bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–06–22
twenty-one papers selected by
Marc Segarra Mondejar
  1. Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis.
  2. Constraint-based modeling of bioenergetic differences between synaptic and non-synaptic components of dopaminergic neurons in Parkinson's disease.
  3. Immunometabolism in systemic lupus erythematosus.
  4. Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
  5. Integrated spatial omics of metabolic reprogramming and the tumor microenvironment in pancreatic cancer.
  6. Low-Glucose Culture Conditions Bias Neuronal Energetics Towards Oxidative Phosphorylation.
  7. Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.
  8. Resting Ca2+ fluxes protect cells from fast mitochondrial fragmentation, cell stress responses, and immediate transcriptional reprogramming.
  9. Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
  10. Shaping the composition of the mitochondrial outer membrane.
  11. Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
  12. ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.
  13. Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
  14. Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper.
  15. Glycolytic flux controls retinal progenitor cell differentiation via regulating Wnt signaling.
  16. PUMA reduces FASN ubiquitination to promote lipid accumulation and tumor progression in human clear cell renal cell carcinoma.
  17. The RNA demethylase FTO promotes glutamine metabolism in clear cell renal cell carcinoma through the regulation of SLC1A5.
  18. Brain Adenylosuccinate Is Dramatically Increased Under Global Ischemia Without Evidence for Purine Nucleotide Cycle Activation.
  19. Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
  20. ACLY links mutant α-synuclein to metabolism, autophagy and neurodegeneration.
  21. Multiple roles for a mitochondrial enzyme.
  1. Nat Cell Biol. 2025 Jun;27(6): 902-917
    Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis.
    Maria Livia Sassano, Yulia Y Tyurina, Antigoni Diometzidou, Ellen Vervoort, Vladimir A Tyurin, Sanket More, Rita La Rovere, Francesca Giordano, Geert Bultynck, Benjamin Pavie, Johan V Swinnen, Hülya Bayir, Valerian E Kagan, Luca Scorrano, Patrizia Agostinis.
      The peroxidation of membrane phospholipids (PLs) is a hallmark of ferroptosis. The endoplasmic reticulum and mitochondria have been implicated in ferroptosis, but whether intracellular PL peroxidation ensues at their contact sites (endoplasmic reticulum-mitochondria contact sites, EMCSs) is unknown. Using super-resolution live imaging, we charted the spatiotemporal events triggered by ferroptosis at the interorganelle level. Here we show that EMCSs expand minutes after localized PL peroxides are formed and secondarily spread to mitochondria, promoting mitochondrial reactive oxygen species and fission. Oxidative lipidomics unravels that EMCSs host distinct proferroptotic polyunsaturated-PLs, including doubly proferroptotic polyunsaturated-acylated PLs, demonstrating their high propensity to undergo PL peroxidation. Endoplasmic reticulum-mitochondria untethering blunts PL peroxidation and ferroptosis, while EMCS stabilization enhances them. Consistently, distancing EMCSs protects the ferroptosis-susceptible triple-negative breast cancer subtype, harbouring high EMCS-related gene expression and basal PL peroxide levels. Conversely, in insensitive triple-negative breast cancer subtypes, bolstering EMCSs sensitizes them to ferroptosis. Our data unveil endoplasmic reticulum-mitochondria appositions as initial hubs of PL peroxide formation and posit that empowering EMCSs endorses ferroptosis in cancer cells.
    DOI:  https://doi.org/10.1038/s41556-025-01668-z
  2. Front Comput Neurosci. 2025 ;19 1594330
    Constraint-based modeling of bioenergetic differences between synaptic and non-synaptic components of dopaminergic neurons in Parkinson's disease.
    Xi Luo, Diana C El Assal, Yanjun Liu, Samira Ranjbar, Ronan M T Fleming.
       Introduction: Emerging evidence suggests that different metabolic characteristics, particularly bioenergetic differences, between the synaptic terminal and soma may contribute to the selective vulnerability of dopaminergic neurons in patients with Parkinson's disease (PD).
