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The molecular mechanisms of mitochondrial behavior.

线粒体行为的分子机制。

基本信息

批准号：
8672957
负责人：
Suzanne C Hoppins
金额：
$ 23.7万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-16 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8672957
关键词：
Address Apoptosis Apoptotic Bax protein Behavior Biochemical Biological Assay Cardiac Cell Death Cell physiology Cells Characteristics Chimeric Proteins Chronic Complex Coupled Data Deletion Mutation Disease Progression Dynamin Embryo Event Foundations GTP Binding Grant Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Heart Heart Diseases Hydrolysis In Vitro Knowledge Light Link Mammals Maps Mediating Membrane Membrane Fusion Microtubules Mitochondria Molecular Movement Myocardial Infarction Nature Neurodegenerative Disorders Organelles Organism Pathway interactions Physiological Play Process Property Protein Family Proteins Regulation Relative (related person)Role Shapes Signal Pathway Signal Transduction Testing Therapeutic Time Tissues Translating abstracting base cell motility chemical genetics drug development fusion gene in vitro Assay insight member novel protein function research study therapeutic development

项目摘要

Project Summary/Abstract: Mitochondrial fusion regulates the shape, distribution and function of the organelle and plays critical roles in protection from cell death and therefore offers a valid target for theurapeutic approaches to protect the heart from progression of disease or myocardial infarction events. Mitochondrial fusion is mediated by members of the dynamin related protein (DRP) family, large GTPases that, through their ability to self-assemble and hydrolyze GTP, control membrane remodeling events. In mammals, MFN1 and MFN2 function in place of a single outer membrane DRP in simple organisms, both are expressed ubiquitously but the relative expression level of each varies in a tissue dependent manner. Although MFN1 and MFN2 both function in mitochondrial fusion, they are not completely redundant, although the nature of the functional differences are not known. Our data indicate that the MFN1-MFN2 heterotypic trans complex is significantly more efficacious for fusion than either homotypic complex. From this, we predict that MFN1 and MFN2 have distinct molecular properties and that the functional significance of the two outer membrane DRPs in mammals is to provide a relatively simple regulatory fusion mechanism via their respective and relative expression levels. Further, data suggest that specific regulatory mechanisms exist, as we have shown that soluble Bax stimulates only MFN2 homotypic complexes. In order to understand the functional significance of two outer membrane fusion proteins and the regulatory mechanisms that govern their activity, we propose to characterize the biochemical properties of each DRP including GTP binding, GTP hydrolysis and complex assembly. These biochemical approaches together will determine the mechanistic basis for why MFN1 only, MFN2 only and MFN1/MFN2 mediated fusion efficiencies are distinct and will likely point to why and how they are distinctly regulated in cells. To explore what properties of MFN2 are modulated by the pro-apoptotic Bcl2 protein Bax, we will test the effect of Bax on the biochemical properties of MFN2, of particular significance in the heart where MFN2 is the predominantly expressed fusion DRP. We will further characterize the regulation of fusion by Bax through identification of interaction domains and exploring their functional significance in vitro and in cells. Bax also negatively effects mitochondrial fusion following activation by apoptotic signals and we will investigate whether the inhibition of fusion is direct or mediated through outer membrane permeabilization. As observed with the apoptotic pathway and mitochondrial dynamics, an interdependence also exists between mitochondrial fusion and mitochondrial motility, but the significance of this is relatively unexplored. We propose that mitochondrial tethering to microtubules and short range motility are both important regulators of mitochondrial fusion. We will determine the role that mitochondrial movement and tethering play in regulating mitochondrial fusion and investigate the molecular basis for the requirement of MFNs in these processes using an in vitro mitochondrial fusion-motility assay and complimentary biochemical approaches.

项目总结/文摘: