Mitochondrial Fidelity in Mammalian Neurons
哺乳动物神经元的线粒体保真度
基本信息
- 批准号:10592168
- 负责人:
- 金额:$ 12.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AgingAmino AcidsAnimalsArchitectureAxonBiogenesisBiologyBrainBuffersCalciumCell DeathCell physiologyCellsComplexCrista ampullarisDNADendritesDockingEnergy-Generating ResourcesGene ExpressionGene ProteinsGoalsHalf-LifeHeartHomeostasisImpairmentInvestigationKineticsLabelLinkLongevityMaintenanceMass Spectrum AnalysisMeasuresMembraneMetabolicMetabolismMethodsMicrofluidic MicrochipsMitochondriaMitochondrial DNAMitochondrial ProteinsMolecularMolecular TargetMorphologyMusNerve DegenerationNeurodegenerative DisordersNeurodevelopmental DisorderNeurogliaNeuronsNuclearNuclear Pore ComplexOpticsOrganellesPatternPhasePhysiologic pulsePlayPositioning AttributeProcessProductionProtein BiosynthesisProteinsProteomeProteomicsQuality ControlRejuvenationResearchResearch ProposalsRoleSiteStable Isotope LabelingStimulation of Cell ProliferationStructureSynapsesTechniquesTissuesTranslationsTubular formationage related neurodegenerationexperimental studyfitnessfluorescence imaginggenetic manipulationgenome integrityinsightmitochondrial dysfunctionmitochondrial fitnessmitochondrial genomenervous system disordernovelpostmitoticpreservationprotein degradationribosome profilingspatiotemporalsuperresolution microscopyultra high resolution
项目摘要
Summary
Mitochondria are multifaceted organelles that play vital roles in a myriad of cellular functions, including energy
production, metabolism, calcium homeostasis, and cell death. It is generally accepted that a decline in
mitochondria quality is a key contributor to mitochondrial dysfunction, aging, and represents a key point of
convergence for several neurological disorders. Yet, precisely how dysfunctional mitochondria contribute to
these conditions remains elusive. Mitochondria are thought to be constantly rejuvenated via collaborative
processes of mitogenesis, fission-fusion, and multi-level quality-control mechanisms. Accordingly, the average
half-life of mitochondrial proteins in the brain has been estimated at less than 3 weeks. Recently, I identified a
discrete number of mitochondrial long-lived proteins (mt-LLPs) that last at least four months in mouse brain and
heart. These long-lived mitochondrial proteins (mt-LLPs) include OxPhos complexes and several mitochondrial
cristae associated proteins, which similarly to other architecturally stable and long-lived structures (i.e. nuclear
pore complexes) are recognized for their highly defined and elaborate ultrastructure. Therefore, we hypothesized
that the exceptional longevity of mt-LLPs could play an essential role in the long-term stabilization of the
mitochondrial cristae in long-lived, post-mitotic cells.
The goal of this research proposal is to delineate the localization of mt-LLPs within mitochondria in neurons,
examine their temporal dynamics and integration with newly synthesized proteins, and investigate their potential
contribution to mitochondrial fitness and long-term cristae stability. In Aim 1, using a combination of pulse-chase
protein labeling methods, super-resolution fluorescent imaging and mass spectrometry I propose to (1) examine
the spatio-temporal dynamics of mt-LLPs in axonal and somato-dendritic domains of primary neurons. In Aim
2, we propose to extend our analysis to include mitochondrial DNA (mtDNA) by investigating the coordination
between mt-LLPs enrichment and mtDNA longevity neurons. In Aim 3, I will investigate the mechanism(s)
involved in persistence of mt-ELLPs in neurons using genetic manipulations targeting mitochondrial cristae
stability. Lastly, in Aim 4 we will begin the investigation into the coordination between nuclear and mitochondrial
genome expression in neurons. In summary, insights from the proposed experiments will significantly advance
our understanding of long-term of mitochondrial proteome homeostasis and genome integrity in neurons, which
could provide with new molecular targets for modulating the mitochondrial network dynamics in the processes
of neurodegeneration.
总结
项目成果
期刊论文数量(0)
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Ewa Karolina Bomba-Warczak其他文献
Ewa Karolina Bomba-Warczak的其他文献
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{{ truncateString('Ewa Karolina Bomba-Warczak', 18)}}的其他基金
Investigating the role of extremely long-lived mitochondrial proteins in mammalian neurons
研究极长寿命线粒体蛋白在哺乳动物神经元中的作用
- 批准号:
9611350 - 财政年份:2018
- 资助金额:
$ 12.37万 - 项目类别:
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