bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–07–19
sixteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.
  2. Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.
  3. A quantum interface with mitochondrial bioenergetics.
  4. Dual-faced metabolic reprogramming powers proliferation: FGF21 drives lung squamous carcinoma progression via CaMKII-DRP1-mediated mitochondrial fission.
  5. Deep learning reveals FLAD1-mediated mitochondrial metabolic reprogramming in hypoxic tumors.
  6. Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
  7. More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.
  8. Survivin Associates with VDAC2 and Bcl2-Family Proteins at the Mitochondrial Outer Membrane.
  9. Resensitizing drug-resistant cancers by co-targeting apoptosis and mitochondrial stress pathway.
  10. Copper(II)-Mediated Mitochondria-Targeting in Cancer Cells.
  11. Somatic pathogenic mitochondrial DNA mutations independently predict worse prognosis in hepatocellular carcinoma.
  12. A high-fat, low-carbohydrate diet can feed intestinal tumours.
  13. SLC25A1 drives lipid metabolic reprogramming promoting liver injury leading to hepatocellular carcinoma.
  14. Mitochondrial DNA mutations drive tumor heterogeneity in papillary thyroid carcinoma.
  15. Beyond Bioenergetics: Moonlighting Functions of F1FO-ATPase From ATP Synthesis to an ATP-Wasting Death Switch.
  16. Standardised dual-flow cytometry workflows for quantitative assessment of mitochondrial superoxide and mitochondrial mass in live cancer cells and primary multiple myeloma cells.
  1. Cell Commun Signal. 2026 Jul 14.
    Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.
    Karthik Reddy Kami Reddy, Vasanta Putluri, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Aaditya Krishna Arun, Sachin B Jorvekar, Yongchao Dou, Mohammed Khurshidul Hassan, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Jun Xu, Daniel Kraushaar, Adriana Langer Gramer, Allison C Bellman, Leomar Y Ballester, Yuan Xu, Robert Taylor Ripley, Seth P Lerner, Roni J Bollag, Martha K Terris, Chong-Xian Pan, Benny Abraham Kaipparettu, Yair Lotan, Nagireddy Putluri.
       BACKGROUND: Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15-25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined.
    METHODS: To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism.
    RESULTS: PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth.
    CONCLUSION: PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3Kα inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.
    DOI:  https://doi.org/10.1186/s12964-026-03058-w
  2. Br J Cancer. 2026 Jul 14.
    Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.
    Salma Sharmin, Jennifer A Kashatus, Sara J Adair, Emma Bakall Loewgren, Mohammad Fallahi-Sichani, Todd W Bauer, David F Kashatus.
       BACKGROUND: In RAS-mutant tumours, ERK phosphorylates the mitochondrial fission GTPase DRP1 to promote mitochondrial fission. DRP1 activity is tumour-promoting in pancreatic and other RAS-driven cancers, but its role in therapeutic resistance is unknown.
    METHODS: We developed a panel of patient-derived pancreatic cancer cell lines resistant to the MEK inhibitor trametinib. We used immunofluorescence imaging, in vitro growth assays and orthotopic xenografts to determine the role of DRP1 in trametinib resistance.
    RESULTS: We find that trametinib-resistant cells exhibit increased expression and phosphorylation of DRP1 compared to sensitive counterparts. Quantitative analysis of mitochondrial structure reveals that mitochondria in resistant cells are morphologically distinct and relatively smaller than sensitive cells treated with trametinib. Genetic and pharmacological inhibition of both c-Myc and CDK6 are sufficient to block DRP1 phosphorylation in resistant cells, suggesting that activation of a c-Myc-CDK6 signalling axis drives reactivation of mitochondrial fission in the absence of MAPK signalling. Importantly, deletion of DRP1 leads to either growth inhibition or re-sensitisation to trametinib in resistant lines.
    CONCLUSION: These findings suggest DRP1 contributes to drug resistance, and that inhibition of mitochondrial fission might be a promising therapeutic strategy to combat resistance to MAPK and RAS inhibitors.
    DOI:  https://doi.org/10.1038/s41416-026-03542-7
  3. bioRxiv. 2026 Jul 09. pii: 2026.07.03.736226. [Epub ahead of print]
    A quantum interface with mitochondrial bioenergetics.
    Parisa Aghaei, Sangjun Noh, Javier Noé Ramos-Silva, Minghao Jiang, Phang-Lang Chen, Yumay Chen, Fatemeh Goodarzinia, Robert Usselman, Philip Hemmer, Douglas C Wallace, Peter J Burke.
