bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–08–09
thirteen papers selected by
Marc Segarra Mondejar, AINA
  1. The coordinated actions of metformin in the intestine and liver improves hyperglycemia.
  2. Mitochondrial metabolism and PD-1 blockade: mechanisms and therapeutic opportunities in cancer immunotherapy.
  3. A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
  4. Rab10 Promotes Atlastin-Mediated Endoplasmic Reticulum Membrane Fusion.
  5. An updated view of glucose pathways in cyanobacteria.
  6. Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.
  7. The emerging role of NADPH oxidases (NOX) in Alzheimer's disease pathogenesis.
  8. Mannose supports lung cancer metabolism during glycolytic limitation.
  9. Metabolic Profiling of Circulating and Tumour-Infiltrating T Cells Uncovers Bioenergetic Checkpoints Linked With Immune and Clinical Skewing in Melanoma Patients.
  10. Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
  11. PGAM1 rheostat in glycolysis and autophagy.
  12. A stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer.
  13. Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
  1. Cell Rep. 2026 Aug 05. pii: S2211-1247(26)00869-7. [Epub ahead of print]45(8): 117791
    The coordinated actions of metformin in the intestine and liver improves hyperglycemia.
    Ling He, Hongying An, Karina Ramirez, Sally Radovick, Fredric E Wondisford.
      Metformin is the first-line oral anti-diabetic agent. Metformin concentrations in the intestine can reach up to 1.3 mM, while those in the portal vein are approximately 0.075 mM. It is unclear whether this metformin concentration difference contributes to metformin's antidiabetic effects. Here, we showed that high metformin concentrations upregulate G6PC expression through AMP-activated protein kinase (AMPK) activation to prevent glucose release in intestinal epithelial cells (IECs). The inhibition of mitochondrial activity by high metformin concentrations leads to drastically increased glucose utilization through glycolysis, along with lactate overproduction in the IECs. Subsequently, glycolytic metabolite lactate is released from IECs into portal vein and delivered to the liver. In the liver, low concentrations of metformin activate AMPK to promote mitochondrial fission and mitophagy to maintain a healthy mitochondrial population, resulting in increased lactate utilization in the mitochondria. These coordinated actions of metformin in the intestine and liver improve hyperglycemia in diabetes and obesity.
    Keywords:  CP: metabolism; insulin sensitivity; intestine epithelial cells; lactate overproduction; metformin action; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.celrep.2026.117791
  2. Mol Biol Rep. 2026 Aug 06. pii: 1350. [Epub ahead of print]53(1):
    Mitochondrial metabolism and PD-1 blockade: mechanisms and therapeutic opportunities in cancer immunotherapy.
    Khadijeh Dizaji Asl, Hossein Kalarestaghi, Ali Rafat, Mohammadmahdi Bahramloo, Sina Alinejad Shahabi, Hasti Shakouri Mollayousefi, Seyyede Sepide Ashraf Moosavi, Zeinab Mazloumi.
      The development of immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has brought about a breakthrough in cancer treatment; nevertheless, therapeutic resistance remains a significant challenge. Recent research shows that mitochondrial metabolism plays an essential role in T-cell function and therapeutic efficacy. Activation of PD-1 inhibits glycolytic metabolism, mitochondrial biogenesis, and oxidative phosphorylation (OXPHOS), resulting in T-cell exhaustion and impaired function. Concurrently, metabolic reprogramming in tumor cells, characterized by increased glycolysis, glutaminolysis, and fatty acid oxidation (FAO), creates an immunosuppressive tumor microenvironment (TME) through nutrient deprivation and the accumulation of metabolites such as lactate and 2-hydroxyglutarate (2-HG). In this review, we analyze the bidirectional relationship between PD-1 signaling and mitochondrial dysfunction and discuss emerging therapeutic approaches that combine metabolic reprogramming with immune checkpoint blockade.
    Keywords:  Immune checkpoint blockade; Immunotherapy; Mitochondrial metabolism; PD-1/PD-L1 signaling
    DOI:  https://doi.org/10.1007/s11033-026-12519-x
  3. Science. 2026 Aug 06. 393(6811): 601-606
    A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
    Christina Gladkova, Maria G Paez-Segala, William P Grant, Mark Kittisopikul, Samuel A Myers, Yuxiao Wang, Ronald D Vale.
