bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–09–27
ten papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Wired to Survive: How AML Cytogenetics Shape Apoptotic Dependence and Venetoclax Resistance.
  2. ADCK1 Regulates Mitochondrial Bioenergetics in Hepatocellular Carcinoma In Vitro.
  3. Ceramide synthesis mediates colorectal cancer metastasis through a YAP-driven regenerative program.
  4. Nucleolin Alterations and ROS Production Associate With Sensitivity of AML Cells to Venetoclax.
  5. Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.
  6. FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.
  7. Hepatocytes promote liver metastasis of pancreatic cancer by providing serine.
  8. Mitotic assembly of respiratory supercomplexes ensures accurate cell division and fuels tumor growth.
  9. The predicted interactome of the human mitochondrial proteome.
  10. Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
  1. Genes (Basel). 2026 Sep 15. pii: 1122. [Epub ahead of print]17(9):
    Wired to Survive: How AML Cytogenetics Shape Apoptotic Dependence and Venetoclax Resistance.
    Arnold Rojas, Sahil Jethi, Tulin Budak-Alpdogan, Manoj K Pandey.
      Acute myeloid leukemia (AML) is cytogenetically and phenotypically heterogeneous, and this diversity contributes to differences in how patients respond to therapies that target apoptosis. Venetoclax, a selective BCL-2 inhibitor, has been demonstrated to improve outcomes when combined with hypomethylating drugs (HMAs) such as azacitidine or decitabine; nonetheless, clinical trials have indicated that resistance and recurrence are prevalent. This review examines the current evidence linking chromosomal abnormalities and cellular differentiation state to mitochondrial apoptotic pathways, with an emphasis on how these factors influence dependence on certain anti-apoptotic BCL-2 family proteins. We summarize how specific cytogenetic subtypes and high-risk groups (including monosomy 7/del(7q) and complex karyotype/TP53-altered AML) frequently show stress-adaptive signaling and reliance on multiple anti-apoptotic pathways, which can limit the durability of response to BCL-2 inhibition. Lineage-associated dependencies are also examined, such as monocytic differentiation (which leads to increased MCL-1 reliance) and erythroid/megakaryocytic differentiation, which has been associated with increased BCL-XL dependence and venetoclax resistance. Finally, we discuss the therapeutic implications of dependence mapping, including venetoclax combinations and direct MCL-1/BCL-XL targeting, and propose promising biomarker strategies that can detect dependence shifts early and guide appropriate treatment selection.
    Keywords:  BCL-2 family proteins; BH3 mimetics; acute myeloid leukemia; cytogenetics; mitochondrial apoptosis; targeted therapy; therapeutic resistance; venetoclax
    DOI:  https://doi.org/10.3390/genes17091122
  2. Int J Mol Sci. 2026 Sep 08. pii: 7984. [Epub ahead of print]27(18):
    ADCK1 Regulates Mitochondrial Bioenergetics in Hepatocellular Carcinoma In Vitro.
    Noel Jacquet, Yunfeng Zhao.
      Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming and mitochondrial dysfunction, yet the molecular regulators underlying these alterations remain incompletely understood. AarF domain-containing kinase 1 (ADCK1) is an evolutionarily conserved protein associated with mitochondrial function, but its role in HCC bioenergetics has not been defined. In this study, we investigated the effects of ADCK1 on mitochondrial metabolism using CRISPR/Cas9-mediated ADCK1 knockout in HepG2 and SNU-449 HCC cells. Mitochondrial respiration, glycolytic activity, ATP production, lactate generation, mitochondrial membrane potential, and superoxide production were assessed following ADCK1 KO. ADCK1 KO resulted in marked reductions in basal and maximal mitochondrial respiration, ATP-linked respiration, glycolytic activity, intracellular ATP, and lactate production in both HCC cell models. ADCK1 KO also reduced mitochondrial membrane potential in a clone-dependent manner. Despite these profound bioenergetic defects, mitochondrial superoxide production was not consistently altered across the knockout clones. These findings indicate that ADCK1 supports both oxidative phosphorylation and glycolytic metabolism and is required for maintenance of bioenergetic homeostasis in HCC cells. Collectively, our results identify ADCK1 as a previously unrecognized regulator of HCC mitochondrial metabolism.