      Recent work has shown that genetically engineered proteins can serve as quantum bits in living systems. These quantum bits arise from the photochemistry of protein-bound flavins: blue-light excitation drives electron transfer to form a spin-correlated radical pair whose coherent singlet-triplet interconversion makes the protein's fluorescence sensitive to weak magnetic fields. Because this radical-pair reaction depends on the redox state of the flavin-itself a central electron carrier in cellular metabolism-the magneto-fluorescence of a biological qubit is intrinsically coupled to the biochemistry around it. This suggests a powerful application of fundamental significance in biology, until now an unsolved problem in the field of quantum sensing. Here we show a new class of quantum sensor, mtMagLOV2, that interfaces directly to a defining feature of life itself: the bioenergetic state of the cell. We genetically engineer flavin mononucleotide (FMN)-containing, magnetic-field-sensitive fluorescent proteins ("biological qubits") to be expressed and translocated into the key bioenergetic machinery of the cell: the mitochondrial matrix. Using confocal and super-resolution microscopy, mtMagLOV2 localizes to the mitochondrial cristae, home of the electron transport chain complexes I-V and ATP synthase-the site of oxidative phosphorylation (OXPHOS). By pharmacological manipulation of OXPHOS, we show that the sensor's magneto-fluorescence tracks the redox (oxidation-reduction) state of the mitochondrial flavins, providing a quantum readout of redox status. The response differs between cancer cells (which rely heavily on glycolysis) and cardiomyocytes (which rely predominantly on OXPHOS), demonstrating "quantum bioenergetic profiling". Together, these results establish biological qubits as quantum sensors capable of probing mitochondrial bioenergetics, opening a quantum window into the energetic machinery of living cells. More broadly, we anticipate that coupling quantum redox sensitivity to specific biochemical targets will extend the reach of quantum technologies across the life sciences.
    DOI:  https://doi.org/10.64898/2026.07.03.736226
  4. Cell Death Dis. 2026 Jul 16.
    Dual-faced metabolic reprogramming powers proliferation: FGF21 drives lung squamous carcinoma progression via CaMKII-DRP1-mediated mitochondrial fission.
    Xiao-Xin Pu, Yan Zhang, Bao-Yi Liu, Xiao-Jie Song, Yu-Wen Xue.
      Fibroblast growth factor 21 (FGF21) is upregulated in lung squamous cell carcinoma (LUSC) tissues, cell lines, and tumor-conditioned media. Functional studies using LUSC cell lines (H1703, H520) demonstrate that FGF21 promotes cancer cell proliferation, migration, invasion, and tumor sphere formation in vitro. This pro-tumorigenic effect was validated in vivo through xenograft models, where intra-tumoral FGF21 administration accelerated tumor growth. Mechanistically, FGF21 activates calcium/calmodulin-dependent protein kinase II (CaMKII), which phosphorylates dynamin-related protein 1 (DRP1, encoded by DNM1L) at Ser616. Phosphorylated DRP1 translocates to mitochondria, inducing mitochondrial fission. Metabolic analyses revealed that FGF21 remodels cellular energetics in a cell type-specific manner, enhancing glycolysis in H520 cells and oxidative phosphorylation (OXPHOS) in H1703 cells, consistent with their inherent predominant metabolic states. Knockdown of DRP1 or pharmacological inhibition of CaMKII (KN93) abolished FGF21-driven mitochondrial fission, metabolic reprogramming, and tumor-promoting effects. Collectively, FGF21 acts as a tumor-promoting factor in LUSC by activating the CaMKII/DRP1-Ser616 axis to induce pathological mitochondrial fission and metabolic reprogramming, identifying this pathway as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-026-09084-3
  5. Cell Rep. 2026 Jul 17. pii: S2211-1247(26)00789-8. [Epub ahead of print]45(7): 117711
    Deep learning reveals FLAD1-mediated mitochondrial metabolic reprogramming in hypoxic tumors.
    Xiangyu Zhao, Tao Wu, Sanan Wu, Yujin Chen, Yu Zhang, Jing Chen, Kaixuan Diao, Zaoke He, Jiawei Yan, Tianzhu Lu, Chao Xu, Lu Liu, Gaofeng Fan, Dongliang Xu, Xinxiang Li, Xiaopeng Xiong, Jianjun Cheng, Fang Bai, Xue-Song Liu.
