2025
Metabolic cross-feeding of a dietary antioxidant enhances anaerobic energy metabolism by human gut bacteria
Zhou Z, Jiang A, Jiang X, Hatzios S. Metabolic cross-feeding of a dietary antioxidant enhances anaerobic energy metabolism by human gut bacteria. Cell Host & Microbe 2025, 33: 1321-1332.e9. PMID: 40763732, DOI: 10.1016/j.chom.2025.07.008.Peer-Reviewed Original ResearchConceptsHuman gut bacteriaCross-feedingGut bacteriaHuman fecal microbial communitiesDegradation of complex carbohydratesMetabolic cross-feedingFecal microbial communitiesMicrobial energy metabolismEnergy metabolismFecal metagenomesClostridium symbiosumBacteroides xylanisolvensMicrobial communitiesAnaerobic respirationATP synthesisAnaerobic energy metabolismBacteriaComplex carbohydratesAnaerobic conditionsDietary compoundsGutDisease riskMetabolismMetagenomicsPhylaTriglycerides are an important fuel reserve for synapse function in the brain
Kumar M, Wu Y, Knapp J, Pontius C, Park D, Witte R, McAllister R, Gupta K, Rajagopalan K, De Camilli P, Ryan T. Triglycerides are an important fuel reserve for synapse function in the brain. Nature Metabolism 2025, 7: 1392-1403. PMID: 40595405, PMCID: PMC12286841, DOI: 10.1038/s42255-025-01321-x.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsBrainEnergy MetabolismFatty AcidsLipaseMaleMiceMice, Inbred C57BLMitochondriaNeuronsSynapsesTriglyceridesConceptsLipid dropletsFatty acidsMitochondrial ATP productionFunction in vivoActivity-dependent fashionNerve terminalsATP productionNeuronal function in vivoSynapse functionAdult male miceTriglyceride lipaseIn vivo neuronsDDHD2Neuronal bioenergeticsMale miceAcute blockElectrical silenceMetabolic supportNeuronsNerveFuel reservesElectrical activityMitochondriaCognitive functionBioenergeticsATP-gated P2x7 receptors express at type II auditory nerves and required for efferent hearing control and noise protection
Liang C, Zhai T, Chen J, Fang S, Zhu Y, Liu L, Yu N, Zhao H. ATP-gated P2x7 receptors express at type II auditory nerves and required for efferent hearing control and noise protection. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2421995122. PMID: 40540593, PMCID: PMC12207453, DOI: 10.1073/pnas.2421995122.Peer-Reviewed Original ResearchConceptsCochlear efferent systemHearing sensitivityATP-gated P2X7 receptorP2X7 receptorOuter hair cellsAuditory nerveInnervate outer hair cellsEfferent systemAuditory brainstem responseSpiral ganglion (SGActive cochlear amplificationActive cochlear mechanicsEfferent nervesP2X7 KO miceIncreased susceptibility to noiseSusceptibility to noiseNeuronal functionAcoustic startle responseHair cellsBrainstem responseHearing lossEfferent suppressionHearing disordersOHC electromotilityNoise exposureHierarchical glycolytic pathways control the carbohydrate utilization regulator in human gut Bacteroides
Kabonick S, Verma K, Modesto J, Pearce V, Winokur K, Groisman E, Townsend G. Hierarchical glycolytic pathways control the carbohydrate utilization regulator in human gut Bacteroides. Nature Communications 2025, 16: 4488. PMID: 40368925, PMCID: PMC12078602, DOI: 10.1038/s41467-025-59704-3.Peer-Reviewed Original ResearchConceptsFructose-1,6-bisphosphateMammalian gutGut BacteroidesBacterial phylumGut microbiomeIntestinal colonizationTranscription factorsGlycolytic pathwayBacteroides speciesCarbohydrate utilizationHost immunomodulationGutCarbohydrateCurIntestinal disordersFructoseHostRegulationAbundant amountSugarPhylumBacteroidetesMicrobiomeBacteroidesTranscriptionHigh-resolution structures of Myosin-IC reveal a unique actin-binding orientation, ADP release pathway, and power stroke trajectory
