bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–07–12
sixteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Engineered exosomes deliver structurally optimized toad BAX to reactivate mitochondrial apoptosis in colorectal cancer.
  2. Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
  3. PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
  4. Mitochondria produce lactate to vent redox pressure.
  5. Succinate and lactate produced as conserved biomarkers through chronic and transient substrate-level phosphorylation: from microorganisms to cancer.
  6. Back to the future: "7+3" joins the venetoclax plus intensive chemotherapy movement.
  7. Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
  8. TCA-controlled histone succinylation identifies IDH3B as a prognostic and therapeutic target in AML.
  9. Decoding the Hot-Mitochondrion Paradox.
  10. Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
  11. Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.
  12. Venetoclax with intensive chemotherapy in acute myeloid leukemia.
  13. Chemical-induced colitis lowers mitochondrial bioenergetic function in colonic tissue with minimal impacts on the proteome.
  14. A succinylation-based classifier predicts chemotherapy response in prostate cancer and reveals KAT2A as a therapeutic target.
  15. Metabolomics of healthy hematopoietic stem cells and leukemic stem cells.
  16. A bioenergetic understanding of "aerobic glycolysis".
  1. Front Oncol. 2026 ;16 1882315
    Engineered exosomes deliver structurally optimized toad BAX to reactivate mitochondrial apoptosis in colorectal cancer.
    Xinqiang Xu, Hongjie Wu, Yixin Yan, Hongwei Cui, Tianyi Yu, Ye Yang, Zhendong Deng, Jinjun Qian.
       Introduction: Mitochondrial apoptosis evasion, driven by overexpression of anti-apoptotic BCL-2 family proteins, remains a major obstacle in the effective treatment of colorectal cancer (CRC). While BCL-2 homology 3 (BH3) mimetics (such as venetoclax) have shown clinical efficacy in hematologic malignancies, their effectiveness in solid tumors is limited. Direct delivery of pro-apoptotic effectors, including BAX, offers an alternative strategy; yet, the therapeutic potential of non-human BAX orthologs and their delivery methods has not been explored.
    Methods: The functional activity of Xenopus laevis (African clawed frog) BAX was evaluated in human CRC cell lines (HCT116, LOVO) and in cell line-derived xenograft (CDX) and AOM/DSS-induced CRC mouse models. Direct binding to human BCL-2 was quantified by microscale thermophoresis. The mechanism of action was elucidated via JC-10 staining, subcellular fractionation and liposome permeabilization assays.Structure-guided mutagenesis based on the BCL-2-Beclin-1 BH3 complex (PDB: 5VAU) was employed to generate a triple mutant (I86T, A102S, R109M) . Optimized BAX was packaged into engineered exosomes for targeted delivery, and their anti-tumor efficacy and safety were assessed in CDX, patient-derived xenograft (PDX), and AOM/DSS models.
    Results: Toad BAX directly bound human BCL-2 (Kd = 12.7 ± 1.9 µM), triggered mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, and caspase-9/3 activation, thereby suppressing CRC cell proliferation and inducing apoptosis. The rationally designed triple mutant exhibited enhanced BCL-2 affinity and superior in vivo antitumor activity compared to wild-type toad BAX. Exosome-mediated delivery of the optimized BAX efficiently targeted CRC cells, inhibited tumor growth in PDX models, and extended overall survival in AOM/DSS-induced CRC without inducing overt toxicity.
    Discussion: This study establishes structurally optimized cross-species BAX, delivered via engineered exosomes, as a potent and safe strategy to reactivate mitochondrial apoptosis against CRC. It provides a preclinical foundation for protein-based therapeutics targeting apoptosis-evasive solid tumors, offering a mechanistically distinct alternative to conventional BH3 mimetics.
    Keywords:  BAX; BCL2; colorectal cancer; mitochondrial apoptosis; structural optimization; targeted delivery
    DOI:  https://doi.org/10.3389/fonc.2026.1882315
  2. Elife. 2026 07 08. pii: RP107953. [Epub ahead of print]14
    Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
    Joy Omini, Inga Krassovskaya, Taiwo Adeolu Dele-Osibanjo, Connor Pedersen, Toshihiro Obata.
