bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–05–10
twenty papers selected by
Marc Segarra Mondejar, AINA
  1. The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.
  2. FILM: mapping organellar metabolism by mid-infrared photothermal-modulated fluorescence.
  3. How membranes shape up for lipid transfer.
  4. Inflammatory CD4+ T cells can waive NRF2-dependent SLC7A11-mediated cystine uptake by using ASCT1.
  5. Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
  6. All-in-One Fluorescent Probe: Enabling Simultaneous Tracking of Multiple Dynamic Organellar Perturbations during Ferroptosis.
  7. Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
  8. Mitochondrially tethered Mmm1 can function as a sole lipid transporter at ER-mitochondria contacts.
  9. HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content.
  10. Time-resolved tmFRET reveals GTP-coupled conformational changes in Mfn1.
  11. Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
  12. Tumour-driven lipid accumulation in oenocytes reflects systemic lipid alterations.
  13. Tracking Synaptic Vesicles in Live Neurons Using Single-Molecule Super-resolution Microscopy.
  14. A Red Fluorescent Genetically Encoded Biosensor for the Visualization of ATP in Live Cells.
  15. Fluorescent non-canonical amino acid as a site-specific conformational probe of prion formation.
  16. Bioengineered systems to exploit tumor microenvironment metabolism.
  17. Metabolic reprogramming in aortic diseases: insights from metabolomics and therapeutic opportunities.
  18. Author Correction: Partial restoration of mitochondrial dysfunction by AAV-Ant1 protects from dilated cardiomyopathy in Ant1-/- plus mtDNA mutant mice.
  19. Single Particle Tracking Photo-Activated Localization Microscopy.
  20. Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
  1. J Biol Chem. 2026 May 06. pii: S0021-9258(26)02000-4. [Epub ahead of print] 113128
    The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.
    Kumar Suresh, Christopher Rainvillee, David E Sterner, Matthew S Goldberg, Tauseef R Butt.
      Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues, and a major source of ATP in high-energy-demand organs such as brain and heart being vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at Serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-Ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health, and neurodegeneration.
    Keywords:  (10): mitochondria; PINK1; Parkin; aging; autophagy; biomarker; mitophagy; neurodegeneration; phospho-ubiquitin; proteasome
    DOI:  https://doi.org/10.1016/j.jbc.2026.113128
  2. Nat Methods. 2026 May 07.
    FILM: mapping organellar metabolism by mid-infrared photothermal-modulated fluorescence.
    Jianpeng Ao, Jiaze Yin, Haonan Lin, Guangrui Ding, Youchen Guan, Marzia Savini, Bethany Weinberg, Dashan Dong, Qing Xia, Zhongyue Guo, Bowen Liu, Biwen Gao, Ji-Xin Cheng, Meng C Wang.
      Metabolism unfolds within specific organelles in eukaryotic cells. Lysosomes are highly metabolically active organelles, and their metabolic states dynamically influence signal transduction, cellular homeostasis and organismal physiopathology. Despite the importance of lysosomal metabolism, a method for its in vivo measurement is currently lacking. Here we report a fluorescence-detected mid-infrared photothermal microscope (FILM) implemented with optical boxcar demodulation, artificial intelligence-assisted data denoising and spectral deconvolution, to map metabolic activity and composition of individual lysosomes in living cells and organisms. Using this method, we uncovered lipolysis and proteolysis heterogeneity across lysosomes within the same cell, as well as early-onset lysosomal dysfunction during organismal aging. In addition, we discovered organelle-level metabolic changes associated with diverse lysosomal storage diseases. This method holds the broad potential to profile metabolic fingerprints of individual organelles within their native context and quantitatively assess their dynamic changes under different physiological and pathological conditions, providing a high-resolution chemical cellular atlas.
    DOI:  https://doi.org/10.1038/s41592-026-03090-1
  3. Elife. 2026 May 07. pii: e111373. [Epub ahead of print]15
    How membranes shape up for lipid transfer.