      Hypoxia, a hallmark of solid tumors, drives malignant progression and represents a major therapeutic challenge. Metabolic reprogramming induced by hypoxia creates unique metabolic vulnerabilities that can be exploited therapeutically. Here, we systematically compared the metabolic network differences between hypoxic and normoxic cells, and developed DepFormer, a transformer-based deep learning model, to nominate hypoxia-dependent metabolic genes in tumor cells. Oxidative phosphorylation was identified as the most significantly hypoxia-dependent metabolic pathway, and FLAD1 was predicted to be one of the key hypoxia-dependent metabolic genes. FLAD1 locus is amplified, and FLAD1 expression is upregulated across various tumor types, especially in hypoxic tumors. FLAD1 depletion disrupts activity of mitochondrial complex II, causing succinate/fumarate imbalance, which in turn prevents cancer cells from adapting to hypoxia. We further identified a drug-like inhibitor of FLAD1, which selectively inhibits growth of hypoxic tumor cells. Our study establishes DepFormer as an effective framework for predicting state-specific metabolic dependencies and reveals FLAD1 as a metabolic vulnerability and an innovative therapeutic target for hypoxic tumors.
    Keywords:  CP: cancer; FLAD1; deep learning; hypoxia; metabolic dependency; metabolism; therapeutic target
    DOI:  https://doi.org/10.1016/j.celrep.2026.117711
  6. Nature. 2026 Jul 15.
    Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Shixun Han, Xiao Zhang, Johanna Ten Hoeve, Kevin J Williams, Seda Neptun, Tolga Sever, Isabela Fuentes, Sangeeta N Bhatia, Gizem Calibasi-Kocal, Matthew G Vander Heiden, Alex K Shalek, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics1. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis2. However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood3. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours4. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1038/s41586-026-10779-y
  7. J Cell Biol. 2026 Aug 03. pii: e202606160. [Epub ahead of print]225(8):
    More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.
    Mami Sato, Florencio Porto Freitas, José Pedro Friedmann Angeli.
      Coenzyme Q (CoQ or ubiquinone) is an essential cofactor for mitochondrial energy production and a vital radical-trapping antioxidant that maintains membrane integrity. Additionally, CoQ shares an early biosynthetic pathway with cholesterol biosynthesis. In this issue, Ndoci et al. (https://doi.org/10.1083/jcb.202507174) reveal a regulatory system that preserves mitochondrial CoQ levels when the mevalonate pathway is impaired, though this prioritization leaves cells vulnerable to oxidative stress.
    DOI:  https://doi.org/10.1083/jcb.202606160
  8. Int J Mol Sci. 2026 Jun 24. pii: 5707. [Epub ahead of print]27(13):
    Survivin Associates with VDAC2 and Bcl2-Family Proteins at the Mitochondrial Outer Membrane.
    Adesh D Vaidya, Hilmi Arica, Hana Abdelkabir, Lolwah Alsalamah, Kirstie Coe, Sally P Wheatley.
      Survivin is a cancer-associated inhibitor of apoptosis protein (IAP) that can suppress both extrinsic and intrinsic apoptotic pathways. IAPs typically prevent programmed cell death by binding to caspases, but whether survivin behaves as a canonical IAP or can protect cells from death by alternative means has not been fully investigated. Here, we report a novel interaction between survivin and the mitochondrial outer membrane protein, VDAC2, which we show is an indirect association potentially mediated by Bcl2-family members. This novel finding suggests survivin can suppress mitochondrial-mediated apoptosis upstream of caspases and could open a new avenue for targeting survivin in anti-cancer therapy regimes.
    Keywords:  Bak; Bax; Bcl-XL; Bcl2-family; VDAC; apoptosis; mitochondria; porin; survivin
    DOI:  https://doi.org/10.3390/ijms27135707
  9. Drug Resist Updat. 2026 Jul 08. pii: S1368-7646(26)00094-4. [Epub ahead of print]88 101443
    Resensitizing drug-resistant cancers by co-targeting apoptosis and mitochondrial stress pathway.
    Gautam Sethi, Ilnaz Rahimmanesh, Akbar Davoodi, Yujiao Chen, Franklin R Tay, Chandra Sekhar Bhol, Pooyan Makvandi, Yi Xu.