      The tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase (MDH1) and citrate synthase (CIT1) form a multienzyme complex, referred to as a metabolon, that channels intermediate oxaloacetate between their reaction centers. Given that the MDH1-CIT1 metabolon enhances pathway reactions in vitro, its dynamic assembly is hypothesized to contribute to TCA cycle regulation in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the respiratory activity was enhanced by acetate. Pharmacological TCA cycle inhibition dissociated the complex, whereas electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1-CIT1 complex affinity in vitro. Especially, variations in buffer pH within the physiological pH range between 6.0 and 7.0 in the mitochondrial matrix significantly impacted the MDH1-CIT1 affinity. These results demonstrate the dynamic association and dissociation of the MDH1-CIT1 metabolon and its relationship with respiratory activity, supporting metabolon dynamics as an integral factor in metabolic regulation governed by multiple factors such as mitochondrial pH and metabolite levels.
    Keywords:  S. cerevisiae; biochemistry; chemical biology; citrate synthase; malate dehydrogenase; metabolon; mitochondria; oxidative respiration; tricarboxylic acid cycle
    DOI:  https://doi.org/10.7554/eLife.107953
  3. Cell Death Dis. 2026 Jul 10.
    PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
    José Manuel Rodríguez-Vargas, Jerónimo Borrego-Pérez, Vanesa Cabeza-Fernández, Esteban Zamudio-Martínez, Francisco Javier Ríos-Sola, David Martín-Oliva, Francisco Abadía-Molina, Françoise Dantzer, F Javier Oliver.
      Hypoxia, or low oxygen availability, is one of the main factors that determine tumor growth and metastatic survival. The hypoxic response is orchestrated by HIF transcription factors, which activate genetic and metabolic programs that promote angiogenesis, metabolic reprogramming, migration, and ultimately a clinically aggressive phenotype. Mitochondria play a central role in this process, as they are not only the main consumers of oxygen but also undergo morphological and biochemical adaptations that shape how tumor cells respond to a hostile microenvironment. Because the contribution of ADP ribosylation to these mitochondrial adaptations remains unclear, we aimed to define how PARP inhibition influences mitochondrial behavior during hypoxia. To address this question, we first examined how PARP inhibitors affect mitochondrial structure and function under oxygen deprivation. We found that PARP inhibition drives a shift toward a small, globular mitochondrial phenotype characterized by membrane depolarization (ΔΨm) and enhanced fission. Given that mitochondrial morphology is tightly linked to metabolic state, we next investigated whether these structural changes altered hypoxia induced metabolic reprogramming. PARP inhibition prevented the typical shift toward anaerobic glycolysis, forcing tumor cells to activate the AMPk/mitophagy axis as an alternative survival pathway. Finally, to determine the functional consequences of this adaptive response, we assessed tumor cell fitness when mitophagy was impaired. Blocking mitophagy markedly reduced the proliferative and malignant potential of hypoxic tumor cells, thereby increasing their sensitivity to PARP inhibition. Collectively, our results uncover a previously unrecognized pathway of mitochondrial adaptation to hypoxia and reveal a therapeutically relevant crosstalk between mitochondrial dynamics and ADP ribosylation that may be exploited in future anticancer strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09079-0
  4. Trends Endocrinol Metab. 2026 Jul 04. pii: S1043-2760(26)00149-9. [Epub ahead of print]
    Mitochondria produce lactate to vent redox pressure.
    Serwah A Danquah, Lucas B Sullivan.
      Conventionally viewed as a waste product or a cytosolic pyruvate source, recent findings suggest that lactate may also directly contribute to mitochondrial oxidative metabolism. Using an intramitochondrial lactate biosensor, Rauseo et al. instead find that energized mitochondria are producers of lactate, which buffers mitochondrial redox to mitigate reactive oxygen species production.
    DOI:  https://doi.org/10.1016/j.tem.2026.06.005
  5. J Bioenerg Biomembr. 2026 Jul 06. pii: 36. [Epub ahead of print]58(1):
    Succinate and lactate produced as conserved biomarkers through chronic and transient substrate-level phosphorylation: from microorganisms to cancer.