    Takashi Hirashima, Toshiya Endo.
      The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.
    Keywords:  biochemistry; cardiolipin; chemical biology; lipid transport; mitochondria; none; phosphatidic acid
    DOI:  https://doi.org/10.7554/eLife.111373
  4. iScience. 2026 May 15. 29(5): 115680
    Inflammatory CD4+ T cells can waive NRF2-dependent SLC7A11-mediated cystine uptake by using ASCT1.
    Christopher Thomas Neullens, Sudheendra Hebbar Subramanyam, Gerd Horneff, Tilmann Kallinich, Freya Huijsmans, Jorg van Loosdregt, Bas Vastert, Klaus Tenbrock, Kim Ohl.
      Ferroptosis and lipid peroxidation are associated with inflammatory and pathogenic conditions. However, cell-specific mechanisms and functions are not fully understood. Cysteine is an essential amino acid for T cell activation and proliferation and is required to synthesize glutathione, the most abundant antioxidant molecule in cells. Cysteine is predominantly produced intracellularly after uptake of its oxidized form (cystine) by SLC7A11. In this study, we provide a detailed analysis of lipid peroxidation in human T cells and analyzed functional consequences in the chronic inflammatory condition of childhood arthritis. We found that healthy peripheral blood CD4 T cells are not fully dependent on SLC7A11 expression and cystine uptake to prevent ferroptotic cell death, most likely by switching to ASCT1-mediated cysteine uptake. T cells from patients with JIA have a high ASCT1 expression, which most likely prevents exaggerated lipid peroxidation and enables them to maintain their inflammatory phenotype in challenging environments such as inflamed joints.
    Keywords:  Biochemistry; Cell biology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.115680
  5. Nat Metab. 2026 May 08.
    Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
      
    DOI:  https://doi.org/10.1038/s42255-026-01532-w
  6. Anal Chem. 2026 May 06.
    All-in-One Fluorescent Probe: Enabling Simultaneous Tracking of Multiple Dynamic Organellar Perturbations during Ferroptosis.
    Tian Jiang, Mei-Lin Liu, Lin Lei, Jia-Yao Zhang, Zi-Xin Gong, Xiao-Qi Yu, Kun Li, Jin-Ku Bao, Chuan-Fang Wu, Kang-Kang Yu.
      Ferroptosis is a regulated form of cell death driven by lipid peroxidation, involving intricate crosstalk between subcellular organelles and dynamic microenvironmental perturbations. However, this mechanism remains incompletely elucidated due to the lack of versatile tools enabling the simultaneous monitoring of multiple organelles and their microenvironments. Herein, we report a novel single fluorescent probe (ATBI) that allows concurrent discrimination and visualization of three key subcellular organelles: mitochondria, lysosomes, and lipid droplets (LDs). ATBI lights up mitochondria/lysosomes (∼719 nm) and LDs (∼425 nm) simultaneously with high fidelity at distinctly separated emission wavelengths. Notably, mitochondria and lysosomes can be effectively distinguished by their distinct morphological features and fluorescence lifetimes, while changes in viscosity within mitochondria/lysosomes can be further quantified based on lifetime variations. Using this multifunctional probe, we visualized the dynamic process of Erastin-induced ferroptosis: LD accumulation, increased lysosomal viscosity, and decreased mitochondrial viscosity. Furthermore, we demonstrated that SLC7A11, a key regulatory factor of ferroptosis, restores the normal morphology and viscosity homeostasis of these organelles, highlighting the critical role of maintaining subcellular organellar morphology and microenvironmental stability in resisting ferroptosis.
    DOI:  https://doi.org/10.1021/acs.analchem.5c08096
  7. Nat Metab. 2026 May 04.
    Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
    Madeleine L Hart, David Sokolov, Serwah Danquah, Eric Zheng, Alex D Doan, Kristian Davidsen, David MacPherson, Lucas B Sullivan.
      Decreased availability of the amino acid aspartate constrains cell function across diverse biological contexts, but the temporal interplay between aspartate abundance, downstream metabolic changes and functional effects remains poorly understood. Here we show that succinate dehydrogenase (SDH) inhibition suppresses pyrimidine synthesis via dual effects of cellular aspartate depletion and succinate accumulation. Using an aspartate biosensor and live-cell imaging, we monitor aspartate levels and cell proliferation across several models of aspartate limitation. While complex I inhibition or knockout of aspartate biosynthetic enzymes lead to a strict decrease in aspartate levels and impair proliferation, SDH inhibition produces a unique aspartate rebound, yet fails to restore proliferation. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis via succinate accumulation, which competitively inhibits aspartate utilization by mammalian aspartate transcarbamylase (ATCase), a key step in pyrimidine biosynthesis. This metabolic interaction occurs in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress and sensitivity to ATR kinase inhibition. Taken together, these findings define an unexpected role for succinate in modulating cellular nucleotide homeostasis and demonstrate how cascading metabolic interactions can unfold to impact cell function.
    DOI:  https://doi.org/10.1038/s42255-026-01524-w
  8. J Cell Biol. 2026 Jul 06. pii: e202411196. [Epub ahead of print]225(7):
    Mitochondrially tethered Mmm1 can function as a sole lipid transporter at ER-mitochondria contacts.
    Christian Covill-Cooke, Takashi Hirashima, Shin Kawano, Joe Ganellin, Andrew Moody, Sabine N S van Schie, Arun T John Peter, Chika Horie Saito, Toshiya Endo, Benoît Kornmann.
      Yeast mitochondria receive the majority of their lipids from the ER via the heterotetrameric ERMES lipid transport complex. This complex is thought to establish a lipid-transporting bridge of fixed composition spanning the space between both organelles. Intriguingly, however, some of the lipid-transporting components of the complex can be replaced by an artificial ER-mitochondria tether without lipid transport activity, questioning ERMES' relevance in lipid transport. Here, we show that Mmm1, one of the four ERMES subunits, alone is sufficient to support ERMES function when it is artificially tethered to mitochondria, provided its lipid-binding domain is intact. Combined with our previous finding that the absence of Mdm12 and Mdm34 can be rescued by the presence of Mmm1 and the artificial tethering protein ChiMERA, our results suggest that Mmm1 can act as the sole lipid transporter at the ER-mitochondrial contact sites, provided that Mdm10 is present, even in the absence of the other two subunits. Thus, our work reconciles ERMES' importance in lipid transport with the fact that the lipid transport activity of some of its components is not strictly necessary for function.
    DOI:  https://doi.org/10.1083/jcb.202411196
  9. Elife. 2026 May 06. pii: RP104079. [Epub ahead of print]14
    HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content.
    Sara M Frangos, Henver S Brunetta, Dongdong Wang, Maria Joy Therese Jabile, Leslie M Jeffries, Grace Mencfeld, David W L Ma, William J Muller, Cezar M Khursigara, Kelsey H Fisher-Wellman, Jim Petrik, Gregory R Steinberg, Graham P Holloway.
      It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I-IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.
    Keywords:  HER2; bioenergetics; cancer biology; cancer metabolism; cell biology; mitochondria; mouse; proteomics; transcriptomics
    DOI:  https://doi.org/10.7554/eLife.104079
  10. J Cell Biol. 2026 Jul 06. pii: e202511077. [Epub ahead of print]225(7):
    Time-resolved tmFRET reveals GTP-coupled conformational changes in Mfn1.
    Sophie M Hurwitz, William N Zagotta, Sharona E Gordon, Suzanne Hoppins.
      Outer mitochondrial membrane fusion is mediated by the mitofusin paralogs Mfn1 and Mfn2. Nucleotide-driven self-assembly and conformational changes are required for regulated membrane fusion activity, but the allosteric mechanisms remain enigmatic due to incomplete structural information. In this study, we investigate the GTP-coupled conformational dynamics of Mfn1 using time-resolved transition metal ion fluorescence resonance energy transfer (tmFRET). Using the minimal Mfn1 construct with the GTPase domain and helical bundle 1 (HB1) connected by Hinge 2, we engineered FRET pairs by incorporating a fluorescent noncanonical amino acid donor and a metal ion acceptor. For each state of the catalytic cycle, we measured tmFRET with fluorescence lifetimes and determined distance distributions, which can capture complex structural heterogeneity. Our distance measurements for the GDP-bound state matched predictions from the atomic resolution structure, establishing that the same open state, with GTPase and HB1 domains far apart, exists in solution. Our data reveal that the transition state is not a single closed state with HB1 stably contacting the GTPase domain. Rather, the distance distributions indicate that the presence of GDP + Pi results in an equilibrium between the open and closed states. We also captured the GTP-bound and nucleotide-free states of Mfn1. GTP binding favors the open state, and the conformation of the apo state is distinct from any nucleotide-bound state. Together, these findings redefine our understanding of GTP-driven conformational dynamics in Mfn1, demonstrating an unexpected conformational reversal in a single catalytic cycle and a heterogeneous transition state ensemble with implications for the mechanism and regulation of mitochondrial membrane fusion.
    DOI:  https://doi.org/10.1083/jcb.202511077
  11. Nat Metab. 2026 May 08.
    Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
    Zachary L Sebo, Ram P Chakrabarty, Rogan A Grant, Karis B D'Alessandro, Alec R Koss, Jenna L E Blum, Shawn M Davidson, Colleen R Reczek, Navdeep S Chandel.
      Metformin is a versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear. Here we map these and other effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving the uptake of excess glucose and its conversion to lactate and lactoyl-phenylalanine. We also find that glucose lowering by metformin is due to repeated bolus exposure rather than a cumulative chronic response. Notably, the efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.
    DOI:  https://doi.org/10.1038/s42255-026-01530-y
  12. PLoS Genet. 2026 May 07. 22(5): e1012150
    Tumour-driven lipid accumulation in oenocytes reflects systemic lipid alterations.
    Chang Liu, Sofya Golenkina, Natasha Fahey, Priya Kumar, Louise Y Cheng.
      Cancer cachexia is a multifactorial syndrome characterized by systemic metabolic dysfunction, including liver steatosis. In this study, we examined the role of larval oenocytes - hepatocyte-like cells, in a Drosophila model of cancer cachexia. We found that oenocytes in tumour-bearing larvae accumulate lipid droplets in response to tumour-secreted signals, Gbb and ImpL2. This lipid accumulation reflects systemic changes in lipid metabolism, responding to lipid metabolism manipulations in either the fat body or the muscle. Disrupting lipid synthesis/breakdown (via FASN1 and Bmm), storage (via Lsd2), or trafficking (via apolipoproteins) in these tissues significantly modulated lipid droplet accumulation in oenocytes. Moreover, oenocyte-specific knockdown of FASN1 reduced their lipid content and non-autonomously affected lipid droplet size in the fat body, suggesting cross-regulatory interactions between these tissues. Cachectic oenocytes also exhibited altered signaling profiles, characterized by reduced PI3K signalling. Enhancing PI3K signalling through Akt overexpression restored oenocyte size and reduced lipid levels; however, these changes did not significantly improve muscle integrity. Together, our data suggests that dynamic exchange of lipids occur between the fat body, oenocytes and the muscle during cancer cachexia. While the fat body and muscle lipid pools are key regulators of muscle integrity, oenocytes - despite their metabolic responsiveness, do not appear to play an active role in preserving muscle function during cachexia.
    DOI:  https://doi.org/10.1371/journal.pgen.1012150
  13. Methods Mol Biol. 2026 ;3034 189-209
    Tracking Synaptic Vesicles in Live Neurons Using Single-Molecule Super-resolution Microscopy.
    Shanley F Longfield, Frédéric A Meunier.
      Neurotransmitter release relies on the regulated fusion of synaptic vesicles (SVs) that are densely packed within the presynaptic bouton of neurons. The mechanisms by which SVs are clustered at the presynapse while dynamically organizing themselves into different SV pools with distinct fusion probabilities remain unknown. The study of SVs has historically been limited to ultrastructural studies of the presynapse. Examining the nanoscale dynamic organization of SVs in live neurons requires the use of innovative optical labelling approaches, super-resolution microscopy techniques, and appropriate stimulation paradigms that can mimic neuronal physiology. In this chapter, we discuss these aspects by highlighting the use of single-particle tracking photoactivated localization microscopy (sptPALM) to resolve the mobility and clustering of the total pool of SVs, Universal Point Accumulation Imaging in Nanoscale Topography (uPAINT) to study the mobility of SV proteins transiting on the plasma membrane, Dual-pulse subdiffractional Tracking of Internalized Molecules (DsdTIM) to simultaneously track the reserve and recycling pool of SVs and electrical field stimulation for depolarizing primary neurons.
    Keywords:  Electric field stimulation; Endocytosis; Exocytosis; Fluorescence microscopy; Nanobodies; Presynapse; Single particle tracking; Synaptic vesicles; TIRF microscopy
    DOI:  https://doi.org/10.1007/978-1-0716-5268-8_9
  14. ACS Sens. 2026 May 06.
    A Red Fluorescent Genetically Encoded Biosensor for the Visualization of ATP in Live Cells.
    Jianliang Deng, Yu Hou, Rui Gong, Minghai Chen, Peng Peng, Dong Men, Xian-En Zhang.
      Adenosine triphosphate (ATP) serves as the universal energy currency in cellular metabolism. However, real-time analysis of ATP dynamics in prokaryotes remains a challenge due to significant intracellular pH fluctuations and high background interference. To address this, we developed IGAS, a novel genetically encoded biosensor engineered by integrating a binding protein derived from Bacillus subtilis PS3 with the acid-resistant fluorescent protein cpmCherry and miRFP670nano3. Characterization revealed that IGAS exhibits a robust 2.8-fold dynamic range, high selectivity for ATP, and remarkable pH stability. When expressed in E. coli, IGAS enabled real-time monitoring of intracellular ATP fluctuations throughout the bacterial growth cycle, demonstrating high consistency with standard luciferase assays. Furthermore, guided by molecular dynamics (MD) simulations, we identified key residues to engineer IGAS variants with tunable affinities. These sensors were successfully applied to diverse cellular environments, ranging from cytoplasmic targeting to mammalian cell surface display. Collectively, our results demonstrate the excellent reversibility and versatility of IGAS, establishing it as a powerful tool for dynamic ATP detection in complex biological systems.
    Keywords:  ATP; FRET; fluorescence biosensor; live-cell monitoring; synthetic biology
    DOI:  https://doi.org/10.1021/acssensors.5c04623
  15. bioRxiv. 2026 Apr 24. pii: 2026.04.21.719968. [Epub ahead of print]
    Fluorescent non-canonical amino acid as a site-specific conformational probe of prion formation.
    Jessica de Alcantara Ferreira, Daniel J Walsh, Evelyn Turnbaugh, Jeremy H Mills, Surachai Supattapone.
      The pathogenic conversion of the cellular prion protein (PrP C ) into the β-sheet-rich isoform PrP Sc is the pivotal pathogenic event in prion disease, yet the molecular steps that govern this structural transition remain elusive. In this study, we introduce a new approach to monitor site-specific conformational transitions that occur during infectious prion formation. The method relies on genetically encoded substitution of a fluorescent, environmentally sensitive non-canonical amino acid, L-(7-hydroxycoumarin-4-yl)ethylglycine (7-HCAA), into recombinant PrP substate molecules, allowing real-time monitoring of structural changes in high-efficiency in vitro PrP Sc conversion reactions. As proof of principle, we show that the W99 7-HCAA recPrP substate efficiently propagates two different PrP Sc conformers (infectious cofactor PrP Sc and non-infectious protein-only PrP Sc ). Bioassays in knock-in mice expressing bank vole PrP confirm that W99 7-HCAA cofactor PrP Sc produced by serial propagation is infectious, causing scrapie with an incubation period and neuropathological profile like those induced by wild-type cofactor PrP Sc . Marked differences in fluorescence intensity were observed between native, misfolded, and denatured states of W99 7-HCAA PrP, confirming that 7-HCAA reports on local changes in PrP conformation. Together, these findings establish 7-HCAA as a site-specific and sensitive probe of local PrP conformation. Moreover, the results suggest a new and broadly applicable strategy for studying conformational dynamics in amyloid-forming proteins.
