Iron in Mitochondrial Physiology and Disease

铁在线粒体生理学和疾病中的作用

• 批准号: 7896648
• 负责人: PAUL A. LINDAHL
• 金额: $ 28.37万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896648
• 关键词: ABCB6 gene; Address; Affect; Afferent Neurons; Affinity; Aging; Aminolevulinic Acid; Anemia; Ataxia; Binding; Biochemical; Biochemistry; Brain; Carbon; Cell Death; Cell Line; Cell physiology; Cells; Cellular biology; Chelating Agents; Chemicals; Chemistry; Chromatography; Complex; Consumption; Coupled; Coupling; Culture Media; Cytosol; DNA Damage; Data; Defect; Density Gradient Centrifugation; Deposition; Detection; Disease; Electron Microscopy; Electron Spin Resonance Spectroscopy; Electronics; Electrons; Enzymes; Eukaryota; Ferritin; Fluorescence; Fluorescence Microscopy; Future; Genetic; Genotype; Growth; HL-60 Cells; HL60; Heme; Heme Group; Heme Iron; Herpes zoster disease; Homologous Gene; Homologous Protein; Human; Hydrogen Peroxide; Hydroxyl Radical; Hypersensitivity; Individual; Ions; Iron; Isotopes; Knowledge; Lead; Ligands; Light; Mammalian Cell; Mass Spectrum Analysis; Membrane; Metabolic; Metabolism; Metals; Methods; Minerals; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Proteins; Molecular; Molecular Weight; Mono-S; Mononuclear; Mossbauer Spectroscopy; Mutation; NMR Spectroscopy; Nature; Neonatal; Neurodegenerative Disorders; Neurons; Organelles; Organism; Orthologous Gene; Oxidants; Oxidation-Reduction; Parkinson Disease; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Physiological; Physiology; Plasma; Play; Polymers; Porphyrias; Preparation; Process; Proteins; Publishing; Reaction; Reactive Oxygen Species; Relative (related person); Reporting; Residual state; Resolution; Respiratory Chain; Role; Saccharomyces cerevisiae; Sampling; Scheme; Sideroblastic Anemia; Source; Spectrum Analysis; Spinal Ganglia; Spinocerebellar Tracts; Structure; Substantia nigra structure; Succinate Dehydrogenase; Sulfur; Suspension Culture; System; Systems Biology; Techniques; Tissues; Transferrin; Transition Elements; Western Blotting; Yeasts; absorption; age related; analog; base; biological systems; cell type; design; driving force; drug development; electronic structure; enzyme mechanism; ferrihydrite; frataxin; genetic strain; greigite; heme biosynthesis; human disease; insight; iron metabolism; metal chelator; metal complex; mutant; neuromelanin; packaging material; prevent; public health relevance; research study; respiratory; tool; trafficking; yeast protein

DESCRIPTION (provided by applicant): A significant portion of cellular iron metabolism occurs in the mitochondria, including iron import, iron-sulfur cluster assembly and heme biosynthesis. Some heme and iron-sulfur clusters are installed into respiratory complexes, while others are exported to the cytosol and other cellular compartments. The entire system is tightly regulated. In this project, iron components and iron-related processes in mitochondria will be investigated from a systems-biology perspective to gain new insights into the metabolism of healthy and diseased states. Isolated and intact mitochondria from yeast and human cells will be subjected to M"ssbauer spectroscopy, electron paramagnetic resonance, electronic absorption spectroscopy and inductively coupled plasma emission mass spectrometry to evaluate the "iron-ome" of the organelle. This biophysical approach will be used to study mitochondria isolated from wild-type yeast cells grown under different conditions (fermenting vs. respiring; Fe deficient vs. Fe replete) and from different genetic strains. The yeast strains to be investigated (depleted in Yah1p, Atm1p, Mrs3p/4p, and Mtm1p) are known to affect iron metabolism, generally by causing iron to accumulate in the mitochondria. There are analogous situations in humans, in which defects in homologous proteins result in iron accumulation. The accumulated iron will be characterized and its reactivity investigated. Low molecular weight mononuclear nonheme complexes that are used in "trafficking" iron in the mitochondria will be isolated by chromatography, and then identified by mass spectrometry and NMR spectroscopy. The metabolic function of these complexes will also be investigated. The iron-ome of mitochondria from human HL60 cells will be compared to that of yeast mitochondria and differences will be interpreted in terms of iron mitochondrial biochemistry and physiology. The project is significant because the mechanism of disease-related Fe accumulation in mitochondria will be explored and iron complexes that are used in cellular trafficking will be isolated and identified. Such knowledge may allow better control of iron trafficking into and out of the organelle. These iron complexes may also play a role in generating reactive oxygen species (ROS) which are thought to be responsible for some aspects of cellular damage and aging. PUBLIC HEALTH RELEVANCE: Iron is exceedingly important in cellular processes; it is found as heme groups and iron-sulfur clusters. Ingested iron is packaged and then sent to the mitochondria, a cellular organelle, where it is converted into these forms. The structure of the packaging material will be determined; this structure probably "tells" the iron where to go within the cell. Methods will be developed to detect all of the different forms of iron in mitochondria isolated from yeast and human cells. In some genetic states, iron aggregates and can cause disease; this aggregated iron will be characterized in an attempt to eliminate it.

描述（由申请人提供）：线粒体中发生了很大一部分细胞铁代谢，包括铁进口，铁硫簇组装和血红素生物合成。一些血红素和铁硫簇被安装到呼吸道中，而另一些则将其导出到细胞质和其他细胞室。整个系统都受到严格调节。在该项目中，将从系统生物学的角度研究线粒体中的铁成分和与铁相关的过程，以获得对健康和患病状态的代谢的新见解。来自酵母和人类细胞的分离和完整的线粒体将经过“ ssbauer光谱，电子顺磁共振，电子吸收光谱和敏感性耦合等离子体发射质谱法，以评估这种生物物理的“ iron-Ome”，将使用iChophysical ikepe i Intery i Inter-ikepe i Intertiry Chorepe i IntertririochtririochdririochdririochdririochnectririaChemece i Intertririochdririochdririochneptririoochtria i隔离。 （发酵与呼吸; Fe缺乏与Fe的伴侣）以及不同的遗传菌株（在YAH1P，ATM1P，MRS1P，MRS3P/4P和MTM1P中耗尽）。在铁中，将表征累积的铁，并研究其反应性。这些复合物的代谢功能也将被研究。将人类HL60细胞的线粒体铁 - 将其与酵母线粒体的线粒体进行比较，并且将用线粒体生物化学和生理学来解释差异。该项目很重要，因为将探索与疾病相关的Fe积累机理，并且将分离和鉴定在细胞运输中使用的铁配合物。这样的知识可以更好地控制铁杆中和从细胞器中进行。这些铁配合物也可能在产生活性氧（ROS）中发挥作用，这些物种被认为是细胞损伤和衰老的某些方面的原因。公共卫生相关性：铁在细胞过程中至关重要；它被发现为血红素组和铁硫簇。摄入的铁被包装，然后发送到细胞细胞器的线粒体，并将其转换为这些形式。包装材料的结构将被确定；该结构可能会“告诉”熨斗在细胞内的位置。将开发方法来检测从酵母和人类细胞分离的线粒体中所有不同形式的铁。在某些遗传状态下，铁骨料并可能引起疾病；这种聚合的铁将被特征在于试图消除它。