    Method: To investigate the metabolic differences, we generated four thermodynamically flux-consistent metabolic models representing the synaptic and non-synaptic (somatic) components under both control and PD conditions. Differences in bioenergetic features and metabolite exchanges were analyzed between these models to explore potential mechanisms underlying the selective vulnerability of dopaminergic neurons. Bioenergetic rescue analyses were performed to identify potential therapeutic targets for mitigating observed energy failure and metabolic dysfunction in PD models.
    Results: All models predicted that oxidative phosphorylation plays a significant role under lower energy demand, while glycolysis predominates when energy demand exceeds mitochondrial constraints. The synaptic PD model predicted a lower mitochondrial energy contribution and higher sensitivity to Complex I inhibition compared to the non-synaptic PD model. Both PD models predicted reduced uptake of lysine and lactate, indicating coordinated metabolic processes between these components. In contrast, decreased methionine and urea uptake was exclusively predicted in the synaptic PD model, while decreased histidine and glyceric acid uptake was exclusive to the non-synaptic PD model. Furthermore, increased flux of the mitochondrial ornithine transaminase reaction (ORNTArm), which converts oxoglutaric acid and ornithine into glutamate-5-semialdehyde and glutamate, was predicted to rescue bioenergetic failure and improve metabolite exchanges for both the synaptic and non-synaptic PD models.
    Discussion: The predicted differences in ATP contribution between models highlight the bioenergetic differences between these neuronal components, thereby contributing to the selective vulnerability observed in PD. The observed differences in metabolite exchanges reflect distinct metabolic patterns between these neuronal components. Additionally, mitochondrial ornithine transaminase was predicted to be the potential bioenergetic rescue target for both the synaptic and non-synaptic PD models. Further research is needed to validate these dysfunction mechanisms across different components of dopaminergic neurons and to explore targeted therapeutic strategies for PD patients.
    Keywords:  Parkinson’s disease; bioenergetics; modeling; non-synaptic; synaptic
    DOI:  https://doi.org/10.3389/fncom.2025.1594330
  3. Nat Rev Rheumatol. 2025 Jun 16.
    Immunometabolism in systemic lupus erythematosus.
    Eduardo Patiño-Martinez, Mariana J Kaplan.
      Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by chronic inflammation, tissue damage, accelerated cardiovascular disease and the synthesis of autoantibodies that target nucleic acids and nuclear protein complexes. Emerging evidence underscores the key role of immune metabolic dysregulation in SLE, revealing how metabolic reprogramming during immune cell activation influences disease development and progression. Alterations in key metabolic pathways such as glycolysis and oxidative phosphorylation profoundly affect the activation, differentiation and function of B and T cells, monocytes, neutrophils and other immune cells, driving inflammation and tissue injury. This Review synthesizes current findings on immune cell metabolism in animal models of lupus and in patients with SLE, highlighting the interplay of metabolic disturbances, mitochondrial dysfunction and disease pathogenesis. Furthermore, it explores the potential of targeting metabolic pathways as therapeutic strategies to mitigate organ damage and improve outcomes in SLE.
    DOI:  https://doi.org/10.1038/s41584-025-01267-0
  4. Cancer Res. 2025 Jun 20.
    Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
    Natalia V Oleinik, Firdevs Cansu Atilgan, Mohamed Faisal Kassir, Han Gyul Lee, Alhaji H Janneh, Wyatt Wofford, Chase Walton, Zdzislaw M Szulc, Elizabeth G Hill, Alexander V Alekseyenko, Huseyin Cimen, Jessica H Hartman, Christina Voelkel-Johnson, Michael B Lilly, John J Lemasters, Norma Frizzell, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen.