    Derek C Lee, Tomas Duraj, Christos Chinopoulos, Thomas N Seyfried.
      ATP is the primary energy currency required by living organisms. Mitochondrial oxidative phosphorylation (OxPhos) produces most of the ATP in quiescent and differentiated cells. OxPhos interruption results in analogous bioenergetic adaptations across divergent evolutionary taxa, yet this adaptation is poorly recognized. Oxygen availability is a major determinant of the source of ATP generation across most eukaryotic cell types. Acute oxygen deprivation, mitochondrial dysfunction, high energy demand, or other metabolic cues can shift relative ATP production from OxPhos to high-throughput fermentation via substrate-level phosphorylations (SLPs). Glucose-derived lactate and glutamine-derived succinate are biomarkers of cytosolic and mitochondrial SLP, respectively. The extracellular accumulation of these metabolites is observed in a broad range of biological systems, including unicellular bacteria and yeast to more complex mammalian cells, including those of the immune system, retina, and muscle. Unsurprisingly, many cancer cells accumulate excess lactate and succinate due to chronic OxPhos insufficiency. This review links ostensibly unique cases of metabolic disruption to the accumulation of lactate and succinate as biomarkers of compensatory fermentative metabolism through cytosolic and mitochondrial SLP. Fundamental principles of cellular energy and environmental adaptation are reviewed that span a broad range of biological complexity.
    Keywords:  ATP; Fermentation; Lactate; Substrate-level phosphorylation; Succinate
    DOI:  https://doi.org/10.1007/s10863-026-10117-x
  6. Chin Clin Oncol. 2026 Jun;15(3): 49
    Back to the future: "7+3" joins the venetoclax plus intensive chemotherapy movement.
    Michael Canonico, Somedeb Ball.
      
    Keywords:  B-cell lymphoma 2 (BCL2); PARADIGM; Venetoclax (VEN); acute myeloid leukemia (AML); “7+3”
    DOI:  https://doi.org/10.21037/cco-2026-1-0021
  7. J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):
    Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
    Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.
      Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.
    DOI:  https://doi.org/10.1083/jcb.202511211
  8. Clin Epigenetics. 2026 Jul 05.
    TCA-controlled histone succinylation identifies IDH3B as a prognostic and therapeutic target in AML.
    Minhui Shi, Kepeng Yang, Hao Ding, Na Zhao, Jiewen Ma, Aijie Huang, Yun Wang, Xiaoyu Zhu, Domenico Iuso, Mengqing Gao.
       BACKGROUND: Mitochondrial metabolism-driven epigenetic modifications have emerged as crucial regulators for acute myeloid leukemia (AML) progression, linking metabolic activity in leukemic stem cells to epigenetically controlled transcriptional programs that drive oncogenic gene expression.
    RESULTS: Here, by integrating proteomic and transcriptomic data, we identified six genes whose expression were able to predict outcome in AML. Among these, IDH3B was highly expressed in leukemic stem cells and associated with poor prognosis. Functional studies revealed that IDH3B deletion in KMT2A-rearranged AML increased global protein succinylation, reduced acetylation, and sensitized cells to the menin-KMT2A inhibitor, both in vitro and in vivo. Mechanistically, loss of IDH3B, by increasing histone succinylation and reducing H3K79 methylation at the MYC promoter, amplified Revumenib-induced transcriptional repression of MYC.
    CONCLUSIONS: These findings establish IDH3B as a key metabolic-epigenetic regulator in AML and highlight it as a potential synergistic target to enhance menin inhibition therapy.
    Keywords:  Acute myeloid leukemia; IDH3B; Menin–KMT2A inhibition; Mitochondrial metabolism; Succinylation
    DOI:  https://doi.org/10.1186/s13148-026-02197-8
  9. Bioessays. 2026 Jul;48(7): e70159
    Decoding the Hot-Mitochondrion Paradox.
    Peyman Fahimi, Michael Lynch, Chérif F Matta.
