Mitochondrial Fidelity and Homeostasis

线粒体保真度和稳态

• 批准号: 10597652
• 负责人: Oleh Khalimonchuk
• 金额: $ 8.2万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597652
• 关键词: Address; Age; Amyotrophic Lateral Sclerosis; Bioenergetics; Biogenesis; Biological; Cardiovascular Diseases; Cell Survival; Cell physiology; Cells; Clinical; Dedications; Defect; Degenerative Disorder; Dementia; Development; Disease; Dissection; Etiology; Event; Failure; Glaucoma; Goals; Health; Homeostasis; Human; Inner mitochondrial membrane; Investigation; Knowledge; Life Cycle Stages; Malignant Neoplasms; Mediating; Mitochondria; Mitochondrial Matrix; Modeling; Molecular; Neuropathy; Organelles; Organism; Outcome; Parkinsonian Disorders; Pathology; Pathway interactions; Physiological; Process; Prophylactic treatment; Proteins; Proteome; Quality Control; Regulation; Research; Role; Saccharomyces cerevisiae; Signal Transduction; Therapeutic; Time; Vision; Work; Yeasts; cost effective treatment; effective therapy; hearing impairment; insight; mitochondrial metabolism; novel; preservation; programs; protein complex; proteostasis; repaired; spatiotemporal

PROJECT SUMMARY/ABSTRACT The overall vision of the proposed research program is to determine how evolutionary conserved mitochondrial quality control modules function to maintain cell survival, and how these functions can be manipulated to achieve clinical benefits. Research in the Khalimonchuk lab is focused on providing a better understanding of multilayered processes that mediate mitochondrial biogenesis, function and integrity. The general goals include: 1) thorough molecular characterization of factors involved; 2) dissection of their roles and concerted action in relevant biological mechanisms; and 3) investigation of associated regulatory and signaling events and their potential therapeutic relevance. To that end, this MIRA proposal focuses on a group of fundamental mechanisms that mediate mitochondrial fidelity and preserve normal mitochondrial functions throughout a lifecycle of a cell/organism. The mitochondria and its complex protein homeostasis (proteostasis) network involve multiple dynamic processes and pathways that adapt to homeostatic challenges and change over time. The multifaceted biological roles of these mechanisms are highly relevant to both normal cellular physiology and a wide range of human disorders for which no effective therapies presently exist. Progressive mitochondrial failure has emerged as a central causative factor of prevalent degenerative diseases such as glaucoma, hearing loss, Parkinsonism, amyotrophic lateral sclerosis, various neuropathies, dementia, cardiovascular disorders, and certain cancers. In spite of much research, the molecular etiology of these pathologies remains obscure. Thus, a greater understanding of the mechanisms that mediate mitochondrial fidelity, function, and integrity, and how failure of these mechanisms drives the above clinical manifestations, is of central importance. Unified by an overarching topic of mitochondrial fidelity and protein homeostasis, this research program seeks to study: 1) the mechanisms that proteolytically control/regulate protein stability, abundance, assembly, and repair within the inner mitochondrial membrane and 2) how a delicate protein homeostasis in the mitochondrial matrix is established and maintained. In each case, the proposed work will focus on a group of dedicated versatile factors that mediate mitochondrial self-preservation and are highly relevant to human health. The goal is to address unresolved questions concerning the functional roles of key molecular factors using two lauded complementary models, the yeast Saccharomyces cerevisiae and cultured human cells. The research will uncover novel mechanisms of regulation, dynamic integration, and concerted spatiotemporal action that are critical for mitochondrial sub-proteomes to adjust to homeostatic insults and physiological demands and challenges. Successful outcomes from this project will provide unprecedented insights into the coordination of mitochondrial metabolism, bioenergetics, and proteostasis and challenge current views on mechanisms of age-associated maladies. They may also aid in the development of new treatment/prophylaxis strategies against degenerative diseases and related pathologies that occur with age.

