MITOCHONDRIAL IRON STORAGE

线粒体铁储存

• 批准号: 7370500
• 负责人: HELEN NICHOL
• 金额: $ 0.41万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370500
• 关键词: MITOCHONDRIAL; IRON; STORAGE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Metals can accumulate in cellular compartments during the normal aging process, through excessive dietary or environmental exposure and from genetic errors in proteins that regulate metal flux within cells. Mitochondrial iron overload is a common feature of several neurological and metabolic diseases. We have shown that in yeast with various errors in iron-sulfur cluster biosynthesis, the form of iron that accumulates differs. In particular, ferrihydrite of the type sequestered by frataxin in vitro is found only in yeast that express frataxin. We now propose to expand this work to compare mitochondrial iron in two human diseases, Friedreich's ataxia (FRDA) and sideroblastic anemia (SA) and to begin to address the chemistry of treatment strategies. The following questions will be addressed using XAS 1. How does frataxin's ferroxidase activity contribute to iron core assembly? Iron K-edge spectra will be collected for XANES and EXAFS analysis of iron cores assembled after amino acid substitutions to frataxin's ferroxidation site. 2. Does frataxin assemble an iron core in vivo that is structurally similar to that assembled in vivo? Frataxin assembled in vivo will be separated on a non-denaturing gel and K-edge spectra collected in situ. 3. Is mitochondrial iron that accumulates in yeast FRDA models and human FRDA the same? Mitochondria will be isolated from FRDA fibroblast cultures and K-edge spectra collected for XANES analysis. 4. Can selenium form a complex with iron in frataxin deficient mitochondria? Mitochondria will be isolated from frataxin-deficient yeast grown on selenium-supplemented media and spectra collected at the iron and selenium K-edges for EXAFS analysis. 5. Do iron deposits differ between SA and FRDA? Mitochondria will be isolated from an SA model and iron K-edge spectra collected for XANES analysis. This work will contribute to the development of better treatment strategies for these mitochondrial iron overload disorders.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。在正常衰老过程中，通过过度的饮食或环境暴露以及调节细胞内金属通量的蛋白质中的遗传误差，金属可以在细胞室中积聚。线粒体铁超负荷是几种神经系统和代谢疾病的共同特征。我们已经表明，在铁硫簇生物合成中有各种误差的酵母中，积累的铁的形式有所不同。特别是，仅在表达frataxin的酵母中发现了在体外被frataxin隔离的类型的铁石。现在，我们建议扩大这项工作，以比较两种人类疾病中的线粒体铁，弗里德里希的共济失调（FRDA）和副细胞性贫血（SA），并开始解决治疗策略的化学反应。将使用XAS 1解决以下问题。Frataxin的铁氧化酶活性如何有助于铁核组件？将收集铁K边缘光谱，以用于XANES，并将氨基酸取代后组装的铁核分析与Frataxin的铁氧化位点组装在一起。 2。frataxin在结构上类似于体内组装的体内组装铁核吗？在体内组装的frataxin将在原位收集的非降解凝胶和K边缘光谱上分离。 3。在酵母FRDA模型中积累的线粒体铁和人类FRDA是否相同？线粒体将从FRDA成纤维细胞培养物中分离出来，并收集的k边缘光谱进行XANES分析。 4。硒可以在frataxin缺乏线粒体中与铁形成络合物吗？线粒体将从缺乏硒和硒k-Edges收集的硒供应培养基和光谱上生长的Frataxin缺陷酵母中分离出来，以进行EXAFS分析。 5。铁沉积在SA和FRDA之间是否有所不同？线粒体将从SA模型中分离出来，并收集的铁K边缘光谱进行XANES分析。这项工作将有助于制定这些线粒体铁超载疾病的更好治疗策略。