      Bioactive ceramide induces cell death in part by promoting mitophagy. C18-ceramide levels are commonly reduced in head and neck squamous cell carcinoma (HNSCC), which correlates with poor prognosis, suggesting the potential of harnessing ceramide for cancer treatment. Here, we evaluated the ability of the ceramide analog LCL768 to induce mitophagy and metabolic stress in HNSCC. Mechanistically, LCL768 induced CerS1-mediated endogenous C18-ceramide accumulation in mitochondria to mediate mitophagy, which did not require the CerS1 transporter p17/PERMIT but was dependent on DRP1 activation via nitrosylation at C644. DRP1 facilitated anchoring of the endoplasmic reticulum (ER) and mitochondrial membranes by promoting the association between phosphatidylethanolamine in the ER and cardiolipin in mitochondrial membranes. Mutations of Drp1 that prevented its binding to ER and mitochondrial membranes blocked CerS1/C18-ceramide mitochondrial accumulation, inhibiting LCL768-mediated mitophagy. In addition, LCL768-driven mitophagy altered mitochondrial metabolism, resulting in fumarate depletion and leading to tumor suppression in vivo. Exogenous fumarate supplementation prevented LCL768-mediated mitophagy, mitochondrial trafficking of CerS1, ER-mitochondrial tethering, and tumor suppression in mice. Fumarate metabolism was associated with PARKIN succination at a catalytic cysteine (Cys431), inhibiting its association with PINK1 and ubiquitin and thereby preventing mitophagy. LCL768-induced fumarate depletion attenuated PARKIN succination to promote PARKIN activation and mitophagy, indicating a feed-forward mechanism that regulates mitophagy and fumarate metabolism through PARKIN succination. These data provide a mechanism whereby LCL768/CerS1-C18-ceramide-mediated mitophagy and tumor suppression are regulated by Drp1 nitrosylation, fumarate depletion, and PARKIN succination, providing a metabolic stress signature for lethal mitophagy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4042
  5. iScience. 2025 Jun 20. 28(6): 112681
    Integrated spatial omics of metabolic reprogramming and the tumor microenvironment in pancreatic cancer.
    Hao Wu, Qiyao Zhang, Zhen Cao, Hongtao Cao, Mengwei Wu, Mengdi Fu, Tingping Huang, Xianlin Han, Xiaoyan Chang, Ziwen Liu.
      Metabolic reprogramming is a defining feature of pancreatic cancer, influencing tumor progression and the tumor microenvironment. By integrating single-cell transcriptomics, spatial transcriptomics, and spatial metabolomics, this study visualized the spatial co-localization of metabolites and gene expression within tumor samples, uncovering metabolic heterogeneity and intercellular interactions. Spatial transcriptomics identified distinct pathological regions, which were further characterized using single-cell transcriptomic data and pathologist annotations. Pseudotime trajectory analysis revealed metabolic shifts along the malignant progression, while single-cell Metabolism (scMetabolism) delineated metabolic differences between pathological regions, classifying them as hypermetabolic or hypometabolic. Notably, aberrant cell communication between cancer cells, macrophages, and fibroblasts was observed, with key receptor-ligand pairs significantly co-expressed in malignant regions and correlated with poor prognosis. Spatial metabolomics imaging identified signature metabolites, highlighting metabolic alterations in amino acid metabolism, polyamine metabolism, fatty acid synthesis, and phospholipid metabolism. This integrated analysis provides critical insights into pancreatic cancer metabolism, offering potential avenues for targeted therapeutic interventions.
    Keywords:  Cancer; Metabolomics; Microenvironment; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.112681
  6. J Neurochem. 2025 Jun;169(6): e70125
    Low-Glucose Culture Conditions Bias Neuronal Energetics Towards Oxidative Phosphorylation.
    Sarpras Swain, David M Roberts, Saad Chowdhry, Ryan Durbin, Reece Boyd, Juli Petereit, Robert Renden.