    Keywords:  ADCK1; AarF domain-containing kinase 1; cellular bioenergetics; cellular metabolism; hepatocellular carcinoma; liver cancer; mitochondria
    DOI:  https://doi.org/10.3390/ijms27187984
  3. Science. 2026 09 24. 393(6818): eadw8520
    Ceramide synthesis mediates colorectal cancer metastasis through a YAP-driven regenerative program.
    Swagata Goswami, Qiming Zhang, Abdullah Burak Yildiz, Upasana Das Adhikari, Akhouri Kishore Raghawan, Manon Bulliard, Sabhyata Sedhain, Odai Darawshi, Cigdem Elif Celik, Feyza Cansiz, Constantin P Krempe, Jonas Rösler, Gabriele Allies, Sven W Meckelmann, Chiashin Chi, Felix-Levin Hormann, Sven Heiles, Joseph Sedlak, Wesley Grace, George Eng, Ethan Reich, Chiara Alquati, Kevin J Williams, Benjamin J Read, Edrees H Rashan, Zhixin Li, Anup Jnawali, Jose A Ortiz, Chesta Jain, Charles A Whittaker, Osman H Yilmaz, Vikram Deshpande, Oliver J Schmitz, Albert Sickmann, Autumn G York, Douglas S Kwon, Ulf Neumann, Maria Fedorova, Matthew G Vander Heiden, Besim Ogretmen, Nilay S Sethi, Alpaslan Tasdogan, Ömer H Yilmaz.
      Mechanisms by which primary tumor cells acquire metastatic capability through metabolic and signaling adaptations are currently poorly understood. We demonstrate that tumor-intrinsic ceramide metabolism, amplified by dietary fat, initiates colorectal cancer metastasis. We observed that dietary fat exposure triggers a sustained increase in de novo ceramide biosynthesis, mediated by the dihydroceramide desaturase Degs1. Ceramide accumulation activates yes-associated protein (YAP) through protein phosphatase 2A (PP2A)-mediated dephosphorylation, promoting a durable shift toward a distinct YAP-driven regenerative (YAP-DR) program, marked by Basp1, that promotes metastasis. Selective elimination of Basp1high cancer cells prevented metastatic seeding. Degs1 loss reduced ceramide levels, YAP activity, YAP-DR signatures, and metastasis without affecting primary tumor growth, whereas blocking ceramide degradation enhanced YAP activity and metastasis. These findings identify ceramide-induced YAP signaling as a key mediator of metastatic initiation, operating independently of primary tumor expansion.
    DOI:  https://doi.org/10.1126/science.adw8520
  4. FASEB J. 2026 Oct 15. 40(19): e72341
    Nucleolin Alterations and ROS Production Associate With Sensitivity of AML Cells to Venetoclax.
    Kateřina Wolfová, Petra Otevřelová, Barbora Brodská.
