bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–01–04
seven papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Evaluation of Metabolic Characteristics of Cancer Cells.
  2. A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
  3. Mapping metabolic dependences and capacities using ATP as a biomarker.
  4. Adaptation to cystine limitation stress confers a targetable lipid metabolism vulnerability in pancreatic ductal adenocarcinoma.
  5. Mitochondrial pyruvate dehydrogenase kinase 1 drives bevacizumab resistance and malignant phenotype of TNBC by enhancing mitophagy.
  6. Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts.
  7. CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia.
  1. Methods Mol Biol. 2026 ;2983 159-167
    Evaluation of Metabolic Characteristics of Cancer Cells.
    Riddhi Mehta, Pritpal Kaur, Fatema Zohra Sadia, Patricia Maziarz, Ales Vancura.
      Cancer cells undergo a complex rearrangement of metabolic pathways that allows them to satisfy the needs of increased proliferation. Since many cancers are characterized by a high glycolytic rate regardless of oxygen availability, targeting glycolysis, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS) have emerged as a potential therapeutic strategy. In this chapter, we describe a protocol that utilizes the Agilent Seahorse XFp Analyzer to assess mitochondrial respiration and glycolysis in ovarian cancer cells.
    Keywords:  Cancer metabolism; Extracellular acidification; Glycolysis; Mitochondrial respiration; Ovarian cancer; Oxygen consumption rate
    DOI:  https://doi.org/10.1007/978-1-0716-4901-5_15
  2. bioRxiv. 2025 Dec 19. pii: 2025.12.17.694756. [Epub ahead of print]
    A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
    Yumi Kim, Samantha Caldwell, Meredith Long, Dominique Abrahams, Margi Baldwin, Gina M DeNicola.
      Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. Glycolytic and TCA cycle intermediates, sulfur and aromatic amino acid metabolites, acylcarnitines, and nucleotide pools decreased, while branched-chain amino acids, their ketoacids, ketone bodies, and fatty acids increased. These coordinated changes were suggestive of mitochondrial complex I inhibition and reduced oxidative catabolism, leading to shifts in metabolite pool sizes that compromise isotopologue-based flux interpretation. We established a tail vein catheterization method completed in minutes under brief anesthesia that enables multi-hour tracer infusion in awake, freely moving mice. This method achieved steady-state labeling of cystine and downstream products comparable to jugular infusion without supraphysiologic cystine accumulation. This platform provides a practical, physiologically accurate method for in vivo steady-state isotope tracing.
    DOI:  https://doi.org/10.64898/2025.12.17.694756
  3. Res Sq. 2025 Apr 23. pii: rs.3.rs-4836421. [Epub ahead of print]
    Mapping metabolic dependences and capacities using ATP as a biomarker.
    Peter McGuire, Jose Marin, Amanda Fuchs, Tatiana Tarasenko, Emily Warren, Martha Kirby, Stacie Anderson, Eliza Gordon-Lipkin, Shannon Kruk, A West.
      Metabolic dependences highlight a cell's reliance on specific pathways to meet its bioenergetic needs, with these pathways being interrogated using chemical inhibitors to assess their significance. While surrogate markers of bioenergetics (e.g., oxygen consumption) have yielded important insights, we asked whether metabolic dependences could be defined using ATP as a biomarker. To address this gap, we developed Mitochondrial/Energy Flow Cytometry (MitE-Flo), a method that evaluates the contributions of glycolysis, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS) to cellular ATP content. In models of mitochondrial disease due to complex I or complex IV deficiency, we identified impaired OXPHOS with a compensatory shift to glycolysis. To define the utility of ATP monitoring in immunometabolism research, we analyzed previously inaccessible cell populations: light zone (LZ) and dark zone (DZ) germinal center (GC) B cells. Highly proliferative DZ B cells exhibited elevated ATP levels and a preference for FAO and OXPHOS over glycolysis, with uniform increased activity across ETC complexes. In contrast, less proliferative LZ B cells showed lower ATP levels and an equal reliance on glycolysis and OXPHOS. Using ATP as a biomarker to define metabolic dependences provides valuable insights into disease states and elusive immune cell subtypes, thereby enhancing the metabolism research toolkit.
    DOI:  https://doi.org/10.21203/rs.3.rs-4836421/v2
  4. Nat Commun. 2025 Dec 31.
    Adaptation to cystine limitation stress confers a targetable lipid metabolism vulnerability in pancreatic ductal adenocarcinoma.
    Yunzhan Li, Zekun Li, Qin Li, Dongxiao Sun, Bo Ni, Mingjun Tan, Ashley E Shay, Min Wang, Chenyang Meng, Guangcong Shen, Boyang Fu, Yueying Shan, Shiqi Zhang, Rifah Rownak Tanshee, Tianxing Zhou, Yongjie Xie, Kun-Ming Chen, Bin Qiao, Yunkun Dang, Scot R Kimball, Guanshi Zhang, Girish H Rajacharya, Pankaj K Singh, Xiuchao Wang, Jihui Hao, Shengyu Yang.
      Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. On the other hand, CLSA-mediated lipidomic reprogramming depends on triacylglycerides synthesis and lipid droplet formation to mitigate lipotoxicity. Through drug screening, we identify lomitapide as an inhibitor of CLSA PDAC tumor growth and a potent sensitizer of chemotherapy. Lomitapide inhibits triacylglycerides synthesis to interfere with CLSA and chemotherapy-induced lipidomic reprogramming. Taken together, we demonstrate that CLSA promotes PDAC tumor growth through metabolic reprogramming and lomitapide could be used to target the dysregulated lipid metabolism in PDAC.