      Therapeutic resistance is a major barrier to durable cancer control in contemporary oncology practice. Despite extensive studies on individual cell death pathways and mitochondrial stress responses, a comprehensive framework describing how mitochondrial organization contributes to the coordination of multiple regulated cell death programs and therapeutic resistance remains insufficiently defined. This review examines resistance as malignant cells evade regulated cell death and adapt to mitochondrial stress. Mitochondria are framed as integrative hubs that link bioenergetics, redox regulation, metabolic flexibility, and stress signaling to apoptotic competence. It also describes how apoptosis connects with other death programs through mitochondrial compartmentalization. Signals from the matrix, inner membrane, and cristae, intermembrane space, and outer membrane influence ferroptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and immunogenic cell death. Stress-response pathways are highlighted as interfaces between mitochondrial dysfunction and fate decisions, including the OMA1-DELE1-heme-regulated inhibitor kinase axis that activates the integrated stress response and ATF4-dependent transcription. Translationally, the review proposes a co-targeting framework that pairs apoptosis-directed therapies, especially BH3 mimetics, with interventions that destabilize mitochondrial homeostasis or tune stress signaling. Examples include electron transport chain inhibitors, integrated stress response modulators, and compartment-targeted strategies that alter cristae remodeling, calcium flux, or cardiolipin oxidation.
    Keywords:  BCL-2 family regulation; BH3 mimetics; Integrated stress response (ISR); Mitochondrial stress signaling; Therapeutic resistance
    DOI:  https://doi.org/10.1016/j.drup.2026.101443
  10. J Med Chem. 2026 Jul 13.
    Copper(II)-Mediated Mitochondria-Targeting in Cancer Cells.
    Marlies Körber, Fabian Halter, Dina Attia, Eva Körber, Rainer Tietze, Christoph Alexiou, Frank Hampel, Karsten Meyer, Andriy Mokhir.
      Mitochondria are attractive anticancer targets, but selective targeting remains challenging. We report a Cu2+-mediated strategy for mitochondria-directed activity based on intracellular metal coordination. Aminoferrocene drugs were functionalized with Cu2+-binding ligands to exploit elevated copper levels in cancer cells. Among these, the bipyridine conjugate AFb-L4 displays pronounced Cu2+-dependent cytotoxicity, with an IC50 of 29 nM in ovarian carcinoma cells (∼500-fold enhancement upon Cu2+ addition). Spectroscopic, magnetic, and mass spectrometric analyses confirm formation of a 1:1 AFb-L4-Cu2+ complex without electronic coupling between the Cu2+ and ferrocene centers. Intracellular Cu2+ coordination converts AFb-L4 into a cationic species that accumulates in mitochondria, inducing loss of membrane potential, mitochondrial remodeling, and mitochondrial ROS generation. Structure-activity relationships show that stabilization of Cu2+ is critical, as a sterically hindered isomer with reduced Cu2+ binding is largely inactive. These results establish intracellular Cu2+ coordination as a trigger for mitochondrial targeting.
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c00588
  11. Sci Rep. 2026 Jul 13.
    Somatic pathogenic mitochondrial DNA mutations independently predict worse prognosis in hepatocellular carcinoma.
    Camelia Alexandra Coada, Monica De Luise, Rosanna Clima, Stefano Miglietta, Marcella Attimonelli, Veronica De Sanctis, Roberto Bertorelli, Chiara Valentini, Paolo Cavallerio, Federico Manuel Giorgi, Catia Giovannini, Ivana Kurelac, Luisa Iommarini, Laura Gramantieri, Anna Maria Porcelli, Fabio Piscaglia, Giuseppe Gasparre.
      Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide, but its cancerization and progression mechanisms are still poorly understood. Mitochondrial DNA (mtDNA) mutations have been involved in tumor progression by influencing metabolic rewiring and plasticity. In this work, we aimed to investigate the contribution of mtDNA mutations to the pathogenesis and prognosis of HCC. Whole exome sequencing data from the TCGA-LIHC project were used to reconstruct the mitochondrial genomes. Discovered variants were classified using the HmtVar pathogenicity scoring system and the ACMG/AMP standard guidelines. The validation of results was performed on a separate in-house cohort of selected HCC cases from our hospital. Pathogenic mtDNA mutations were present in 33.6% of patients. GSEA revealed pathogenic mtDNA mutations mainly targeting the reactive oxygen species (ROS) pathway, suggesting an increased ROS production in these tumors which may contribute to the survival, proliferation and metastatization capacity. Survival analysis revealed a significant decrease in the overall survival of patients harboring pathogenic mtDNA variants (p = 0.01). A similar trend was observed in the validation cohort. Overall, we showed that somatic mtDNA mutations occur in a significant proportion of HCC cases, expectedly acting as modifiers on the ROS pathway, and that their occurrence confers a worse prognosis.