      In a 2018 paper and a subsequent article published in 2023, researchers reported that mitochondria maintain temperatures 10°C-15°C higher than the surrounding cytoplasm-a finding that deviates by five to six orders of magnitude from theoretical predictions based on Fourier's law of heat conduction. In 2022, we proposed a solution to this apparent paradox. In the present perspective, we build upon that framework and introduce new ideas to further unravel how a biological membrane-whether of an organelle or a whole cell-can become significantly warmer than its environment. We propose that ion-translocating proteins embedded in the inner mitochondrial membrane (IMM) can be modeled as ratchet engines, introducing a novel, previously overlooked mode of heat transfer. This mechanism, coupled with localized heat release during the cyclical dehydration-translocation-hydration of ions through membrane proteins, may generate transient but substantial temperature spikes. The cumulative thermal occupancy of these microscopic events across the three-dimensional surface of the IMM can account for the elevated temperatures detected by molecular probes.
    DOI:  https://doi.org/10.1002/bies.70159
  10. Nat Metab. 2026 Jul 08.
    Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
    Ankur Garg, Brandon R Desousa, Raju Roy, Amy Flis, Skyler Y Blume, Yohei Abe, Arthur A Melo, Ryan R Cupo, Gabriela Grigorean, Daniel R Southworth, James Shorter, Isha H Jain.
      Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Here we show that deficiency of HTRA2, a mitochondrial intermembrane space protease, can be rescued by hypoxia therapy. Using an Htra2 mutant mouse model that displays severe neurodegeneration and early lethality, we find that continuous hypoxia rescues striatal degeneration and extends lifespan. Mechanistically, we demonstrate that HTRA2 forms a functional complex with the disaggregase CLPB. Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction. These changes impair tissue oxygen consumption and probably cause pathological hyperoxia, which is corrected by hypoxia. Together, these findings define a proteostasis pathway linking intermembrane space quality control to complex I function and expand the potential of hypoxia therapy to secondary complex I disease.
    DOI:  https://doi.org/10.1038/s42255-026-01566-0
  11. Cell Rep. 2026 Jul 08. pii: S2211-1247(26)00708-4. [Epub ahead of print]45(7): 117630
    Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.
    Kenkyo Matsuura, Ririko Shinonaga, Mizuki Yamamoto, Yoshiki Yamamoto, Hsin Chen, Ayaka Maeno, Kayo Okuda, Haruki Inoue, Sota Imotani, John Glushka, Koji Miki, Yukako Watanabe, Mamoru Takada, Hironori Kaji, Jun-Ichiro Inoue, Ayuna Hattori, Hiromi Imamura, Takahiro Ito.
      Triple-negative breast cancer (TNBC) lacks effective molecularly targeted therapies. Here, we identify branched-chain amino acid (BCAA) metabolism as a selective vulnerability in human TNBC, particularly in the claudin-low subtype. TNBC cells show greater dependence on BCAAs than other breast cancer subtypes, and intracellular BCAA levels are heterogeneous within tumors in vivo. Cells with high BCAA levels exhibit enhanced sphere formation and cancer stem cell potential in xenograft models. BCAT1, a cytoplasmic BCAA aminotransferase, is upregulated in claudin-low TNBC and enables tumor growth by promoting BCAA production from branched-chain ketoacids. BCAT1 knockdown impairs TNBC growth in vivo, and high BCAT1 expression predicts poor prognosis in patient cohorts. Conversely, BCAA catabolism via the BCKDH complex is suppressed in TNBC, and reactivation of BCKDH by BCKDK knockout blocks clonogenic growth. These findings reveal BCAA metabolic balance as a key regulator of TNBC stemness and malignancy.
    Keywords:  CP: cancer; TNBC; branched-chain amino acid; claudin-low; metabolic vulnerability; metabolite imaging
    DOI:  https://doi.org/10.1016/j.celrep.2026.117630
  12. Chin Clin Oncol. 2026 06;15(3): 54
    Venetoclax with intensive chemotherapy in acute myeloid leukemia.
    Logan Shaver, Omer Jamy.
      
    Keywords:  7+3; Acute myeloid leukemia (AML); intensive chemotherapy (IC); venetoclax
    DOI:  https://doi.org/10.21037/cco-2026-1-0005
  13. Sci Rep. 2026 Jul 06.
    Chemical-induced colitis lowers mitochondrial bioenergetic function in colonic tissue with minimal impacts on the proteome.