      Neurons are almost exclusively cultured in media containing glucose at much higher concentrations than found in the brain. To test whether these "standard" hyperglycemic culture conditions affect neuronal respiration relative to near-euglycemic conditions, we compared neuronal cultures grown with minimal glial contamination from the hippocampus and cortex of neonatal C57BL/6NCrl mice in standard commercially available media (25 mM Glucose) and in identical media with 5 mM glucose. Neuronal growth in both glucose concentrations proceeded until at least 14 days in vitro, with similar morphology and synaptogenesis. Neurons grown in high glucose were highly dependent on glycolysis as their primary source of ATP, measured using ATP luminescence and cellular respirometry assays. In contrast, neurons grown in 5 mM glucose showed a more balanced dependence on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), greater reserve mitochondrial respiration capacity, and increased mitochondrial population relative to standard media. Our results show that neurons cultured in artificially high glucose-containing media preferentially use glycolysis, opposite to what is known for neurons in vivo as the primary pathway for ATP maintenance. Changes in gene and protein expression levels corroborate these changes in function and additionally suggest that high glucose culture media increases neuronal inflammation. We suggest using neuronal culture systems in 5 mM glucose to better represent physiologically relevant neuronal respiration.
    Keywords:  cell culture; glucose; mitochondrial respiration; neurobasal media; neuronal bioenergetics; primary mouse neuron
    DOI:  https://doi.org/10.1111/jnc.70125
  7. Biochim Biophys Acta Rev Cancer. 2025 Jun 11. pii: S0304-419X(25)00115-5. [Epub ahead of print]1880(4): 189373
    Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.
    Fan Gao, Kang Sun, Sicheng Wang, Xiaozhen Zhang, Xueli Bai.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. During tumor progression, metabolic reprogramming plays a crucial role in both tumor proliferation and immune evasion. In PDAC, genetic mutations and environment limitations lead to resulting in increased lactate production through enhanced glycolysis. Elevated glycolysis is a significant metabolic feature in pancreatic cancer, leading to lactate accumulation within both the tumor cells and tumor immune microenvironment. Lactate not only promotes tumor growth and sustains its survival but also has a profound impact on the immune-suppressive phenotype switch of immune cells. Lactate promotes tumor progression through various biological processes. Pharmacological agents targeting lactate generation, accumulation and lactate-related molecular pathways show potential clinical translation value in cancer treatment.
    Keywords:  GPR81; Lactate metabolism; Lactylation; Metabolic reprogramming; PDAC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189373
  8. Cell Mol Life Sci. 2025 Jun 14. 82(1): 238
    Resting Ca2+ fluxes protect cells from fast mitochondrial fragmentation, cell stress responses, and immediate transcriptional reprogramming.
    Caroline Fecher, Annemarie Sodmann, Felicitas Schlott, Juliane Jaepel, Franziska Schmitt, Isabella Lengfelder, Thorsten Bischler, Bernhard Nieswandt, Konstanze F Winklhofer, Robert Blum.
      Homeostatic calcium ion (Ca2+) fluxes between the endoplasmic reticulum, cytosol, and extracellular space occur not only in response to cell stimulation but also in unstimulated cells. Using murine astrocytes as a model, we asked whether there is a signaling function of these resting Ca2+ fluxes. The data showed that endoplasmic reticulum (ER) Ca²⁺ depletion, induced by sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition, resulted to prolonged Ca²⁺ influx and mitochondrial fragmentation within 10 to 30 min. This mitochondrial fragmentation could be prevented in Ca2+-free medium or by inhibiting store-operated Ca2+ entry (SOCE). Similarly, attenuation of STIM proteins, which are vital ER Ca2+ sensors, protected mitochondrial morphology. On the molecular level, ER Ca2+ depletion, achieved either by removing extracellular Ca2+ or through acute SERCA inhibition, led to changes in gene expression of about 13% and 41% of the transcriptome within an hour, respectively. Transcriptome changes were associated with universal biological processes such as transcription, differentiation, or cell stress. Strong increase in expression was observed for the transcription factor ATF4, which is under control of the kinase PERK (EIF2AK3), a key protein involved in ER stress. Corroborating these findings, PERK was rapidly phosphorylated in Ca2+-free medium or after acute pharmacological inhibition of SOCE. In summary, resting, homeostatic Ca2+ fluxes prevent immediate-early cell stress and transcriptional reprogramming.