      The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite-polarity microtubule motors remains unknown. In this study, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein [trafficking kinesin-binding protein (TRAK)] that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.
    DOI:  https://doi.org/10.1126/science.aeh1475
  4. FASEB J. 2026 Aug 15. 40(15): e72170
    Rab10 Promotes Atlastin-Mediated Endoplasmic Reticulum Membrane Fusion.
    Minseok Kim, Kongmin Na, Hyeonji Kim, Eunhong Jang, So Young Yoon, Changwook Lee, Youngsoo Jun.
      Intracellular membrane fusion typically involves two distinct classes of GTPases. Dynamin-like GTPases mediate homotypic fusion between organelles, such as mitochondria and the endoplasmic reticulum (ER), while Rab GTPases facilitate fusion of transport vesicles with target membranes through vesicle tethering. Notably, these two classes of GTPases have not previously been implicated in the same fusion event. In this study, we demonstrate that Rab10 promotes ER membrane fusion driven by the dynamin-like GTPase atlastin (ATL). Rab10 interacted physically with ATL2, a human ATL predominantly expressed in non-neuronal cells, and co-localized with ATL2 throughout the ER, including at three-way junctions where fusion occurs. Fusion between ER microsomes isolated from HEK293T cells, in which ATL2 is the primary ATL isoform, was inhibited by affinity-purified anti-Rab10 antibodies, and was reduced in microsomes derived from Rab10 knockout cells. Moreover, co-reconstitution of Rab10 markedly enhanced fusion of ATL2-containing liposomes. Our findings reveal crosstalk between dynamin-like and Rab GTPases during ATL-mediated ER membrane fusion, uncovering a novel regulatory mechanism for organelle dynamics.
    Keywords:  Rab10; atlastin; endoplasmic reticulum; membrane fusion; organelle dynamics
    DOI:  https://doi.org/10.1096/fj.202503069RR
  5. Elife. 2026 Aug 05. pii: e112405. [Epub ahead of print]15
    An updated view of glucose pathways in cyanobacteria.
    José Manuel García-Fernández.
      Contrary to previous belief, the cyanobacterium Synechocystis lacks the Entner-Doudoroff pathway for glucose metabolism.
    Keywords:  Entner-Doudoroff; cyanobacteria; enzymes; glucose; glucose metabolism; mixotrophy; plant biology
    DOI:  https://doi.org/10.7554/eLife.112405
  6. Nat Metab. 2026 Aug 05.
    Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.
    Anke Vandekeere, Juan Fernández-García, Yiming Peng-Winkler, Miguel Martín Pérez, Ming Liu, Sara Isabel Fernandes, Janine Theile, Philipp Willnow, Sanne Verheul, Gitte Zels, Anirudh Pabba, Christine Desmedt, Cornelis Verhoef, Patricia Altea-Manzano, Salvador Aznar Benitah, Ilaria Elia, Ilaria Malanchi, Sarah-Maria Fendt.
      Liver metastases are frequent and challenging to treat owing to the liver's metabolically active and immune-tolerant environment. However, how cancer cells exploit nutrient availability in the liver to evade immune surveillance remains unknown. Here we show that cancer cells use the palmitate availability in the liver to impair the neutrophil antitumour function. Mechanistically, we find that breast and colorectal cancer cells metastasizing to the liver, but not the lung, require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to stabilize laminin-511 enabling its secretion. In turn, neutrophils in the liver metastasis environment respond to laminin-511 by decreasing their cancer cell-killing capacity. Consistently, silencing ZDHHC17 in cancer cells decreases liver metastases only in the presence of neutrophils, while metastasis growth is restored in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we find that liver palmitate not only supports tumour intrinsic processes but also enables immune evasion.
    DOI:  https://doi.org/10.1038/s42255-026-01582-0
  7. Neuroscience. 2026 Aug 06. pii: S0306-4522(26)00533-6. [Epub ahead of print]
    The emerging role of NADPH oxidases (NOX) in Alzheimer's disease pathogenesis.
    Anuradha Yadav, Harkomal Verma, Sakshi Kumari, Prabhakar Gangwar, Rashmi Rao, Bharti Yadav, Sharanjot Kaur, Monisha Dhiman, Anil Kumar Mantha.
      Alzheimer's disease (AD) is a slow-progressing neurodegenerative disease, mainly characterized by the accumulation of amyloid beta (Aβ) plaques and intracellular hyperphosphorylated Tau protein, along with the generation of free radicals. In normal physiology free radicals play a promising role. However, the imbalance in the formation and clearance of the free radicals or reactive oxygen species/reactive nitrogen species (ROS/RNS) disrupts redox homeostasis, resulting in oxidative stress. Cellular disruption through the oxidation of lipids, proteins, and nucleic acids along with the disruption of the blood-brain barrier (BBB) integrity, and neuroinflammation are linked with AD pathogenesis. Albeit there are various ROS-generating sources, notably mitochondria, endoplasmic reticulum (ER), peroxisomes, NADPH oxidase (NOX), and several other oxidases, but out of all, the second most well-studied ROS-generating component after mitochondria is thought to be NOX. It is a multi-subunit enzyme family, activated by the phosphorylation of its cytosolic subunit, culminating in the production of superoxide (O2•-) anions. It comprises seven different isoforms, where NOX2 is the most studied isoform found to be the major source of ROS production in the brain. Therefore, inhibiting NOX-induced oxidative stress in the brain might be a promising therapeutic approach for AD. Thus, the current review enlightens the role of NOX in neurodegenerative AD progression, Aβ pathology and focusing on the therapeutic interventions by employing different phytochemicals as natural inhibitors and the synthetic inhibitors to combat the pathogenicity associated with NOX in the case of AD.
    Keywords:  Alzheimer’s disease; Free radicals; NADPH oxidase; Oxidative stress; Phytochemicals; Synthetic inhibitors
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.08.004
  8. EMBO Rep. 2026 Aug 07.
    Mannose supports lung cancer metabolism during glycolytic limitation.
    Theresa Haitzmann, Niklas B Thompson, Hardik Shah, Katharina Schindlmaier, Joseph Jelwan, Thomas O Eichmann, Nia G Hammond, Maia G Clare, Robert B Cameron, Brandon Faubert, Katharina Leithner.
      Cancer cells frequently show elevated glucose consumption to support proliferation and survival. This led to the assumption that glycolytic inhibitors could be effective in cancer treatment. However, barriers to clinical implementation remain. Adaptive strategies, such as metabolizing alternative nutrients, may play a role. Here, we investigated the use of an understudied sugar, mannose, in lung cancer cells and xenografts. Stable isotope tracing reveals enhanced contribution of mannose to GDP-mannose and GDP-fucose, key glycosylation precursors, upon treatment with the glycolytic inhibitor 2-deoxyglucose (2-DG) or glucose starvation in vitro. Mannose restores the glucose-withdrawal-induced decrease of GDP-mannose and GDP-fucose pools, and partially rescues proliferation upon 2-DG treatment or glucose deprivation. 13C6-mannose infusion in patient-derived xenograft mice reveals a considerable contribution of mannose to GDP-mannose and GDP-fucose in tumors, which is further enhanced by 2-DG. In normal lungs, the pathway is only partially active. Mannose is also shuttled towards glycolysis in lung tumors in vivo and glucose-deprived cells in vitro. In conclusion, mannose utilization for glycosylation precursor synthesis represents an adaptive strategy in lung cancer cells under metabolic stress.
    DOI:  https://doi.org/10.1038/s44319-026-00874-6
  9. Immunology. 2026 Aug 04.
    Metabolic Profiling of Circulating and Tumour-Infiltrating T Cells Uncovers Bioenergetic Checkpoints Linked With Immune and Clinical Skewing in Melanoma Patients.
    Hugo Brouque, Kareem Mahdy, Stephane Mouret, Sylvain Henry, Camille Niveau, Mélanie Cettour-Cave, Martin Pelosse, Florence de Fraipont, Julie Charles, Andrei Turtoi, Philippe Saas, Caroline Aspord.
