org/10.1016/j.trecan.2025.06.002
  22. Science. 2025 Jul 03. eadw1836
      The anti-apoptotic protein MCL-1 (myeloid cell leukemia-1) is essential for embryogenesis and the survival of many cell types that tolerate loss of its relatives, BCL-XL and BCL-2. Apoptosis-unrelated roles of MCL-1 in metabolism may contribute to this requirement, though their relevance for embryogenesis and postnatal life remains unclear. We hypothesized that BCL-XL and BCL-2 may substitute MCL-1's anti-apoptotic but not its apoptosis-unrelated functions. Replacing MCL-1 with BCL-XL or BCL-2 supported embryo development by rescuing the Mcl-1-/- preimplantation lethality. Mcl-1Bcl-xL/Bcl-xL but not Mcl-1Bcl-2/Bcl-2 mice were born on a mixed background, though they showed metabolic defects. Thus MCL-1's apoptosis-unrelated functions appear critical in later development, with BCL-XL, but not BCL-2, partially compensating. These findings clarify MCL-1's distinct physiological roles, critically informing MCL-1 inhibitor development as cancer therapeutics.
    DOI:  https://doi.org/10.1126/science.adw1836
  23. Biosystems. 2025 Jul 02. pii: S0303-2647(25)00137-6. [Epub ahead of print] 105527
      The synthesis of adenosine triphosphate (ATP), the universal biological currency, by oxidative phosphorylation and photophosphorylation catalyzed by the FOF1-ATP synthase is the fundamental means of cellular energy generation in animals, plants, and microorganisms. Since the ocean area and the amount of biomass is very large, the formation of ATP and its utilization by the myriad energy-consuming processes in the cell is the principal net chemical reaction taking place on the surface of the earth. This is indeed a most important reaction. How exactly does it occur? Since the development of the famous colorimetric assay for measurement of inorganic phosphate (Pi) in 1925, followed by the discovery of ATP in 1929, an enormous amount of research has been done to understand these intracellular energy-linked processes. I present an account of the major developments on ATP synthesis and hydrolysis in a century of research, and summarize the current state of knowledge. My account focuses on the fields of bioenergetics, muscle contraction, and motility in cell life, and covers key aspects of metabolic disease, mitochondrial apoptosis, and cell death in relation to ATP and the ATP synthase, and the permeability transition pore. It includes developments at molecular, cellular, and macroscopic levels-ascending into ecology-thanks to the conservative nature of metabolic pathways, with ATP as the universal intermediate in the coupled reactions of biological energy transduction. New, emerging sub-fields on ATP and the Warburg Effect, purinergic signaling, condensates and the role of ATP as a biological hydrotope are discussed briefly, and possible applications in aging and precision medicine are foreseen. I have divided the subject matter into the following five eras to cover the vast ground. (i)-the beginning era of the 1920s (Section 2), (ii)-an era of trials and trails of the 1930s ‒ 1940s (Sections 3.1 ‒ 3.5), (iii)-an era of population-based biochemistry and enzymology in the 1950s ‒ 1980s (Sections 4.1 ‒ 4.9), (iv)-a high-tech era of the 1990s ‒ 2020s of high-resolution structural and single-molecule studies, but also an interdisciplinary era of systems biology that integrates approaches from physics, chemistry, biology, mathematics, and engineering (Sections 5.1 ‒ 5.15), (v)-future prospects (Section 6). The article works out new explanations-with quantitative equations or physical criteria developed for the first time-that may help resolve longstanding issues in muscle contraction, bioenergetics, and transport. My tryst with ATP during 35-years of research is also described, and the search for a theory with greater numerical accuracy is emphasized. Errors of previous theories are identified and corrected, and apparent contradictions are resolved. The aim is to explain and correctly interpret the cumulative experimental record, check for consistency of theory with experiment, remove the inconsistencies in previous theories, and arrive at a unified molecular theory of energy coupling, transduction, ATP synthesis, and ATP hydrolysis. To conclude, a number of recommendations for the progress of scientific research in interdisciplinary and multidisciplinary areas have been made.
    Keywords:  ATP hydrolysis; ATP metabolism; ATP synthesis; Apoptosis; Bioenergetics; Boyer’s binding change mechanism; Cancer biology; Detailed kinetic models of ATP synthesis; F(O)F(1)-ATP synthase and F(1)-ATPase; History of science; Metabolic diseases; Mitchell’s chemiosmotic theory; Mitochondria and chloroplasts; Molecular motors; Muscle contraction; Myosins and kinesins; Nath’s biothermokinetic theory; Nath’s torsional mechanism of energy transduction and ATP synthesis; Nath’s two-ion theory of energy coupling and ATP synthesis; Nath’s unified theory of ATP synthesis/hydrolysis; Nonequilibrium/irreversible thermodynamics and the P/O ratio in cells; OXPHOS; Oxidative phosphorylation; Photosynthesis; Rotation-twist-tilt (RTT)/Rotation-uncoiling-tilt (RUT) energy storage mechanism of muscle contraction; Swinging crossbridge/lever arm model of muscle contraction; aging and precision medicine; and the Warburg Effect; and the permeability transition pore (PTP); cell death
    DOI:  https://doi.org/10.1016/j.biosystems.2025.105527