Chavali S, Carman P, Shuman H, Ostap E, Sindelar C. High-resolution structures of Myosin-IC reveal a unique actin-binding orientation, ADP release pathway, and power stroke trajectory. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2415457122. PMID: 40014570, PMCID: PMC11892617, DOI: 10.1073/pnas.2415457122.Peer-Reviewed Original ResearchMeSH KeywordsActinsAdenosine DiphosphateAdenosine TriphosphateAnimalsCryoelectron MicroscopyModels, MolecularMyosin Type IProtein BindingProtein ConformationConceptsN-terminal extensionATP bindingRegulating ATP bindingADP releaseClass I myosinsLever arm swingStructure of myosinCryo-EM structureHigh-resolution structuresMembrane-bound vesiclesActin interfaceMyosin superfamilyMyosin familyActin filamentsAbsence of ADPMembrane remodelingNucleotide pocketMotile behaviorMyo1cPlasma membraneBiological functionsActinCryo-EM dataMotor domainMyosinMicroglia modulate the cerebrovascular reactivity through ectonucleotidase CD39
Fu Z, Ganesana M, Hwang P, Tan X, Kinkaid M, Sun Y, Bian E, Weybright A, Chen H, Sol-Church K, Eyo U, Pridans C, Quintana F, Robson S, Kumar P, Venton B, Schaefer A, Kuan C. Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39. Nature Communications 2025, 16: 956. PMID: 39843911, PMCID: PMC11754601, DOI: 10.1038/s41467-025-56093-5.Peer-Reviewed Original ResearchConceptsCerebral blood flowEctonucleotidases CD39Whisker stimulationResponse to whisker stimulationCerebrovascular reactivityDeletion of CD39Blood flowInjection of adenosine triphosphateModulation of cerebral blood flowRegulation of cerebral blood flowExtracellular adenosine triphosphateInjection of adenosineBorder-associated macrophagesMicroglia repopulationExtracellular adenosineAdenosine triphosphateFemale miceBlood flow anomaliesP2RY12 receptorCo-transmitterMouse modelPharmacological inhibitionCD39MicrogliaMiceStructural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2
Koide E, Pietz H, Beltran J, Chen J. Structural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2. Nature Communications 2025, 16: 484. PMID: 39779684, PMCID: PMC11711199, DOI: 10.1038/s41467-024-55810-w.Peer-Reviewed Original ResearchConceptsAutoinhibited stateR domainPost-translocation stateSubstrate-binding sitePre-translocation stateATP-binding siteProtein 2Nucleotide-binding domain 2Cryogenic electron microscopyStructural basisDiverse array of compoundsDomain 2Cryo-EMRegulation mechanismChemotherapeutic resistanceConformational changesMultidrug resistanceArray of compoundsDiverse arrayConformational statesLiver homeostasisMultidrug resistance-associated protein 2Initial transportSubstrateCytosol
2024
Development of a 31P magnetic resonance spectroscopy technique to quantify NADH and NAD+ at 3 T
Mevenkamp J, Bruls Y, Mancilla R, Grevendonk L, Wildberger J, Brouwers K, Hesselink M, Schrauwen P, Hoeks J, Houtkooper R, Buitinga M, de Graaf R, Lindeboom L, Schrauwen-Hinderling V. Development of a 31P magnetic resonance spectroscopy technique to quantify NADH and NAD+ at 3 T. Nature Communications 2024, 15: 9159. PMID: 39443469, PMCID: PMC11499639, DOI: 10.1038/s41467-024-53292-4.Peer-Reviewed Original ResearchConceptsPhysically active older adultsActive older adultsMetabolic healthHuman skeletal musclePhosphorous magnetic resonance spectroscopySedentary individualsOlder adultsStimulate mitochondrial biogenesisHealthSkeletal muscleMitochondrial biogenesisNAD+Physiological decreaseNADH contentNADHQuantify NADHClinical 3Magnetic resonance spectroscopy techniquesMR sequencesAdultsMeasurement reproducibilityAstrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis
Ardanaz C, de la Cruz A, Minhas P, Hernández-Martín N, Pozo M, Valdecantos M, Valverde Á, Villa-Valverde P, Elizalde-Horcada M, Puerta E, Ramírez M, Ortega J, Urbiola A, Ederra C, Ariz M, Ortiz-de-Solórzano C, Fernández-Irigoyen J, Santamaría E, Karsenty G, Brüning J, Solas M. Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis. Science Advances 2024, 10: eadp1115. PMID: 39423276, PMCID: PMC11488540, DOI: 10.1126/sciadv.adp1115.Peer-Reviewed Original ResearchConceptsPeripheral glucose homeostasisBrain glucose metabolismGlucose metabolismAstrocytic glucose transporterGlucose homeostasisPeripheral glucose metabolismSystemic glucose metabolismATP releasePurinergic signalingBlood-borne glucoseBrain metabolismAstrocytesBrain energeticsInsulin signalingCognitive functionGlucose transportBrain functionMiceBrainGLUT1MetabolismHomeostasisObesityOrganization of a functional glycolytic metabolon on mitochondria for metabolic efficiency
Wang H, Vant J, Zhang A, Sanchez R, Wu Y, Micou M, Luczak V, Whiddon Z, Carlson N, Yu S, Jabbo M, Yoon S, Abushawish A, Ghassemian M, Masubuchi T, Gan Q, Watanabe S, Griffis E, Hammarlund M, Singharoy A, Pekkurnaz G. Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency. Nature Metabolism 2024, 6: 1712-1735. PMID: 39261628, PMCID: PMC12282641, DOI: 10.1038/s42255-024-01121-9.Peer-Reviewed Original ResearchConceptsO-GlcNAc transferaseO-GlcNAcylation sitesGlycolytic metabolonO-GlcNAcylationEnzyme O-GlcNAc transferaseOuter mitochondrial membraneDynamic O-GlcNAcylationPost-translational modificationsReduced ATP generationMitochondrial ATP productionMetabolic efficiencyEnergy-demanding tissuesCellular energy sourceOGT activityMitochondrial associationRegulatory domainMitochondrial membraneMultiple cell typesATP generationATP productionMitochondrial functionMitochondrial couplingMetabolonCell typesGlucose fluxPhosphoglycerate kinase is a central leverage point in Parkinson’s disease–driven neuronal metabolic deficits
Kokotos A, Antoniazzi A, Unda S, Ko M, Park D, Eliezer D, Kaplitt M, De Camilli P, Ryan T. Phosphoglycerate kinase is a central leverage point in Parkinson’s disease–driven neuronal metabolic deficits. Science Advances 2024, 10: eadn6016. PMID: 39167658, PMCID: PMC11338267, DOI: 10.1126/sciadv.adn6016.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsEnergy MetabolismGlycolysisHumansMiceNeuronsParkinson DiseasePhosphoglycerate KinaseConceptsPhosphoglycerate kinase 1Metabolic deficitsExpressions of Phosphoglycerate Kinase 1Dopamine axonsParkinson's diseasePD-associated pathologyViral expressionLoss of functionNeuronal glycolysisSusceptibility lociIn vivoFamilial Parkinson's diseasePD therapeuticsMetabolic lesionsProduction kineticsKinase 1Mitochondrial integrityPhosphoglycerate kinaseBioenergetic deficitsSynaptic dysfunctionGenetic originDeficitsPARK7/DJ-1PhosphoglycerateMechanism of phosphate release from actin filaments
Wang Y, Wu J, Zsolnay V, Pollard T, Voth G. Mechanism of phosphate release from actin filaments. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2408156121. PMID: 38980907, PMCID: PMC11260136, DOI: 10.1073/pnas.2408156121.Peer-Reviewed Original ResearchMeSH KeywordsActin CytoskeletonActinsAdenosine TriphosphateCryoelectron MicroscopyHydrogen BondingMagnesiumMolecular Dynamics SimulationPhosphatesConceptsCryo-EM structureAll-atom molecular dynamics simulationsATP-actinRate of phosphate releaseActin filamentsMechanism of phosphate releaseMolecular dynamics simulationsPhosphate releaseDissociation of phosphateR177Salt bridgesHydrogen bondsEnergy barrierDynamics simulationsComputational studyRelease of phosphateFilamentsRelease pathwayInternal cavityResiduesStudy residuesOccluding interactionsGatePrimary eventD179A metabolic dependency of EBV can be targeted to hinder B cell transformation
