The Hig1 protein family and the cytochrome c oxidase complex

Hig1 蛋白家族和细胞色素 c 氧化酶复合物

• 批准号: 8289869
• 负责人: ROSEMARY A STUART
• 金额: $ 33.75万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289869
• 关键词: Address; Adenine Nucleotide Translocase; Animal Model; Animals; Apoptotic; Bacteria; Binding; Caenorhabditis elegans; Caliber; Carrier Proteins; Cell Respiration; Cells; Complex; Cues; Data; Databases; Diabetes Mellitus; Energy-Generating Resources; Ensure; Enzymes; Eukaryota; Family; Family member; Functional disorder; Gene Expression; Genes; Glycolysis; Goals; Grant; Homologous Gene; Hypoxia; Knowledge; Lead; Malignant Neoplasms; Metabolic; Metabolic Control; Mission; Mitochondria; Molecular; Myocardial Ischemia; Nature; Neurologic Dysfunctions; Organism; Oxidases; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Oxygen Consumption; Pathway interactions; Population; Process; Production; Protein Analysis; Protein Family; Proteins; Reactive Oxygen Species; Regulation; Research; Research Personnel; Role; Saccharomyces cerevisiae; Signal Transduction; Students; System; Tissues; Universities; Variant; Yeasts; base; cytochrome c; cytochrome c oxidase; design; enzyme activity; experience; graduate student; innovation; member; novel; plant fungi; research study; response; tumor; undergraduate research; undergraduate student

DESCRIPTION (provided by applicant): Mitochondria produce ATP for the cell's metabolic needs through an oxygen consuming process called oxidative phosphorylation (OXPHOS). The survival of many organisms is therefore dependent on the availability of oxygen, which is directly utilized by the cytochrome c oxidase (COX) enzyme of the OXPHOS system. Organisms, tissues and cells have developed mechanisms to sense, respond and adapt to limiting oxygen levels (hypoxia). The hypoxic response involves both short-term changes in OXPHOS activities and long-term adaptive changes include changes in gene expression and metabolic reprogramming to promote glycolysis. Reduced OXPHOS potential due to limiting oxygen levels can lead to increased mitochondrial reactive oxygen species production and oxidative stress. A family of proteins termed the hypoxia-induced gene 1 (Hig1) family has been shown in diverse organisms to be up-regulated during hypoxic and oxidative stress conditions. Hig1 family members are found bacteria through eukaryotes, where they show widespread conservation through plants, fungi and animals, indicating their potential importance. Although of unknown function, the presence of the Hig1 proteins has been suggested to confer an anti-apoptotic function under hypoxic/oxidative stress conditions. We demonstrate here that the Hig1 proteins are novel components of the COX complex and their presence is required for COX enzyme activity. Moreover, we demonstrate that Hig1 proteins physically interact with subunit 3 (Cox3) prior to and following its assembly into the COX complex. Preliminary evidence that the Hig1-Cox3/COX interaction may also involve the highly conserved Cox12 (mCox6b) protein has also been obtained. We also provide evidence that a population of the Hig1 proteins is found in association with a nonCOX complex, and in a manner, which is influenced by the activity of the ADP/ATP carrier proteins. The experiments proposed here are designed to further our understanding of the Hig1 protein family and their role in modulating the OXPHOS activity and ensuring the hypoxic response pathway. We will specifically address the features of the Hig1 proteins that are required for the Cox3 interaction and further analyze the proposed relationship between the Hig1, Cox3 and Cox12 proteins. Another major objective of the proposed research is the determination of the identity of the nonCOX proteins that interact with the Hig1 protein and the analysis of the conserved region of Hig1 proposed to support these interactions. We hypothesize that the Hig1 protein act as intermediary between COX and nonCOX enzymes in the mitochondria and in doing so functions as a rheostat to modulate the activity of the COX complex in response to metabolic changes in the cell. PUBLIC HEALTH RELEVANCE: ATP, the vital energy source for the cell's diverse metabolic needs, is produced by mitochondria through the process of oxidative phosphorylation (OXPHOS), which involves oxygen consumption by the cytochrome c oxidase (COX) enzyme. The survival of many organisms is therefore dependent on oxygen availability and consequently organisms and cells have developed adaptive mechanisms to respond to and survive hypoxic conditions, which involves the OXPHOS system and the COX complex and the production of reactive oxygen species. Understanding the mitochondria's participation in the hypoxic response pathway is of fundamental importance because oxygen dysregulation and oxidative stress are hallmarks in the pathophysiology of many conditions such as cancer/tumors, ischaemic heart disease, diabetes, and neurological dysfunction.