    Keywords:  Calcium signaling; ER calcium; ER calcium leak; Mitochondrial fragmentation; Resting calcium fluxes; Store-operated calcium entry; Transcriptome changes
    DOI:  https://doi.org/10.1007/s00018-025-05745-2
  9. Cell Rep. 2025 Jun 19. pii: S2211-1247(25)00659-X. [Epub ahead of print]44(7): 115888
    Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
    Chul-Hong Park, Minsung Park, Miranda E Kelly, Helia Cheng, Sang Ryeul Lee, Cholsoon Jang, Ji Suk Chang.
      Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FAs) and glucose under cold stress but favors FAs as the primary fuel for heat production. It remains unclear how BAT steers fuel preference toward FAs over glucose. Here, we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the β-adrenergic receptor-PKA-PGC-1α axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FAs under cold conditions.
    Keywords:  CP: Metabolism; GOT1; NADH shuttle; PGC-1α; brown adipocytes; fatty acid oxidation; glucose oxidation; glutamic oxaloacetic transaminase 1; glycolysis; malate-aspartate shuttle; mitochondrial thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115888
  10. Nat Cell Biol. 2025 Jun;27(6): 890-901
    Shaping the composition of the mitochondrial outer membrane.
    Gayathri Muthukumar, Jonathan S Weissman.
      Mitochondria are critical double-membraned organelles that act as biosynthetic and bioenergetic cellular factories, with the outer membrane providing an interface with the rest of the cell. Mitochondrial outer membrane proteins regulate a variety of processes, including metabolism, innate immunity and apoptosis. Although the biophysical and functional diversity of these proteins is highly documented, the mechanisms of their biogenesis and the integration of that into cellular homeostasis are just starting to take shape. Here, focusing on α-helical outer membrane proteins, we review recent insights into the mechanisms of synthesis and cytosolic chaperoning, insertion and assembly in the lipid bilayer, and quality control of unassembled or mislocalized transmembrane domains. We further discuss the role convergent evolution played in this process, comparing key biogenesis players from lower eukaryotes, including yeast and trypanosomes, with multicellular metazoan systems, and draw comparisons with the endoplasmic reticulum biogenesis system, in which membrane proteins face similar challenges.
    DOI:  https://doi.org/10.1038/s41556-025-01683-0
  11. Nat Commun. 2025 Jun 20. 16(1): 5355
    Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
    Megan R Teh, Nancy Gudgeon, Joe N Frost, Linda V Sinclair, Alastair L Smith, Christopher L Millington, Barbara Kronsteiner, Jennie Roberts, Bryan P Marzullo, Hannah Murray, Alexandra E Preston, Victoria Stavrou, Jan Rehwinkel, Thomas A Milne, Daniel A Tennant, Susanna J Dunachie, Andrew E Armitage, Sarah Dimeloe, Hal Drakesmith.
      Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
    DOI:  https://doi.org/10.1038/s41467-025-60204-7
  12. Cell Rep. 2025 Jun 13. pii: S2211-1247(25)00622-9. [Epub ahead of print]44(6): 115851
    ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.
    Huiyan Ji, Wanwan Jiang, Juan Zhang, Mengdi Liu, Danhua Su, Jiaxin Lei, Lingyi Li, Ming Zheng, Ting Liu, Zhichun Liu, Qinghua Cao, Lin Xu, Sidong Xiong, Zhenke Wen.
      T cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), yet the underlying molecular mechanisms governing their fate remain elusive. Here, we identify cytosolic mitochondrial DNA (mtDNA) as an intrinsic trigger for driving effector T cell differentiation in patients with SLE. Specifically, accumulated cytosolic mtDNA is sensed by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which enhances the transcription of GLUT1 and glycolysis in SLE T cells. This metabolic shift reduces lipogenesis and depletes free fatty acids (FFAs), impairing the N-myristylation and lysosomal localization of AMP-activated protein kinase (AMPK). Inactive AMPK fails to restrain mammalian target of rapamycin complex 1 (mTORC1), leading to its hyperactivation and driving the mal-differentiation of effector T cells. Consequently, interventions targeting ENPP1, glycolysis, AMPK, and mTORC1 effectively inhibit the generation of immunoglobulin (Ig)G anti-double-stranded DNA (dsDNA) and the progression of lupus nephritis in humanized SLE chimeras. Overall, our findings uncover an mtDNA-ENPP1-metabolic axis that governs effector T cell fate in autoimmunity.