    DOI:  https://doi.org/10.64898/2026.04.21.719968
  16. Trends Cancer. 2026 May 07. pii: S2405-8033(26)00078-6. [Epub ahead of print]
    Bioengineered systems to exploit tumor microenvironment metabolism.
    Christine Sanganoo, Ilaria Caturegli, Zachary Mattes, Jordan Ryan, Wilson W Wong, Mark W Grinstaff.
      Our understanding of cancer metabolism has afforded the opportunity to develop therapies specific to tumor metabolic dysregulation. While molecular therapeutics targeting cancer metabolism have found success in the clinic, bioengineering approaches are nascent. Here, we describe key metabolic pathways and their genetic dysregulations in the tumor microenvironment (TME) that are ripe for intervention. We examine bioengineered biomaterial and cellular systems that harness the metabolic and immune landscape of the TME to target metabolic dependencies of tumor growth. These therapeutic strategies include, for example, preventing the uptake of essential metabolites, delivering metabolic inhibitors, and restoring an immunostimulating environment. With a focus toward clinical applications and tolerability, we identify key limitations and conclude with future directions.
    Keywords:  antimetabolite delivery; biomaterials; cancer metabolism; immunosuppressive metabolite modulation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2026.04.003
  17. Med Rev (2021). 2026 Apr;6(2): 142-161
    Metabolic reprogramming in aortic diseases: insights from metabolomics and therapeutic opportunities.
    Yingjie Liu, Linlu Zhao, Chi Zhang, Xiao Ruan, Hualong Yu, Yangpo Cao, Wenhao Ju, Haocheng Lu.
      Aortic diseases (aortic aneurysm, aortic dissection, atherosclerosis) represent a substantial clinical and economic burden due to the lack of effective early diagnostic tools and mechanism-based therapies. Metabolomics, the systematic study of low-molecular-weight metabolites, has emerged as a powerful approach for elucidating pathogenesis, screening candidate biomarkers, and discovering novel drug targets. Rather than merely cataloging metabolic perturbations, this review highlights how metabolic reprogramming, particularly involving amino acid pathways, mitochondrial dysfunction, and gut microbiota-derived metabolites, actively drives aortic pathology. While specific metabolites (e.g., succinate and trimethylamine N-oxide) show promises as prognostic biomarkers, their greatest value lies in revealing actionable therapeutic nodes. Although challenges remain regarding metabolite identification, biological heterogeneity, and clinical translation, continued technological advances and integrative multi-omics approaches offer clear pathways to overcome these barriers. Ultimately, we posit that prioritizing these convergent metabolic axes, especially the gut-vascular interface, could unlock next-generation precision therapies that transcend the limitations of conventional hemodynamic management.
    Keywords:  aortic aneurysm; aortic dissection; atherosclerosis; metabolomics; therapeutic targets
    DOI:  https://doi.org/10.1515/mr-2026-0010
  18. Nat Commun. 2026 May 06. pii: 4103. [Epub ahead of print]17(1):
    Author Correction: Partial restoration of mitochondrial dysfunction by AAV-Ant1 protects from dilated cardiomyopathy in Ant1-/- plus mtDNA mutant mice.
    Alessia Angelin, Kierstin Keller, Peiran Lu, Joseph W Guarnieri, Gabrielle A Widjaja, Rasheed Sule, Kevin Janssen, Arnold Olali, Zimu Cen, Valeria Carosi, Maina Beauplan, Deborah G Murdock, Prasanth Potluri, Liming Pei, Douglas C Wallace.
      
    DOI:  https://doi.org/10.1038/s41467-026-72532-3
  19. Methods Mol Biol. 2026 ;3034 111-144
    Single Particle Tracking Photo-Activated Localization Microscopy.
    Alex J McCann, Christopher Small, Frédéric A Meunier.
      Synaptic neurotransmission is an adaptive process in which synapses exhibit short- and long-term plasticity, dynamically strengthening or weakening their output in response to stimulation. Central to this fine-tuning is the reorganization of synaptic machinery and architecture, with nanoscale alterations in receptor clustering, vesicle trafficking and cytoskeletal rearrangements taking place over a short time frame. Traditionally, visualizing the dynamic organization of the synapse through confocal imaging has been challenging, considering the synapse's small size and the resolution limits imposed by light diffraction. The emergence of super-resolution imaging, and especially single-molecule localization microscopy (SMLM), over the last couple of decades, has allowed scientists to achieve nanoscale resolution and start unravelling the molecular underpinnings of synaptic transmission and plasticity in real-time. One such approach is single particle tracking Photo-Activated Localization Microscopy (sptPALM), which takes advantage of total internal reflection fluorescence (TIRF) and sparse, stochastic activation of fluorophores to achieve low spatiotemporal density labelling required to track single synaptic proteins in real time. In this chapter, we provide a conceptual breakdown of sptPALM: its key principles, implementation, and impact on the field of neurotransmission. Further, we detail a systematic protocol for performing sptPALM imaging of synaptic proteins in primary neuronal cultures. This technique allows the experimenter to determine the mobility, cluster patterns, and behavior of the synaptic proteins with nanoscale localization precision.
    Keywords:  Endocytosis; Exocytosis; Fluorophore; Nanoclustering; Neurotransmission; Photoconversion; Plasma membrane; Single-particle tracking; Synapse; TIRF microscopy
    DOI:  https://doi.org/10.1007/978-1-0716-5268-8_6
  20. Sci Adv. 2026 May 08. 12(19): eaec0795
    Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
    Alice M Ma, Peter H Tran, Nicole L Yang, Jennifer Ngo, Hirotaka Iwasaki, Wenjuan Ren, Simone Livit, Linsey Stiles, Sarah Wang, Trinity Ho, Emma Y Yim, Noelle Morrow, Morgan M Johnson, Caroline Cleary, Kai Zou, Rachelle H Crosbie, Yuwei Jiang, Orian S Shirihai, Jonathan Wanagat, Sushil Mahata, James A Wohlschlegel, Andrea L Hevener, Zhenqi Zhou.
      The maintenance of skeletal muscle mass relies on mitochondrial quality control, including balanced dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a central mediator of mitochondrial fission, is essential for these processes, yet its role in muscle mass regulation remains incompletely defined. Here, we show that acute Drp1 deletion in the skeletal muscle increases Parkin-mediated mitochondrial degradation, reduces mitochondrial DNA (mtDNA) content, and leads to severe muscle atrophy. Although dual deletion of Drp1 and Parkin restores mtDNA content, muscle loss persists. Mechanistically, Drp1 loss impairs mitochondrial respiratory chain activity, suppressing extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and down-regulating the nuclear receptor subfamily 4 group A member 1 (Nur77). Pharmacologic β2-adrenergic receptor activation with clenbuterol reactivated Erk1/2, restored Nur77 expression, and rescued muscle atrophy. These findings define a Drp1-Erk1/2-Nur77 signaling axis linking mitochondrial integrity to skeletal muscle mass and identify a potential therapeutic target for muscle degeneration in mitochondrial and metabolic diseases.
    DOI:  https://doi.org/10.1126/sciadv.aec0795
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