描述(申请人提供)：线粒体通过称为氧化磷酸化(OXPHOS)的耗氧过程产生细胞代谢所需的三磷酸腺苷。因此，许多生物的生存依赖于氧气的可用性，氧气直接被OXPHOS系统的细胞色素C氧化酶(COX)酶利用。生物体、组织和细胞已经发展出感知、反应和适应极限氧水平(低氧)的机制。缺氧反应既包括OXPHOS活性的短期变化，也包括长期适应性变化，包括基因表达的变化和促进糖酵解的代谢重新编程。由于限制氧水平而导致的OXPHOS电位降低会导致线粒体活性氧产生增加和氧化应激。一个被称为缺氧诱导基因1(Hig1)家族的蛋白质家族已被证明在不同的生物体中在低氧和氧化应激条件下表达上调。Hig1家族成员通过真核生物发现细菌，在真核生物中，它们通过植物、真菌和动物表现出广泛的保护作用，表明它们潜在的重要性。尽管功能未知，但Hig1蛋白的存在已被认为在低氧/氧化应激条件下具有抗凋亡功能。我们在这里证明了Hig1蛋白是COX复合体的新成分，它们的存在是COX酶活性所必需的。此外，我们证明了Hig1蛋白在组装成COX复合体之前和之后与亚单位3(Cox3)物理上相互作用。初步证据表明，Hig1-Cox3/COX相互作用也可能涉及高度保守的Cox12(MCox6b)蛋白。我们还提供了证据表明，发现了一组Hig1蛋白与非COX复合体相关，并且在某种程度上受到ADP/ATP载体蛋白活性的影响。这些实验旨在加深我们对Hig1蛋白家族及其在调节OXPHOS活性和确保低氧反应途径中的作用的理解。我们将具体讨论Cox3相互作用所需的Hig1蛋白的特征，并进一步分析Hig1、Cox3和Cox12蛋白之间的拟议关系。拟议研究的另一个主要目标是确定与Hig1蛋白和Hig1蛋白相互作用的非COX蛋白的身份。 对Hig1保守区的分析提出了支持这些相互作用的建议。我们假设Hig1蛋白在线粒体中的COX和非COX酶之间起中介作用，并在这样做的过程中起到变阻器的作用，调节COX复合体的活性，以响应细胞中的代谢变化。 与公共健康相关：线粒体通过氧化磷酸化(OXPHOS)过程产生ATP，ATP是细胞多样化代谢需求的重要能量来源，氧化磷酸化过程涉及细胞色素C氧化酶(COX)酶的氧气消耗。因此，许多生物的生存依赖于氧气的供应，因此，生物和细胞已经形成了适应低氧条件的机制，这涉及到OXPHOS系统和COX复合体以及活性氧物种的产生。了解线粒体在低氧反应途径中的作用至关重要，因为氧失调和氧化应激是许多疾病的病理生理学特征，如癌症/肿瘤、缺血性心脏病、糖尿病和神经功能障碍。

项目成果

Distinct Roles of Mitochondrial HIGD1A and HIGD2A in Respiratory Complex and Supercomplex Biogenesis.

• DOI: 10.1016/j.celrep.2020.107607
• 发表时间: 2020-05
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Alba Timón-Gómez;J. Garlich;R. Stuart;C. Ugalde;A. Barrientos

Supercomplex-associated Cox26 protein binds to cytochrome c oxidase.

超复合物相关的 Cox26 蛋白与细胞色素 c 氧化酶结合。

• DOI: 10.1016/j.bbamcr.2016.04.012
• 发表时间: 2016
• 期刊: Biochimica et biophysica acta
• 作者: Strecker,Valentina;Kadeer,Zibirnisa;Heidler,Juliana;Cruciat,Cristina-Maria;Angerer,Heike;Giese,Heiko;Pfeiffer,Kathy;Stuart,RosemaryA;Wittig,Ilka
• 通讯作者: Wittig,Ilka