    Keywords:  AMPK; CP: Immunology; CP: Molecular biology; ENPP1; SLE; T cell; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.celrep.2025.115851
  13. Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00580-7. [Epub ahead of print]44(6): 115809
    Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
    Jack H Howden, Hanna Hakansson, Manuela Nieto-Rostro, Robyn McAdam, Charles Arber, Nicholas J Brandon, Josef T Kittler.
      Mitochondria are essential for ATP production, calcium buffering, and apoptotic signaling, with mitophagy playing a critical role in removing dysfunctional mitochondria. This study demonstrates that PINK1-dependent mitophagy occurs more rapidly and is less spatially restricted in astrocytes compared to neurons. We identified hexokinase 2 (HK2) as a key regulator of mitophagy in astrocytes, forming a glucose-dependent complex with PINK1 in response to mitochondrial damage. Additionally, exposure to neuroinflammatory stimuli enhances PINK1/HK2-dependent mitophagy, providing neuroprotection. These findings contribute to our understanding of mitophagy mechanisms in astrocytes and underscore the importance of PINK1 in cellular health and function within the context of neurodegenerative diseases.
    Keywords:  CP: Metabolism; CP: Neuroscience; PINK1; Parkinson’s disease; astrocyte; hexokinase; inflammation; metabolism; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2025.115809
  14. Commun Biol. 2025 Jun 17. 8(1): 936
    Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper.
    Elodie Lafargue, Jean-Pierre Duneau, Nicolas Buzhinsky, Pamela Ornelas, Alexandre Ortega, Varun Ravishankar, James Sturgis, Ignacio Casuso, Lucie Bergdoll.
      VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid-protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.
    DOI:  https://doi.org/10.1038/s42003-025-08311-5
  15. Elife. 2025 Jun 17. pii: RP100604. [Epub ahead of print]13
    Glycolytic flux controls retinal progenitor cell differentiation via regulating Wnt signaling.
    Joseph Hanna, Yacine Touahri, Alissa Pak, Lauren Belfiore, Edwin van Oosten, Luke Ajay David, Sisu Han, Yaroslav Ilnytskyy, Igor Kovalchuk, Deborah Kurrasch, Satoshi Okawa, Antonio Del Sol, Robert A Screaton, Isabelle Aubert, Carol Schuurmans.
      Metabolic pathways are remodeled in response to energy and other homeostatic demands and are dynamically regulated during embryonic development, suggesting a role in guiding cellular differentiation. Here, we show that glycolytic flux is required and sufficient to bias multipotent retinal progenitor cells (RPCs) to acquire a rod photoreceptor fate in the murine retina. In RPC-specific Phosphatase and tensin homolog conditional knockout (Pten-cKO) and RPC-specific conditional gain-of-function of dominant active PFKFB3 (cytoPFKFB3) mice, glycolytic gene expression and activity are elevated, correlating with precocious rod photoreceptor differentiation and outer segment (OS) maturation. Conversely, glycolytic inhibition in retinal explants suppresses RPC proliferation and photoreceptor differentiation, achieved either with 2-deoxy-D-glucose, a competitive inhibitor of glucose metabolism, by lowering media pH, which disables PKM2, a rate-limiting enzyme, or by inhibiting lactate/H+ symporters, which lowers intracellular pH. Mechanistically, we show that Wnt signaling, the top-upregulated pathway in Pten-cKO retinas, is a glycolysis-dependent pathway. Pharmacological and genetic perturbation of Wnt signaling by knocking-out Ctnnb1, encoding β-catenin, phenocopies glycolytic inhibition, suppressing RPC proliferation, photoreceptor differentiation, and OS maturation. Thus, developmental rewiring of glycolytic flux modulates Wnt signaling to drive rod photoreceptor differentiation and maturation, an instructive role that may be exploited therapeutically for cell replacement strategies.
    Keywords:  Pten; Wnt signaling; developmental biology; glycolysis; intracellular pH; mouse; photoreceptor differentiation; retinal progenitor cells
    DOI:  https://doi.org/10.7554/eLife.100604
  16. Cell Death Dis. 2025 Jun 19. 16(1): 460
    PUMA reduces FASN ubiquitination to promote lipid accumulation and tumor progression in human clear cell renal cell carcinoma.
    Qianqian Luo, Qi Wang, Jian Shi, Qingyang Lv, Zirui Dong, Wen Li, Yaru Xia, Jingchong Liu, Hongmei Yang.
      While the p53 upregulated modulator of apoptosis (PUMA) is traditionally recognized for promoting cell apoptosis and enhancing chemotherapy efficacy in various cancers, its role in clear cell renal cell carcinoma (ccRCC) remains unclear due to ccRCC's chemotherapy resistance. In this study, we discover a novel oncogenic role for PUMA in ccRCC, diverging from its known apoptotic function, through assessments of public datasets, clinical tissue samples, and cell line experiments. Abnormally high expression of PUMA positively correlates with clinical stages and poor prognosis. Notably, PUMA's role in ccRCC appears to be independent of apoptosis. Instead, it facilitates tumor progression and lipid accumulation through mechanisms involving the key metabolic regulator, fatty acid synthase (FASN). Specifically, the N44-102 amino acid sequence of PUMA, distinct from the previously studied BH3 domain, is crucial for its interaction with FASN. As a mechanism, PUMA stabilizes FASN by binding to ubiquitin-specific protease 15 (USP15), reducing FASN ubiquitination and degradation, thereby forming the PUMA-USP15-FASN axis. These findings challenge the established view of PUMA's role in cancer biology. Furthermore, PUMA knockdown significantly inhibits tumor growth and enhances the sensitivity of ccRCC tumors to metabolic inhibition. These results position PUMA as a novel metabolic regulator and a potential therapeutic target in ccRCC. The combined inhibition of PUMA and FASN further supports the therapeutic potential of targeting this metabolic axis.
    DOI:  https://doi.org/10.1038/s41419-025-07782-y
  17. Sci Adv. 2025 Jun 20. 11(25): eadv2417
    The RNA demethylase FTO promotes glutamine metabolism in clear cell renal cell carcinoma through the regulation of SLC1A5.
    Man Zhao, Dalin Zhang, Haowen Jiang, Nishanth Kuganesan, Suchitra Natarajan, Leighton Pu, Kaushik N Thakkar, Hongjuan Zhao, Quynh Thu Le, Amato J Giaccia, James D Brooks, Donna M Peehl, Jiangbin Ye, Erinn B Rankin.
      Glutamine reprogramming plays a crucial role in the growth and survival of clear cell renal cell carcinoma (ccRCC), although the mechanisms governing its regulation are still not fully understood. We demonstrate that the RNA demethylase fat mass and obesity-associated gene (FTO) drives glutamine reprogramming to support ccRCC growth and survival. Genetic and pharmacologic inhibition of FTO in ccRCC cells impaired glutamine-derived reductive carboxylation, depleted pyrimidines, and increased reactive oxygen species. This led to increased DNA damage and reduced survival, which could be rescued by pyrimidine nucleobases or the antioxidant N-acetylcysteine. Mechanistically, FTO demethylates the glutamine transporter solute carrier family 1 member 5 (SLC1A5) messenger RNA to promote its expression. Restoration of SLC1A5 expression in FTO-knockdown cells rescued metabolic and survival defects. FTO inhibition reduced ccRCC tumor xenograft and PDX growth under the renal capsule. Our findings indicate that FTO is an epitranscriptomic regulator of ccRCC glutamine reprogramming and highlight the therapeutic potential of targeting FTO for the treatment of ccRCC.