    McLane M Montgomery, Masara A Al Obaidi, Raphael T Aruleba, Polina Krassovskaia, Emely A Pacheco, Edziu Franczak, Brett R Chrest, Thomas D Green, Tonya N Zeczycki, Joeseph M McClung, Kelsey H Fisher-Wellman.
      Dextran sulfate sodium (DSS) is widely used to chemically-induce both colitis and colorectal cancer when administered alongside azoxymethane (AOM). DSS functions by disrupting the colonic epithelial barrier, triggering widespread inflammation within the colon. While DSS is a valuable tool for studying colitis-related diseases, its impact on mitochondrial bioenergetics and the proteomic landscape of colonic tissue remains poorly understood. To assess the chronic effects of DSS-induced colitis, we administered three rounds of 3% DSS in drinking water (5-day treatment periods) to C57BL/6 J mice and analyzed resected colonic tissue from DSS-treated and control (non-DSS treated) mice. Longitudinally opened colon segments were cleaned and subjected to high-resolution respirometry and mass spectrometry-based proteomic profiling. DSS treatment led to a global lowering of mitochondrial respiration, with the most pronounced impairments observed in complex I-supported respiration. Proteomic analysis revealed that these functional deficits occurred largely independently of changes in the mitochondrial proteome, except for an apparent upregulation of NIPSNAP1, a mitophagy-related protein. However, lentiviral knockdown of NIPSNAP1 in HCT116 cells did not rescue the observed bioenergetic defects, suggesting it is not the primary driver. Collectively, our findings show that DSS impairs mitochondrial respiration in the colon, most notably at complex I, without major alterations to the mitochondrial proteome. Given the role of mitochondrial dysfunction in various diseases, these effects should be carefully considered when using DSS-based models to study colitis pathophysiology.
    Keywords:  DSS; Energy transduction; Epithelial barrier; Inflammation; Mitochondrial respiration
    DOI:  https://doi.org/10.1038/s41598-026-61224-z
  14. Clin Transl Med. 2026 Jul;16(7): e70737
    A succinylation-based classifier predicts chemotherapy response in prostate cancer and reveals KAT2A as a therapeutic target.
    Antao Dong, Wei Hu, Zhihui Lu, Liangliang Li, Kun Liu, Shiyao Feng, Dongdong Xie.
       BACKGROUND: Chemotherapy resistance remains a critical hurdle in advanced prostate cancer (PCa). Succinylation, an essential post-translational modification linking cellular metabolism with epigenetic regulation, has been implicated in tumour progression; however, its contribution to PCa chemoresistance remains poorly defined.
    OBJECTIVE: This study aimed to evaluate the prognostic significance of succinylation in PCa, develop a succinylation-based biomarker, and elucidate the mechanisms driving chemotherapy resistance.
    METHODS: We generated a succinylation score (SS) by applying single-sample gene set enrichment analysis (ssGSEA) to transcriptomic profiles from the TCGA-PRAD cohort. Its relationships with survival, the tumour microenvironment (TME), and treatment susceptibility were examined using CIBERSORT, GSEA, TIDE, oncoPredict, and single-cell RNA sequencing (scRNA-seq). Findings were functionally validated in patient-derived organoids, PCa cell lines, and xenograft models through genetic manipulation, chemosensitivity assays, and mechanistic studies.
    RESULTS: High SS correlated with favourable prognosis, lower Gleason scores, absent lymph node metastasis, and an immune-active TME enriched in CD8+ precursor exhausted T cells. High-SS tumours showed enhanced sensitivity to docetaxel and cisplatin. scRNA‑seq identified KAT2A as a key driver in low‑SS malignant clusters with chemoresistance features. KAT2A was elevated in chemoresistant tissues, cell lines, and organoids. KAT2A knockout sensitised cells to chemotherapy, while ectopic expression promoted resistance in vitro and in vivo. Mechanistically, KAT2A-mediated succinylation of PIK3R2 at K477 and K564 inhibited its ubiquitination and proteasomal degradation, stabilising PIK3R2 to drive chemoresistance. The KAT2A inhibitor Butyrolactone 3 synergised with standard chemotherapy to suppress tumour growth.