      Acute myeloid leukemia (AML) is a heterogeneous disease with large spectrum of specific mutations and gene aberrations. Recently, the Bcl-2 inhibitor Venetoclax, in combination with hypomethylating agents (HMAs), was approved for older (> 65 years) AML patients, as well as for those unfit for intensive induction chemotherapy. In addition to Bcl-2 inhibition, Venetoclax also induces generation of reactive oxygen species (ROS). We demonstrated that distinct fraction exhibiting specific features arises during 24 h of sample exposure to Venetoclax. This fraction displays characteristic preapoptotic markers as mitochondria depolarization and partial Annexin V surface positivity. Moreover, monitoring of ROS showed negative correlation between signals detected using H2DCFDA and CellROX probes pointing to dynamic ROS changes induced by Venetoclax. The addition of HMA (Decitabine) had almost no effect on cell viability or ROS production but caused proliferation arrest in sensitive cells. In our panel of AML cell lines and primary AML samples we have found a correlation between ROS production, markers of apoptosis, and attenuation of Bcl-2 activity after Venetoclax treatment. Level of Mcl-1, another antiapoptotic protein from the Bcl-2 family, was reduced in sensitive cells, but increased in the resistant samples in response to Venetoclax. Moreover, the nucleolar protein nucleolin (NCL), which is frequently overexpressed in AML cells, was significantly deregulated in Venetoclax-treated cells. In particular, both NCL protein level and specific phosphorylation decreased in fractions sensitive to Venetoclax. Our findings suggest that Venetoclax targets distinct cell subpopulation, and that ability of a cell to follow increased ROS drives its response to Venetoclax.
    Keywords:  Bcl‐2; Decitabine; Doxorubicin; ROS; Venetoclax; acute myeloid leukemia; nucleolin
    DOI:  https://doi.org/10.1096/fj.202504934RR
  5. Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2607452123
    Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.
    Qing Li, Tong Shu, Chen Liu, Min Zheng, Yuanpei Li, Lei Zhang, Gao Fan, Wenbin Lu, Huiwen Zhang, Pingping Liu, Xiaoniu He, Hong Zheng, Wen Liu, Jing Ye, Zhenyu Yin, Xianming Deng, Chensong Zhang, Canhua Huang, Han You.
      PARP inhibitors (PARPis), known to elicit mitochondrial protection in nononcological diseases by elevating the cellular NAD+ pool, exhibit potent cytotoxicity in selected human cancers. The role of mitochondrial metabolism in PARPi-mediated antitumor therapy remains unexplored. Here, we propose a causal link between mitochondrial NAD+ metabolism and PARPi responsiveness. In PARPi-non-responsive tumor cells, PARP inhibition specifically expands mitochondrial NADP(H) [mito-NADP(H)] pool, thereby facilitating de novo mitochondrial dTMP (mito-dTMP) biosynthesis and maintaining mitochondrial dTTP (mito-dTTP) pool to prevent uracil misincorporation into mitochondrial DNA (mtDNA), regardless of homologous recombination (HR) status. Mechanistically, loss of PTPN1 ADPRylation by PARPi abolishes its phosphatase activity toward STAT3, yielding enhanced STAT3 phosphorylation and the subsequent transactivation of FoxO1. FoxO1 modulates transcriptomic signature governing mitochondrial NADPH fluxes to de novo mito-dTMP generation. Our results uncover a fundamental vulnerability that can be leveraged by cotargeting STAT3 and PARP to trigger mitochondrial dysfunction.
    Keywords:  PARPi resistance; de novo mitochondrial dTMP biosynthesis; mitochondrial NAD+ metabolism
    DOI:  https://doi.org/10.1073/pnas.2607452123
  6. Cell Rep. 2026 Sep 24. pii: S2211-1247(26)01107-1. [Epub ahead of print]45(10): 118029
    FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.
    Manas Kohli, Aurélien Tripp, Anastasiia Shcherbakova, George Poulogiannis.
      Metabolic reprogramming is a hallmark of cancer, yet dynamic metabolic flux has been difficult to study systematically. Here, we present FluxAtlas, a pan-cancer atlas of metabolic flux generated from genome-scale metabolic modeling of over 10,000 tumors across 28 The Cancer Genome Atlas (TCGA) cancer types. By integrating enzyme constraints and nutrient diffusion limits, we reveal conserved and tissue-specific metabolic rewiring, including alterations in bile acid recycling, urea metabolism, and amino acid biosynthesis. We identify a bile acid-associated program that remodels glutathione homeostasis and drives gastrointestinal-specific lipid metabolism. Comparisons with matched normal models uncover tumor-selective metabolic dependencies, such as increased reliance of renal cancers on de novo purine synthesis. Under nutrient limitation, modeling predicts convergence on glutamine-dependent aspartate synthesis while preserving tissue-specific metabolic states. Machine learning models based on fluxomics predict patient survival and highlight biotin uptake as a prognostic biomarker. FluxAtlas defines the functional metabolic landscape of human cancer and is accessible at https://software.icr.ac.uk/app/flux-atlas.