    DOI:  https://doi.org/10.1126/sciadv.adv2417
  18. J Neurochem. 2025 Jun;169(6): e70121
    Brain Adenylosuccinate Is Dramatically Increased Under Global Ischemia Without Evidence for Purine Nucleotide Cycle Activation.
    Drew R Seeger, Brennon Schofield, Derek Besch, Svetlana A Golovko, Peddanna Kotha, Mikhail Y Golovko.
      It is well documented that adenosine and adenine nucleotides, such as ATP, ADP, and AMP, undergo significant alterations within seconds upon brain ischemia. For their accurate quantification, in situ deactivation of enzymes involved in their metabolism is required to prevent postmortem alterations. Thus, techniques such as high energy head-focused microwave irradiation (MW) or freeze-blowing are often used prior to metabolome analysis. However, alterations of another important purine nucleotide, adenylosuccinate (AdSucc), under brain ischemia have not been previously addressed. AdSucc is an intermediate in purine nucleotide de novo synthesis. Over 50 years ago, it was also proposed to have a role in brain energy metabolism through the purine nucleotide cycle (PNC) similar to that in muscle, with, to the best of our knowledge, no follow-up studies. In the present study, we applied MW and LC-MS analysis for mouse brain AdSucc quantification in situ at baseline and upon 30 s, 2 min, and 10 min of global ischemia. Our data indicate that in situ enzyme deactivation is required for brain AdSucc quantification. We report, for the first time, that brain AdSucc is dramatically increased 19-fold at 30 s ischemia and 77-fold at 2 min, from 0.007 ± 0.001 to 0.136 ± 0.026 and 0.555 ± 0.036 nmol/mg of brain wet weight (ww), respectively, without further increase at 10 min, positioning it as one of the major brain metabolites under ischemia (~0.56 mM). Quantification of PNC and tricarboxylic acid cycle (TCA) metabolites did not support the role of AdSucc induction in the activation of these pathways under ischemia. Importantly, a significant AdSucc increase up to ~0.56 mM did not affect its precursor aspartate (Asp), which remained at ~1 mM (0.923 ± 0.036 nmol/mg ww) during ischemia, indicating that AdSucc is not produced by the condensation reaction between Asp and IMP in the PNC catalyzed by adenylosuccinate synthase (ADSS). Further studies are required to elucidate the mechanisms for AdSucc increase and its role under brain ischemia.
    Keywords:  adenylosuccinate; brain; ischemia; microwave irradiation; purine nucleotide cycle; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1111/jnc.70121
  19. Nat Commun. 2025 Jun 17. 16(1): 5328
    Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
    Prince Saforo Amponsah, Jan-Eric Bökenkamp, Olha Kurpa, Svenja Lenhard, Anna Myronova, Daniel Osmar Vega Velazquez, Celina Hirschelmann, Christian Behrends, Johannes M Herrmann, Markus Räschle, Zuzana Storchová.
      Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-60857-4
  20. Neuron. 2025 Jun 18. pii: S0896-6273(25)00425-8. [Epub ahead of print]113(12): 1847-1849
    ACLY links mutant α-synuclein to metabolism, autophagy and neurodegeneration.
    Frédéric Saudou.
      In this issue of Neuron, Son et al.1 reveal how pathologic α-synuclein inhibits autophagy, leading to neurodegeneration. Their work highlights the key roles of the acetyl-CoA-producing enzyme ACLY and aberrant cytoplasmic p300 acetylation, uncovering new therapeutic strategies for Parkinson's disease.
    DOI:  https://doi.org/10.1016/j.neuron.2025.05.027
  21. Elife. 2025 Jun 16. pii: e107882. [Epub ahead of print]14
    Multiple roles for a mitochondrial enzyme.
    Xicong Tang, Hongyu Qiu.
      The enzyme arginase-II has an important role in cardiac aging, and blocking it could help hearts stay young longer.
    Keywords:  aging; arginase; fibrosis; heart; human; inflammation; macrophages; medicine; mouse; rat
    DOI:  https://doi.org/10.7554/eLife.107882
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