    Keywords:  Hepatocellular carcinoma; Mitochondria; Prognosis; Reactive oxygen species
    DOI:  https://doi.org/10.1038/s41598-026-61381-1
  12. Nature. 2026 Jul 15.
    A high-fat, low-carbohydrate diet can feed intestinal tumours.
    Souvik Patra, Evan C Lien.
      
    Keywords:  Cancer; Cell biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-02039-w
  13. Mol Biol Rep. 2026 Jul 17. pii: 1188. [Epub ahead of print]53(1):
    SLC25A1 drives lipid metabolic reprogramming promoting liver injury leading to hepatocellular carcinoma.
    Mehak Shahid, Isbah Ashfaq, Burhan Haider, Asima Tayyeb.
       BACKGROUND: Cancer metabolism especially lipid metabolic reprogramming is considered one of the most important metabolic processes involved in hepatocellular carcinoma (HCC). Solute carrier family 25 member A1 (SLC25A1) is a citrate transporter present in mitochondrial membrane and emerged to play role in lipid metabolic reprogramming. This study aimed to elucidate the mechanistic role of SLC25A1 in lipid metabolic reprogramming and its therapeutic potential in HCC.
    METHODOLOGY AND RESULTS: In the current study, enhanced expression of SLC25A1 gene was observed in toxicant induced mouse model of HCC suggesting a correlation with initiation and development of HCC. However, the precise mechanistic involvement of SLC25A1 in HCC is unclear underscoring the need of an in depth study. Clinical relevance of SLC25A1 in HCC was primarily evaluated using The Cancer Genome Atlas database. The in silico results not only demonstrated a strong correlation between the expression of SLC25A1 and HCC but also associated it with poor survival. In depth gain of function analysis using mammalian expression vector, SLC25A1-PCMV3 in human cell lines exhibited enhanced cellular growth, invasion, and migration potentials of cells expressing SLC25A1. Notably, the overexpression of SLC25A1 was associated with increased de novo lipogenesis, consistent with metabolic reprogramming favoring cytosolic citrate utilizationas evident by upregulation of FASN, ACACA, ACLY, SCD1 and downregulation of IDH2 and OGDH. Virtual screening and molecular docking studies presented rutin, a natural flavonoid, as a potential inhibitor of SLC25A1. In vitro inhibition of SLC25A1 by treatment with rutin significantly suppressed SLC25A1 expression leading to reduced lipogenesis.
    CONCLUSION: Collectively, these findings propose SLC25A1 is associated with metabolic reprogramming in HCC and contribute to tumor progression.by promoting lipogenesis. Thus offering a promising therapeutic target for early intervention and treatment.
    Keywords:   de novo lipogenesis; HCC; Hepatocellular carcinoma; Lipid metabolic reprogramming; SLC25A1
    DOI:  https://doi.org/10.1007/s11033-026-12346-0
  14. iScience. 2026 Jul 17. 29(7): 116361
    Mitochondrial DNA mutations drive tumor heterogeneity in papillary thyroid carcinoma.
    Han Sai Lee, Jinsun Lim, Jin-Hyung Heo, Hak Hoon Jun, Young Shin Song.
      Tumor heterogeneity presents a major challenge to understanding cancer evolution and therapeutic resistance in thyroid cancer. While previous studies have focused on nuclear driver mutations, the role of mitochondrial DNA (mtDNA) alterations in this heterogeneity remains elusive. Through multi-regional whole-genome and transcriptome sequencing of aggressive papillary thyroid carcinoma (PTC), we reveal that mtDNA mutations exhibit significant spatial and evolutionary heterogeneity, contrasting with conserved nuclear drivers. High mtDNA mutation burden correlated with increased mitochondrial gene expression, tumor dedifferentiation, and immune pathway activation via damage-associated molecular pattern signaling. This burden further remodeled the tumor microenvironment (TME), favoring pro-inflammatory epithelial states over normal stromal populations. Clinically, these features were associated with reduced disease-free survival. Our findings identify mtDNA mutations as key contributors to heterogeneity and TME remodeling in PTC, suggesting mitochondrial mutational burden as a potential prognostic biomarker and therapeutic target.