    Keywords:  CP: cancer; CP: metabolism; FluxAtlas; cancer; genome-scale metabolic modeling; metabolic flux; metabolic reprogramming; prognostic biomarkers; therapeutic targets
    DOI:  https://doi.org/10.1016/j.celrep.2026.118029
  7. Nature. 2026 Sep 23.
    Hepatocytes promote liver metastasis of pancreatic cancer by providing serine.
    Koelina Ganguly, Keisuke Yamamoto, Jason Rodencal, Joel Encarnacion-Rosado, Albert S W Sohn, Douglas E Biancur, Elaine Y Lin, Ruohong Wang, Carolina Alcantara Hirsch, Anthony Sorrentino, Elshaddai Z White, Paul M Grandgenett, Michael A Hollingsworth, Miwako Kakiuchi, Richard Possemato, Dafna Bar-Sagi, Mitsuhiro Fujishiro, Alec C Kimmelman.
      The liver is the primary site of metastasis in pancreatic ductal adenocarcinoma (PDAC), and liver metastases are a major cause of mortality1,2. Nutrient availability in the metastatic niche influences colonization efficiency; however, the metabolic heterogeneity of disseminated tumour cells can also reshape the local microenvironment3-5. Loss of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine biosynthesis, is observed in nearly 40% of PDACs, and renders these cells dependent on exogenous serine (exSer)6. Although a neuron-tumour metabolic cross-talk supports exSer-dependent PDAC cells at the primary site6, it remains unclear how these cells adapt to the metastatic liver niche. Here we show that exSer-dependent PDAC cells reprogram neighbouring hepatocytes through a CXCL5-CXCR2 axis. Activation of CXCR2 in hepatocytes promotes PI3K-AKT signalling, leading to the sequestration of FOXO3A in the cytoplasm and derepression of PHGDH transcription, thereby enhancing serine production in hepatocytes. This hepatocyte-derived serine supports the outgrowth of exSer-dependent PDAC liver metastases. Accordingly, genetic or pharmacological inhibition of individual nodes within the CXCL5-CXCR2-PI3K-AKT-FOXO3A axis, or hepatocyte-specific deletion of Phgdh or Cxcr2, markedly reduces the liver-metastasis burden in mice and prolongs survival, particularly when dietary serine is restricted. Our findings reveal a cancer cell-hepatocyte metabolic cross-talk and identify therapeutic targets for exSer-dependent PDAC liver metastases.
    DOI:  https://doi.org/10.1038/s41586-026-11051-z
  8. EMBO Rep. 2026 Sep 23.
    Mitotic assembly of respiratory supercomplexes ensures accurate cell division and fuels tumor growth.
    Ting Wang, Aoxing Cheng, Lingyu Kong, Weiyi You, Jihua Liu, Xing Liu, Xuebiao Yao, Yi Yang, Yuzheng Zhao, Weiwei Yang, Kaiguang Zhang, Zhenye Yang, Jing Guo.