      Metabolism is critical for immune cell functions. Tumours shape their microenvironment to render it metabolically hostile for infiltrating immune cells. While targeting immunometabolism emerges as a promising way to reinvigorate anticancer immunity, a deeper understanding of the metabolic disturbances of immune cells is needed. Here, we explored how the metabolic status of T cells governs immune skewing from circulating and tumour-infiltrating CD4+ and CD8+ T cells of melanoma patients at a single-cell level using the SCENITH method and targeted metabolomics. Circulating and tumour-infiltrating T cells from patients displayed a decreased mitochondrial dependency associated with an enhanced glycolytic capacity and a skewed metabolic reprogramming upon stimulation. Such metabolic disturbances were linked to the activation status, immune checkpoint profile and functional orientation of T cells, underlining critical connections between T-cell features and metabolic patterns. Targeted metabolomics within sorted CD4+/CD8+ T cells identified a decrease in citrulline, cysteine and threonine within all subsets in patients, together with a sharp rise in sterol cholesterol CE(20:2) and ceramide dhCer(d18:0/22:0) within tumour-infiltrating CD4+ T cells, and in glycerolipid DG(16:0/16:0) within CD8+ T cells in blood and tumour. We further outlined a metabolic-checkpoint-based signature composed of six genes coding enzymes/transporters connected to the imbalanced metabolites found within tumour-infiltrating T cells (LIPA, DGKA, GLUL, SLC38A1, SLC7A7, GCH1) that shape patients' clinical outcome. These findings outline the skewed bioenergetic profiles of T cells and depict metabolic checkpoints associated with immune subversion. Harnessing metabolic pathways is promising for developing innovative therapies to restore optimal anti-tumour responses and improve clinical success.
    Keywords:  SCENITH; T cells; immunometabolism; melanoma; metabolomics
    DOI:  https://doi.org/10.1111/imm.70185
  10. Elife. 2026 Aug 05. pii: RP106492. [Epub ahead of print]14
    Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
    Patrick B Jonker, Mumina Sadullozoda, Guillaume Cognet, Juan J Apiz Saab, Kelly H Sokol, Violet X Wu, Deepa Kumari, Colin Sheehan, Mete E Ozgurses, Darby Agovino, Grace Croley, Lindsey N Dzierozynski, Chufan Cai, Leah M Ziolkowski, Smit A Patel, Althea Bock-Hughes, Kay F Macleod, Hardik Shah, Jonathan L Coloff, Evan C Lien, Alexander Muir.
      Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising anti-neoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cellular metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1, in part via activation of the amino acid sensor GCN2. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids (PUFAs) in cellular membranes. Because of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to PUFAs, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fats.
    Keywords:  biochemistry; cancer; cancer biology; chemical biology; diet; human; metabolism; mouse; stress; synthetic lethality; tumor microenvironment
    DOI:  https://doi.org/10.7554/eLife.106492
  11. Nat Cell Biol. 2026 Aug 07.
    PGAM1 rheostat in glycolysis and autophagy.
    Kay F Macleod.
      
    DOI:  https://doi.org/10.1038/s41556-026-02033-4
  12. Cancer Cell. 2026 Aug 03. pii: S1535-6108(26)00312-0. [Epub ahead of print]
    A stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer.
    Yang Zheng, Caleb Cheng, Yizhi Cao, Gabriel Cruz, Yuping Zhang, Radha Paturu, Somnath Mahapatra, Jing Hu, Rahul Mannan, Hüseyin Karabürk, Rupam Bhattacharyya, Yitong Yin, Yi Zhao, Wenyan Liu, Xuhong Cao, Hui Xue, Chungen Li, Zhen Wang, Stephanie J Miner, Zachery R Reichert, Rohit Mehra, Ulka Vaishampayan, Vaibhav Sahai, Lois S Weisman, Ke Ding, Costas A Lyssiotis, Yuzhuo Wang, Arul M Chinnaiyan, Yuanyuan Qiao.
      Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-adaptive lipid kinase axis that supports adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, exacerbates ER stress, and activates a compensatory sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.
    Keywords:  PI(3,5)P(2); PIKfyve; SREBP; autophagy; endoplasmic reticulum stress; fatty acid synthase; lipid metabolism; lysosome; neuroendocrine prostate cancer; unfolded protein response
    DOI:  https://doi.org/10.1016/j.ccell.2026.07.003
  13. Cell Metab. 2026 Aug 05. pii: S1550-4131(26)00324-4. [Epub ahead of print]
    Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
    Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.026
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