    Keywords:  bioinformatics; cancer; omics
    DOI:  https://doi.org/10.1016/j.isci.2026.116361
  15. Med Res Rev. 2026 Jul 13.
    Beyond Bioenergetics: Moonlighting Functions of F1FO-ATPase From ATP Synthesis to an ATP-Wasting Death Switch.
    Salvatore Nesci.
      Mitochondrial F1FO-ATPase is classically viewed as the "splendid" rotary nanomachine that sustains life by converting the proton-motive force (pmf) into ATP. Yet this same complex can adopt a second, context-dependent function that links bioenergetics to cell fate. When oxygen becomes limiting during ischemia, stroke, hypoxia, or anoxia, respiratory chain activity declines, pmf collapses, and the enzyme reverses direction: ATP hydrolysis drives rotor turnover and pumps H+ across the inner mitochondrial membrane to partially restore pmf. This reverse mode can be protective by preserving membrane potential and basic mitochondrial homeostasis, but it also imposes a severe energetic burden on the cell. A key determinant of whether F1FO-ATPase acts as an energy-conserving or energy-dissipating machine is the identity of the catalytic divalent cation. Under physiological conditions, Mg2+ supports efficient, reversible ATP synthesis/hydrolysis. In pathology, mitochondrial Ca2+ overload may replace Mg2+ at catalytic sites, shifting catalysis toward ATP hydrolysis and promoting an ATP-wasting state that triggers mitochondrial permeability transition pore (mPTP) formation and regulated cell death. Thus, ATP hydrolysis by F1FO-ATPase beyond regulation by pmf and inhibitory proteins such as IF1, cation cofactor selection emerges as a decisive switch that repurposes the enzyme from "enzyme of life" to "enzyme of death." Here, this cofactor-dependent reversibility is framed as a moonlighting role of F1FO-ATPase, integrating energy conversion with death signaling. Conceptual questions are outlined to resolve current debate and to exploit this switch for therapeutic insight.
    Keywords:  F1FO‐ATPase; cation cofactor switching; mitochondrial permeability transition pore; regulated cell death
    DOI:  https://doi.org/10.1002/med.70088
  16. Front Cell Dev Biol. 2026 ;14 1854542
    Standardised dual-flow cytometry workflows for quantitative assessment of mitochondrial superoxide and mitochondrial mass in live cancer cells and primary multiple myeloma cells.
    Eugenia Giglio, Martina Giuseffi, Marzia Sichetti, Marisabel Mecca.
      Mitochondrial metabolism plays a critical role in carcinogenesis and cancer progression. Quantitative assessment of mitochondrial function in live cells remains technically challenging because existing biochemical assays lack single-cell resolution, and microscopy-based approaches are limited in throughput and quantitative reproducibility. Here we describe a robust and reproducible standardised dual-flow cytometry protocol for simultaneous quantitative assessment of mitochondrial superoxide production and mitochondrial mass in live cancer cells and primary patient-derived multiple myeloma plasma cells using MitoSOX Green and MitoTracker Red. The protocol provides a step-by-step workflow comprising preparation of cultured cancer cells or isolation of primary CD138+ plasma cells, optimised probe staining, viability discrimination, standardised flow cytometry acquisition and gating, and quantitative fluorescence normalisation. Compared with conventional mitochondrial assays requiring cell lysis or imaging-based analysis, this approach enables high-throughput, quantitative mitochondrial profiling at single-cell resolution in heterogeneous populations while preserving cellular integrity. The procedure incorporates defined staining conditions, instrument calibration guidance, quality-control criteria and normalisation strategies to improve reproducibility across experiments and laboratories. The workflow yields robust fluorescence measurements with low technical variability and enables discrimination of mitochondrial oxidative activity relative to mitochondrial content, facilitating analysis of mitochondrial dysfunction, oxidative stress responses and treatment-induced mitochondrial perturbations. The method is compatible with multiparametric flow cytometry and can be adapted to diverse cell types and experimental systems. The complete protocol requires ∼6-8 h for cultured cells or 8-12 h when primary cell isolation is included and can be implemented by researchers with standard cell culture and flow cytometry expertise.
    Keywords:  MitoSOX; MitoTracker; ROS; flow cytometry; live cancer cells; mitochondrial mass; mitochondrial superoxide
    DOI:  https://doi.org/10.3389/fcell.2026.1854542
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒20 at 13:38.