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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：
Ewa Karolina Bomba-Warczak
金额：
$ 12.37万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
https://reporter.nih.gov/project-details/10592168
关键词：
Aging Amino Acids Animals Architecture Axon Biogenesis Biology Brain Buffers Calcium Cell Death Cell physiology Cells Complex Crista ampullaris DNA Dendrites Docking Energy-Generating Resources Gene Expression Gene Proteins Goals Half-Life Heart Homeostasis Impairment Investigation Kinetics Label Link Longevity Maintenance Mass Spectrum Analysis Measures Membrane Metabolic Metabolism Methods Microfluidic Microchips Mitochondria Mitochondrial DNA Mitochondrial Proteins Molecular Molecular Target Morphology Mus Nerve Degeneration Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neurons Nuclear Nuclear Pore Complex Optics Organelles Pattern Phase Physiologic pulse Play Positioning Attribute Process Production Protein Biosynthesis Proteins Proteome Proteomics Quality Control Rejuvenation Research Research Proposals Role Site Stable Isotope Labeling Stimulation of Cell Proliferation Structure Synapses Techniques Tissues Translations Tubular formation age related neurodegeneration experimental study fitness fluorescence imaging genetic manipulation genome integrity insight mitochondrial dysfunction mitochondrial fitness mitochondrial genome nervous system disorder novel postmitotic preservation protein degradation ribosome profiling spatiotemporal superresolution microscopy ultra 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