项目总结/摘要 拟议研究计划的总体愿景是确定进化如何保守 线粒体质量控制模块的功能，以维持细胞的生存，以及如何这些功能可以 以实现临床效益。Khalimonchuk实验室的研究重点是提供一个更好的 了解介导线粒体生物发生、功能和完整性的多层过程。的 总体目标包括：1）彻底的分子特征的因素参与; 2）解剖他们的作用 相关生物学机制中的协同作用; 3）相关调节和 信号事件及其潜在的治疗相关性。为此，这个MIRA提案的重点是一组 介导线粒体保真度和保持正常线粒体功能的基本机制 在细胞/有机体的整个生命周期中。线粒体及其复合蛋白质稳态（Proteostasis） 网络涉及多种动态过程和途径，以适应稳态挑战和变化 随着时间这些机制的多方面生物学作用与正常细胞和细胞外基质高度相关。 生理学和广泛的人类疾病，目前还没有有效的治疗方法。进步 线粒体衰竭已经成为流行的退行性疾病的主要致病因素， 青光眼、听力损失、帕金森综合征、肌萎缩侧索硬化、各种神经病、痴呆， 心血管疾病和某些癌症。尽管有很多研究，但这些疾病的分子病因学 病理学仍不清楚。因此，更好地了解介导线粒体 保真度，功能和完整性，以及这些机制的失败如何驱动上述临床表现， 至关重要。由线粒体保真度和蛋白质稳态的总体主题统一， 研究计划旨在研究：1）蛋白水解控制/调节蛋白质稳定性的机制， 丰富，组装和修复内线粒体膜和2）如何微妙的蛋白质 线粒体基质中的稳态得以建立和维持。在每一种情况下，拟议的工作将 专注于一组专用的多功能因子，介导线粒体自我保护， 与人类健康有关。目标是解决有关关键职能作用的未解决问题， 分子因素使用两个称赞互补模型，酵母酿酒酵母和培养 人类细胞。这项研究将揭示新的监管机制，动态整合，协调一致， 时空作用对于线粒体亚蛋白质组调节稳态损伤至关重要， 生理需求和挑战。该项目的成功成果将提供前所未有的 深入了解线粒体代谢，生物能量学和蛋白质稳态的协调和挑战 目前对年龄相关疾病机制的看法。它们还可以帮助开发新的 针对随年龄发生的退行性疾病和相关病理的治疗/预防策略。

项目成果

The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism.

• DOI: 10.1016/j.celrep.2021.108869
• 发表时间: 2021-03-16
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Acoba MG;Alpergin ESS;Renuse S;Fernández-Del-Río L;Lu YW;Khalimonchuk O;Clarke CF;Pandey A;Wolfgang MJ;Claypool SM
• 通讯作者: Claypool SM

Editorial: Special Issue on mitochondrial fidelity.

社论：线粒体保真度特刊。

• DOI: 10.1016/j.mito.2019.12.007
• 发表时间: 2020
• 期刊: Mitochondrion
• 影响因子: 4.4
• 作者: Khalimonchuk,Oleh

Short Communication: Beta-adrenergic agonists alter oxidative phosphorylation in primary myoblasts.

简短的交流：β-肾上腺素能激动剂改变原代成肌细胞的氧化磷酸化。

• DOI: 10.1093/jas/skac208
• 发表时间: 2022
• 期刊: Journal of animal science
• 影响因子: 3.3
• 作者: Sieck,RenaeL;Treffer,LeahK;Fuller,AnnaM;PonteViana,Martonio;Khalimonchuk,Oleh;Schmidt,TyB;Yates,DustinT;Petersen,JessicaL
• 通讯作者: Petersen,JessicaL

Coordination of metal center biogenesis in human cytochrome c oxidase.

• DOI: 10.1038/s41467-022-31413-1
• 发表时间: 2022-06-24
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Nyvltova, Eva;Dietz, Jonathan V.;Seravalli, Javier;Khalimonchuk, Oleh;Barrientos, Antoni
• 通讯作者: Barrientos, Antoni

Protease OMA1 modulates mitochondrial bioenergetics and ultrastructure through dynamic association with MICOS complex.

• DOI: 10.1016/j.isci.2021.102119
• 发表时间: 2021-02-19
• 期刊: iScience
• 影响因子: 5.8
• 作者: Viana MP;Levytskyy RM;Anand R;Reichert AS;Khalimonchuk O
• 通讯作者: Khalimonchuk O