Müller-Durovic B, Jäger J, Engelmann C, Schuhmachers P, Altermatt S, Schlup Y, Duthaler U, Makowiec C, Unterstab G, Roffeis S, Xhafa E, Assmann N, Trulsson F, Steiner R, Edwards-Hicks J, West J, Turner L, Develioglu L, Ivanek R, Azzi T, Dehio P, Berger C, Kuzmin D, Saboz S, Mautner J, Löliger J, Geigges M, Palianina D, Khanna N, Dirnhofer S, Münz C, Bantug G, Hess C, Berger C, Hess C, Koller M, Rossi S, Stampf S, Müller N. A metabolic dependency of EBV can be targeted to hinder B cell transformation. Science 2024, 385: eadk4898. PMID: 38781354, DOI: 10.1126/science.adk4898.Peer-Reviewed Original ResearchConceptsEpstein-Barr virusIndoleamine 2,3-dioxygenase 1B-cell transformationB cellsEBV-driven B-cell transformationIndoleamine 2,3-dioxygenase 1 expressionIndoleamine 2,3-dioxygenase 1 inhibitionInfection of B cellsEBV-infected B cellsEnzyme indoleamine 2,3-dioxygenase 1Epstein-Barr virus protein EBNA2Increased IDO1 activityNicotinamide adenine dinucleotideDevelopment of lymphomaEBV-related diseasesInfected B cellsHumanized miceTransplant patientsImmune dysregulationAdenosine triphosphateMitochondrial complex I activityComplex I activityMetabolic vulnerabilitiesIDO1 activitySerum signatureF-actin architecture determines the conversion of chemical energy into mechanical work
Sakamoto R, Murrell M. F-actin architecture determines the conversion of chemical energy into mechanical work. Nature Communications 2024, 15: 3444. PMID: 38658549, PMCID: PMC11043346, DOI: 10.1038/s41467-024-47593-x.Peer-Reviewed Original ResearchMeSH KeywordsActin CytoskeletonActinsAdenosine TriphosphateAnimalsBiomechanical PhenomenaHydrolysisMyosin Type IIMyosinsRabbitsConceptsF-actin architectureF-actinATP consumption rateF-actin bundlesIn vitro reconstitutionDynamic cellular processesHigher ATP consumptionActin cytoskeletonFilamentous actinMyosin motorsCellular processesATP hydrolysisPurified componentsAdenosine triphosphateForce generationConversion of chemical energyATP consumptionConsumption rateActinChemical energyMyosinNetwork contractionCytoskeletonEnergetic principlesHydrolysisGlucose Regulation of β-Cell KATP Channels: It Is Time for a New Model!
Merrins M, Kibbey R. Glucose Regulation of β-Cell KATP Channels: It Is Time for a New Model! Diabetes 2024, 73: 856-863. PMID: 38768366, PMCID: PMC11109790, DOI: 10.2337/dbi23-0032.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsGlucoseGlycolysisHumansInsulinInsulin SecretionInsulin-Secreting CellsKATP ChannelsModels, BiologicalOxidative PhosphorylationConceptsB-cell metabolismInsulin secretionEfficiency of mitochondrial ATP productionModel of glucose-stimulated insulin secretionGlucose-stimulated insulin secretionMitochondrial ATP productionNADPH productionGenetic evidenceInitial insulin secretionATP productionGlycolytic enzymesOXPHOSPyruvate kinaseATP/ADP ratioHealthy B cellsKATP channel closureB cellsDiabetes pathophysiologyGlycolysisStoichiometric yieldKATP channelsBioenergeticsATP/ADPMembrane depolarizationMetabolism
2023
Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus
MacColl Garfinkel A, Mnatsakanyan N, Patel J, Wills A, Shteyman A, Smith P, Alavian K, Jonas E, Khokha M. Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus. Developmental Cell 2023, 58: 2597-2613.e4. PMID: 37673063, PMCID: PMC10840693, DOI: 10.1016/j.devcel.2023.08.015.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsHypoxiaHypoxia-Inducible Factor 1, alpha SubunitMitochondriaOrganizers, EmbryonicXenopus laevisConceptsSpemann-Mangold organizerATP productionMitochondrial respirationC subunit ringHIF-1αMitochondrial oxidative metabolismEmbryonic patterningCell fateATP synthaseC subunitVentral mesodermHIF-1α activationInstructive roleHypoxia-inducible factor-1αΒ-cateninGeneral mechanismXenopusFactor-1αRespirationMembrane leakOxidative metabolismMetabolismMesodermActivationOxygen consumptionMitochondrial uncouplers impair human sperm motility without altering ATP content