      As cells progress from interphase into mitosis, fluctuating metabolic demands coincide with mitochondrial fission. However, the mechanisms by which mitochondria coordinate morphological changes and metabolic adjustments during mitosis remain poorly understood. Using proteomic analysis of BN-PAGE fractions, we show that assembly of the mitochondrial respiratory supercomplexes, comprising electron transport chain complexes I, III, and IV, is markedly enhanced during mitosis in HeLa and MDA-MB-468 cancer cells. Mechanistically, the upregulation of specific CI subunits, including NDUFA3, drives the modular assembly of supercomplexes in mitosis. We further demonstrate that CDK1 promotes the translation of NDUFA3 to enable supercomplex formation. Disruption of this process impairs mitochondrial integrity, energy production, and redox homeostasis, leading to ROS accumulation that triggers mitotic cell death and chromosome segregation defects across multiple models. Importantly, inhibiting mitotic supercomplex assembly induces chromosome mis‑segregation and suppresses tumor growth in vivo. Our findings reveal supercomplex assembly as a key mechanism coordinating mitochondrial fission with metabolic adaptation to support cell division and tumor proliferation in these cancer cell contexts.
    DOI:  https://doi.org/10.1038/s44319-026-00937-8
  9. Nat Commun. 2026 Aug 25. pii: 10162. [Epub ahead of print]17(1):
    The predicted interactome of the human mitochondrial proteome.
    Abhinav B Swaminathan, Mohammad Zulkifli, Rachel M Guerra, Sofia M Calabrese, Dimitris T Kalafatis, David J Pagliarini, Vishal M Gohil.
      Despite the fundamental importance of mitochondria in cellular metabolism, the molecular function(s) of many mitochondrial proteins remain unknown. Since protein function can be inferred from their interacting partners, we repurpose the protein structure prediction algorithm AlphaFold Multimer (AFM) as a classification model to predict protein-protein interactions of the entire human mitochondrial proteome. By screening 630,003 protein pairs, we create a compendium of 2,895 previously known and newly observed interactions, which include the interacting partner(s) of 85 uncharacterized mitochondrial proteins, thereby linking them to a known biochemical pathway. Extending the AFM-based analysis to 11 diverse eukaryotes identifies evolutionarily conserved interactions among human hits, including regulators of core bioenergetic pathways. Our experiments, guided by these predictions, nominate protein interactions that form the coenzyme Q metabolon and define the mitochondrial copper delivery pathway to cytochrome c oxidase. Our compendium represents a powerful resource for the systematic, structure-based functionalization of the human mitochondrial proteome.
    DOI:  https://doi.org/10.1038/s41467-026-77112-z
  10. Nat Commun. 2026 Aug 21. pii: 10037. [Epub ahead of print]17(1):
    Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
    Kristina Todorova, Stefano Sol, Fabiana Boncimino, Andrea Clocchiatti, Kazuki Takagaki, Enkhtuul Gantumur, Mihaela Ruseva, Meaghan Cadieux, Michelle Liu, Victor A Neel, Amy S Colwell, Christine G Lian, George F Murphy, Peter Carmeliet, Anna Mandinova.
      Skin barrier function relies on the epidermis, whose integrity is maintained by basal stem cells that continuously renew and differentiate into a multilayered architecture. Disrupted epidermal differentiation underlies numerous hyperproliferative and inflammatory skin disorders. While transcriptional and epigenetic mechanisms are known to regulate late differentiation, the molecular events driving early commitment remain elusive. Here, we reveal that early mitochondrial reprogramming, characterized by the activation of oxidative phosphorylation, is a determinant of differentiation initiation. We identify fatty acid oxidation as the primary metabolic pathway fueling oxidative phosphorylation during this process. Pharmacological and genetic inhibition of fatty acid oxidation, in vitro and in vivo, disrupts differentiation and compromises stratification, causing defective responses to physical insults. Mechanistically, fatty acid oxidation enables ATP production in committed epidermal cells to support the differentiation process, linking lipid metabolism and epidermal homeostasis. These results uncover an unrecognized role for metabolic reprogramming in epidermal stem cell fate and highlight fatty acid oxidation as a promising therapeutic target for restoring differentiation defects in disease.
    DOI:  https://doi.org/10.1038/s41467-026-77023-z
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