    DOI:  https://doi.org/10.1038/s41467-025-68099-0
  5. Pharmacol Res. 2025 Dec 31. pii: S1043-6618(25)00506-7. [Epub ahead of print] 108081
    Mitochondrial pyruvate dehydrogenase kinase 1 drives bevacizumab resistance and malignant phenotype of TNBC by enhancing mitophagy.
    Yan Ye, Qian Zeng, Zuli Ou, Xiaoqian Ju, Qingyu Liao, Canling Li, Dian Zhang, Yu Wei, Xiang Zhang, Kejia Wu, Tingmei Chen.
      Bevacizumab is an anti-angiogenic agent widely used in neoadjuvant chemotherapy for advanced triple-negative breast cancer (TNBC). TNBC patients frequently acquire resistance to bevacizumab due to the hypoxic tumor microenvironment, yet the underlying molecular mechanism remains unclear. Here, we demonstrate that mitochondrial reprogramming under hypoxia is crucial for resistance to bevacizumab. Mechanically, prolonged hypoxia causes the glycolytic pathway enzyme PDK1 to accumulate inside mitochondria. In mitochondria, PDK1 exerts its non-canonical function to phosphorylate mitochondrial protein Prohibitin 2 (PHB2) at Ser190. Phosphorylation at Ser190 stabilizes PHB2 and enhances its binding with LC3, thereby initiating mitophagy. Functionally, mitochondrial PDK1 (mito-PDK1) initiates mitophagy in response to hypoxia-induced mitochondrial damage and promotes the malignant phenotype of TNBC cells. In xenograft tumors, inhibiting the function of mito-PDK1 enhances the sensitivity to bevacizumab. Collectively, our findings identify the crucial function and mechanism of mito-PDK1 in TNBC. Targeting mito-PDK1 function may emerge as a novel therapeutic strategy to address acquired resistance to bevacizumab.
    Keywords:  bevacizumab; hypoxia; mitophagy; pyruvate dehydrogenase kinase 1; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.phrs.2025.108081
  6. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2508911123
    Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts.
    Isidora Molina-Riquelme, Gonzalo Barrientos, Leonhard Breitsprecher, Wileidy Gómez, Francisco Díaz-Castro, Silke Morris, Gonzalo Almarza, Andrea Del Campo, Luis Garrido-Olivares, Hugo E Verdejo, Olympia Ekaterini Psathaki, Karin B Busch, Verónica Eisner.
      Aging is closely associated with cardiovascular diseases, the leading cause of mortality worldwide. Mitochondrial dysfunction is a hallmark of cardiovascular aging. Most of the heart's ATP is produced at the cristae, specialized subcompartments where oxidative phosphorylation (OXPHOS) takes place. In this study, we used multiple-scale electron microscopy approaches to evaluate age-related mitochondrial and ultrastructural alterations of cristae in human and mouse hearts. We found that aged patients' hearts displayed reduced cristae density as seen by transmission electron microscopy (TEM), even before any significant decline in the expression of cristae-shaping proteins. Similarly, a multiscale approach that included TEM and serial block-face scanning electron microscopy (SBF-SEM) showed that in aged mice's hearts, cristae undergo ultrastructural remodeling processes, resulting in a decrease in cristae density and width. Electron tomography suggests an apparent decline in cristae connectivity and an increase in fenestration size. These changes were linked to Opa1 downregulation, accompanied by reduced maximal OXPHOS respiration, but unrelated to alterations in the abundance of OXPHOS core subunits and ATP synthase assembly. Altogether, this indicates that alterations in cristae structure alone are sufficient to impair oxidative metabolism, which highlights its potential as an early signal of cardiac aging, even before noticeable changes in mitochondrial morphology occur.
    Keywords:  Opa1; aging; cristae; heart; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2508911123
  7. Cell Rep Med. 2025 Dec 29. pii: S2666-3791(25)00599-3. [Epub ahead of print] 102526
    CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia.
    Melissa L Stewart, Jessica Gibbs, Kevin Watanabe-Smith, Ariel Nguyen, Isabel Kenna, Karina Thiel-Klare, Andy Kaempf, Daniel Bottomly, Stephen E Kurtz, Christopher A Eide, Nicola Long, Jennifer N Saultz, Luca Sax, Ariane Huang, Shannon K McWeeney, Bill H Chang, Jeffrey W Tyner.
      Venetoclax (ven) combined with azacytadine is a widely used therapy for acute myeloid leukemia (AML). However, most patients develop resistance. To identify more effective combinations, we analyze 302 AML patient samples and find ven plus palbociclib (ven+palbo), a cyclin dependent kinase (CDK)4/6 inhibitor, to be highly effective. Ven+palbo shows synergistic activity in AML cell lines and patient-derived xenograft mouse models. Patient samples exhibiting a synergistic response to ven+palbo show downregulation of genes involved in protein synthesis. Genome-wide (CRISPR) screening shows that loss of translational genes uniquely confers sensitivity to ven but not to ven+palbo. AML cells exposed to ven exhibit an adaptive increase of protein synthesis that is overcome by ven+palbo through regulation of translational machinery. Additionally, ven+palbo mitigates resistance mechanisms observed with single-agent ven (BAX loss) and palbo (RB1 loss). Finally, we identify the loss of IKZF1 as a mechanism of resistance to ven+palbo and show that targeting AXL is effective in IKZF1-mutated AML.
    Keywords:  cell state; monocytic; progenitor; targeted therapy
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102526
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