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Homeostatic Mechanisms Regulating Mitochondrial Health

调节线粒体健康的稳态机制

基本信息

批准号：
10623093
负责人：
David C Chan
金额：
$ 71.01万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2028-06-30
项目状态：
未结题

项目摘要

Project Summary/Abstract Mitochondria are best known as the “powerhouses” of the cell, due to their predominant role in generating cellular energy through the tricarboxylic acid cycle, fatty acid metabolism, and oxidative phosphorylation (OXPHOS). Beyond energy generation, these essential organelles also play central roles in apoptosis, calcium handing, innate immunity, cell signaling, and iron-sulfur cluster assembly. Human health therefore depends critically on mitochondrial function. The research program proposed here seeks to understand three homeostatic mechanisms that regulate mitochondrial health. The first mechanism is mitochondrial fusion and fission dynamics. Mitochondria are dynamic organelles whose physiology is regulated by the balance between the opposing processes of membrane fusion and fission. Second, the quality of the mitochondrial population is maintained by selective degradation of excessive or defective mitochondria through mitophagy, the autophagic pathway that shuttles mitochondria to the lysosome for destruction. Finally, mitochondrial quantity and function are regulated by biogenesis programs that control expression of mitochondrial genes, ensuring that appropriate levels of mitochondria are maintained in response to a specific cellular state. This research project targets key gaps in knowledge in each of these fundamental homeostatic mechanisms. For mitochondrial fusion and fission, we are using mouse genetics and cell biology to understand how mitochondrial dynamics regulates mitochondrial function. The least understood of the core mitochondrial dynamics genes is Fis1. We have found that Fis1 plays essential functions in neurons, astrocytes, and oligodendrocytes in the central nervous system. We are pinpointing the cellular functions of Fis1 and determining which function is responsible for the in vivo phenotypes. Our preliminary data suggest that Fis1 serves as a link between mitochondria and the actin cytoskeleton. Moreover, we are determining the elusive mechanism through which the balance between fusion and fission is regulated. There is evidence that each fusion event is coupled to a future fission event, and we will determine the molecular mechanism of this coupling. To study mitochondrial degradation, we are performing whole- genome CRISPR interference screens and have discovered the integrated stress response as a key regulator of mitophagy. We will elucidate the molecular mechanism through which this cell stress pathway tunes the level of mitophagy. Finally, we are using CRISPR interference screens to identify how mitochondrial density and function are regulated. These studies have identified two chromatin remodeling complexes as critical for mitochondrial function. By determining how these chromatin remodeling complexes regulate mitochondrial biogenesis through control of gene expression, we will gain insight into how cells dynamically adjust mitochondrial density to fit cellular demands. All together, these studies will provide a comprehensive understanding of how mitochondrial health in cells is maintained.

项目总结/摘要线粒体最为人所知的是作为细胞的“发电站”，由于它们在生成细胞中的主要作用，通过三羧酸循环、脂肪酸代谢和氧化磷酸化提供细胞能量（OXPHOS）。除了能量产生，这些必需的细胞器也在细胞凋亡中发挥核心作用，钙处理、先天免疫、细胞信号传导和铁-硫簇组装。因此，人类健康关键取决于线粒体的功能这里提出的研究计划旨在了解三种调节线粒体健康的稳态机制。第一种机制是线粒体聚变和裂变动力学。线粒体是动态的细胞器，其生理学受线粒体的调节。膜融合和分裂的对立过程之间的平衡。第二，质量线粒体群体通过选择性降解过量或缺陷的线粒体来维持通过线粒体自噬，自噬途径将线粒体运送到溶酶体进行破坏。最后，线粒体的数量和功能受到控制线粒体基因表达的生物发生程序的调节。线粒体基因，以确保维持适当水平的线粒体，以响应特定的细胞状态。该研究项目针对这些基本知识中的关键差距，自我平衡机制对于线粒体融合和分裂，我们使用小鼠遗传学和细胞了解线粒体动力学如何调节线粒体功能。最不理解的核心线粒体动力学基因之一是Fis 1。我们发现Fis 1在其中发挥着重要作用中枢神经系统中的神经元、星形胶质细胞和少突胶质细胞。我们正在精确定位 Fis 1的功能，并确定哪种功能负责体内表型。我们的初步数据表明，Fis 1作为线粒体和肌动蛋白细胞骨架之间的联系。而且我们决定了聚变和裂变之间平衡的难以捉摸的机制。有证据表明，每个聚变事件都与未来的裂变事件相耦合，我们将确定未来的裂变事件。这种耦合的分子机制。为了研究线粒体的降解，我们进行了整个- 基因组CRISPR干扰筛选，并发现了整合的应激反应作为关键，线粒体自噬的调节因子。我们将阐明这种细胞应激途径的分子机制调节线粒体自噬的水平。最后，我们正在使用CRISPR干扰屏幕来确定如何线粒体密度和功能受到调节。这些研究已经确定了两种染色质重塑复合物对线粒体功能至关重要。通过确定这些染色质重塑复合物通过控制基因表达来调节线粒体生物合成，我们将深入了解细胞如何动态调整线粒体密度以适应细胞需求。总之，这些研究将提供一个全面了解细胞中线粒体的健康是如何维持的。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1.

DOI：
10.1038/s12276-021-00701-z
发表时间：
2021-11
期刊：
Experimental & molecular medicine
影响因子：
12.8
作者：
Sonn SK;Seo S;Yang J;Oh KS;Chen H;Chan DC;Rhee K;Lee KS;Yang Y;Oh GT
通讯作者：
Oh GT

The HRI branch of the integrated stress response selectively triggers mitophagy.

DOI：
10.1016/j.molcel.2024.01.016
发表时间：
2024-02
期刊：
Molecular cell
影响因子：
16
作者：
Yogaditya Chakrabarty;Zheng Yang;Hsiuchen Chen;David C. Chan
通讯作者：
Yogaditya Chakrabarty;Zheng Yang;Hsiuchen Chen;David C. Chan

Control of mitochondrial dynamics by a fusogenic lipid.

通过融合脂质控制线粒体动力学。

DOI：
10.1016/j.tcb.2023.10.006
发表时间：
2023
期刊：
Trends in cell biology
影响因子：
19
作者：
Yang,Zheng;Chan,DavidC
通讯作者：
Chan,DavidC

De Novo DNM1L Variant in a Teenager With Progressive Paroxysmal Dystonia and Lethal Super-refractory Myoclonic Status Epilepticus.

DOI：
10.1177/0883073818778203
发表时间：
2018-09
期刊：
Journal of child neurology
影响因子：
1.9
作者：
Ryan CS;Fine AL;Cohen AL;Schiltz BM;Renaud DL;Wirrell EC;Patterson MC;Boczek NJ;Liu R;Babovic-Vuksanovic D;Chan DC;Payne ET
通讯作者：
Payne ET

Identification of new OPA1 cleavage site reveals that short isoforms regulate mitochondrial fusion.