    CONCLUSION: The succinylation score serves as a robust prognostic biomarker integrating metabolic and immunological features in PCa. The KAT2A-PIK3R2 succinylation pathway represents a newly defined driver of chemoresistance and points to MB-3-based combination therapy as a potential strategy for resistant advanced disease.
    KEY POINTS: A transcriptome-based succinylation score (SS) stratifies prostate cancer by prognosis, immune contexture, and chemotherapy sensitivity. KAT2A is enriched in low-SS, chemoresistant tumours and promotes resistance by succinylating PIK3R2. KAT2A-mediated succinylation competitively inhibits PIK3R2 ubiquitination, stabilising PIK3R2 and driving chemoresistance. The KAT2A inhibitor MB-3 synergises with chemotherapy to suppress tumour growth in both chemoresistant and chemosensitive models.
    Keywords:  KAT2A; chemoresistance; prostate cancer; succinylation; tumour microenvironment
    DOI:  https://doi.org/10.1002/ctm2.70737
  15. J Clin Transl Res. 2025 Oct 29. 11(5): 50-68
    Metabolomics of healthy hematopoietic stem cells and leukemic stem cells.
    Gavin M Traber, Emely A Pacheco, Ansh Kumar, Edziu Franczak, Kelsey H Fisher-Wellman, Kathleen M Sakamoto.
      Background. Hematopoietic stem cells (HSCs) reside in the bone marrow and are responsible for the life-long production of blood cells by balancing quiescence, self-renewal, and differentiation. A major feature distinguishing quiescent HSCs from their activated counterparts is a shift in the metabolic profile including changes in glycolytic flux and mitochondrial oxidative metabolism. Disruptions to HSC homeostasis can lead to hematologic diseases such as bone marrow failure or clonal hematopoiesis and even oncogenic transformation to form leukemic stem cells (LSCs). Like that of HSCs, LSCs retain stem-like characteristics but also gain features of malignancy including drug resistance and a hijacked metabolism that exhibit distinct metabolic profiles that can underlie their pathogenesis. The aim of this review is to summarize the key metabolic characteristics that distinguish healthy quiescent and active HSCs as well as oncogenic LSCs. Here we also explore the modern tools used to investigate the metabolome and how they can reveal novel metabolites, metabolic interactions and pathways, and targets for diagnosis or therapeutic intervention of hematologic diseases. Understanding and interrogating changes to the metabolic profiles of healthy and leukemic stem cells may lead to the development of innovative techniques, technologies, and therapeutics. In turn, these advances can be used for the identification, treatment, and prevention of hematologic disease. By better understanding their metabolome, therapies can be designed to target the unique metabolic pathways, dependencies, and resistance mechanisms of LSCs.
    Keywords:  hematopoietic stem cells; leukemic stem cells; metabolism; metabolomics
    DOI:  https://doi.org/10.36922/jctr025320053
  16. Commun Biol. 2026 Jul 09. pii: 928. [Epub ahead of print]9(1):
    A bioenergetic understanding of "aerobic glycolysis".
    Valerie L Wasem, Shona A Mookerjee.
      "Aerobic glycolysis" is a widely used term whose current meaning has drifted from its original usage in a way that has created confusion and inaccuracy. This drift has weakened "aerobic glycolysis" as a hypothesis-testing framework, despite the critical importance of glycolysis in understanding cellular bioenergetic behavior. Here, we examine the historical and contemporary uses of "aerobic glycolysis" and the related "Warburg effect". We argue that "aerobic glycolysis" as originally investigated was essentially a bioenergetic phenomenon. We review the bioenergetic model of glycolysis and mitochondrial respiration as ATP supply pathways operating together to meet cellular ATP demand. A bioenergetic view of aerobic glycolysis clarifies that it is not a less desirable contingency or indicator of pathology, but rather a part of a kinetically regulated system of cellular energy supply. On this basis, the operation of glycolysis under many different physiological and pathological conditions can be better interrogated and understood.
    DOI:  https://doi.org/10.1038/s42003-026-10601-5
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒12 at 1:21.