Skinner W, Petersen N, Unger B, Tang S, Tabarsi E, Lamm J, Jalalian L, Smith J, Bertholet A, Xu K, Kirichok Y, Lishko P. Mitochondrial uncouplers impair human sperm motility without altering ATP content. Biology Of Reproduction 2023, 109: 192-203. PMID: 37294625, PMCID: PMC10427809, DOI: 10.1093/biolre/ioad064.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateContraceptive AgentsEthanolamineEthanolaminesHumansMaleMitochondriaNiclosamideProtonsSemenSperm MotilitySpermatozoaConceptsSperm mitochondriaAdenosine triphosphate productionHuman spermSperm motilityNiclosamide ethanolaminePlasma membraneMitochondrial uncouplingSperm physiological processesSperm mitochondrial functionHuman sperm motilitySperm adenosine triphosphateSperm progressive motilityPhysiological processesATP-independent mechanismAdenosine triphosphateSperm functionProgressive motilityHuman spermatozoaSperm fertilitySmall molecule mitochondrial uncouplersSpermPlasma membrane potentialMitochondrial functionMitochondriaMotilityA macrocyclic peptide inhibitor traps MRP1 in a catalytically incompetent conformation
Pietz H, Abbas A, Johnson Z, Oldham M, Suga H, Chen J. A macrocyclic peptide inhibitor traps MRP1 in a catalytically incompetent conformation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2220012120. PMID: 36893260, PMCID: PMC10089224, DOI: 10.1073/pnas.2220012120.Peer-Reviewed Original ResearchConceptsMultidrug resistance protein 1MRP1 overexpressionSubstrate transportAdenosine triphosphate-binding cassetteCatalytically incompetent conformationStructurally unrelated moleculesCpI1Small molecule inhibitorsAdenosine triphosphatePlasma membraneA-resolutionCryoelectron microscopyCryo-EMUnrelated moleculesConformational changesMultidrug resistanceMRP1 functionProtein 1Macrocyclic peptidesMultidrug transporter P-glycoproteinFlexible sidechainsXenobiotic compoundsNanomolar potencyCellular toxicityTherapeutic candidate
2022
Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations
van Alderwerelt van Rosenburgh I, Lu D, Grant M, Stayrook S, Phadke M, Walther Z, Goldberg S, Politi K, Lemmon M, Ashtekar K, Tsutsui Y. Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations. Nature Communications 2022, 13: 6791. PMID: 36357385, PMCID: PMC9649653, DOI: 10.1038/s41467-022-34398-z.Peer-Reviewed Original ResearchStructures of the CcmABCD heme release complex at multiple states
Li J, Zheng W, Gu M, Han L, Luo Y, Yu K, Sun M, Zong Y, Ma X, Liu B, Lowder EP, Mendez DL, Kranz RG, Zhang K, Zhu J. Structures of the CcmABCD heme release complex at multiple states. Nature Communications 2022, 13: 6422. PMID: 36307425, PMCID: PMC9616876, DOI: 10.1038/s41467-022-34136-5.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateBacterial Outer Membrane ProteinsBacterial ProteinsCytochromes cEscherichia coliEscherichia coli ProteinsHemeHemeproteinsConceptsHigh-resolution cryo-EM structuresResolution cryo-EM structureABC transporter complexAttachment of hemeCryo-EM structureLarge membrane complexesHeme-binding siteATP-binding siteATP-dependent releaseTransfer of hemeC-type cytochromesHeme chaperoneHeme traffickingCytochrome c proteinMembrane proteinsHeme transferTransporter complexMembrane complexATP hydrolysisStructural basisC proteinAMP-PNPFunctional studiesHeme releaseUnbound form
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