Role of the Endosomal-Lysosomal Pathway in Mitochondrial Quality Control
Role of the Endosomal-Lysosomal Pathway in Mitochondrial Quality Control
批准号:
9917812
负责人:
Asa B. Gustafsson
金额:
$38.75万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-08-15 至 2022-05-31
关键词:
1-Phosphatidylinositol 3-KinaseAutophagocytosisAutophagosomeBiogenesisCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular systemCellsCellular StressCessation of lifeComplexContractsDangerousnessDataDefectDefense MechanismsDegradation PathwayDevelopmentDiseaseEarly EndosomeEndosomesEnvironmentExcisionFunctional disorderGTP BindingGeneticGoalsHeartHeart failureHomeostasisIn VitroLabelLeadLysosomesMediatingMitochondriaMitochondrial ProteinsMitoticMolecularMonomeric GTP-Binding ProteinsMusMuscle CellsMyocardial InfarctionMyocardiumOrganellesOxidative PhosphorylationPathogenesisPathway interactionsPharmacologyPlayProcessProteinsProteomicsQuality ControlReactive Oxygen SpeciesRegulationResearchRoleScaffolding ProteinSignal TransductionStressTestingTimeUbiquitinUbiquitinationin vivoinsightlate endosomeloss of functionmitochondrial autophagymitochondrial dysfunctionmouse modelmutantnew therapeutic targetnovelparkin gene/proteinparkin proteinpreventprogramsprotein complexrab5A Proteinrecruitrepairedresponsetherapeutic targetubiquitin-protein ligase
中文摘要
项目摘要
心肌细胞线粒体功能障碍发生在心力衰竭发病的早期。在心中,
线粒体的主要功能是通过提供能量来满足跳动的肌细胞的高能量需求
ATP通过氧化磷酸化。然而,线粒体可以迅速转变为促进死亡的
细胞器为了应对细胞内环境的变化,它们可以成为过量的
活性氧并释放促死亡蛋白。毫不奇怪,细胞已经发展出防御能力,
细胞修复自身的能力,
防止不必要的死亡在有丝分裂后细胞如不能被
很容易被取代。研究发现,功能失调的线粒体可以被自噬体隔离
并随后递送至溶酶体进行降解。然而,
线粒体的去除没有得到很好的表征,以及线粒体的其他机制是否
目前尚不清楚是否存在清除。我们以前已经发现E3泛素连接酶Parkin起着重要的作用。
在清除心脏中功能失调的线粒体以应对压力和缺乏帕金导联中的重要作用
与心肌梗死后功能障碍的线粒体堆积有关。帕金以诱导
但我们的初步研究发现,帕金也可以促进线粒体的自噬,
通过自噬非依赖性机制清除线粒体。在本建议书中,我们将探讨
假设小GTCRab 5和内体降解途径在
清除肌细胞中功能失调的线粒体。我们将以两个目标来检验这些假设。目标1将
定义Rab 5和内体介导的线粒体清除在心肌细胞中的功能重要性,
体外和体内。我们还将研究内体途径与
心脏中的传统/替代自噬途径。在目标2中,我们将描述Beclin 1在以下方面的作用:
启动内体途径以响应线粒体损伤。我们将研究Beclin 1
调节内体降解途径的激活,以响应细胞应激,通过形成特异性的
与Rab 5和Vps 34的前内体复合物。使用独特的药物进行体外和体内功能丧失研究
心脏特异性诱导型Beclin 1缺陷小鼠将用于证实Beclin 1的功能重要性
响应线粒体损伤和应激而启动早期内体的形成。这些研究将
提供了重要的新见解,了解功能失调和潜在危险的线粒体是如何被清除的,
心脏这些研究还将为该途径中新的潜在治疗靶点提供见解。
英文摘要
Project Summary
Mitochondrial dysfunction in cardiac myocytes occurs early in the pathogenesis of heart failure. In the heart,
the primary function of mitochondria is to meet the high energy demand of the beating myocytes by providing
ATP through oxidative phosphorylation. However, mitochondria can quickly change into death–promoting
organelles. In response to changes in the intracellular environment, they can become excessive producers of
reactive oxygen species and release pro-death proteins. Not surprisingly, cells have developed defense
mechanisms against aberrant mitochondria that can cause harm to it. The ability of a cell to repair itself and
prevent unnecessary death is particularly important in a post-mitotic cell such as a myocyte that cannot be
easily replaced. Studies have found that dysfunctional mitochondria can be sequestered by autophagosomes
and subsequently delivered to lysosomes for degradation. However, the mechanism and regulation of
mitochondrial removal are not well characterized and whether additional mechanisms of mitochondrial
clearance exist is currently unclear. We have previously found that the E3 ubiquitin ligase Parkin plays an
important role in clearing dysfunctional mitochondria in the heart in response to stress and lack of Parkin leads
to accumulation of dysfunctional mitochondria after a myocardial infarction. Parkin is known to induce
autophagy of mitochondria but our preliminary studies have uncovered evidence that Parkin can also promote
clearance of mitochondria via an autophagy-independent mechanism. In this proposal, we will explore the
hypothesis that the small GTPase Rab5 and the endosomal degradation pathway play an important role in
clearing dysfunctional mitochondria in myocytes. This hypotheses will be tested with two aims. Aim 1 will
define the functional importance of Rab5 and endosomal-mediated mitochondrial clearance in myocytes in
vitro and in vivo. We will also examine the relationships between the endosomal pathway and
traditional/alternative autophagy pathways in the heart. In Aim 2, we will delineate the role of Beclin1 in
initiating the endosomal pathway in response to mitochondrial damage. We will examine whether Beclin1
regulates activation of the endosomal degradation pathway in response to cellular stress by forming a specific
pro-endosomal complex with Rab5 and Vps34. Loss-of-function studies in vitro and in vivo using unique
cardiac specific inducible Beclin1 deficient mice will be utilized to confirm the functional importance of Beclin1
initiating formation of early endosomes in response to mitochondrial damage and stress. These studies will
provide important novel insight into how dysfunctional and potentially dangerous mitochondria are cleared in
the heart. These studies will also provide insights into new potential therapeutic targets in this pathway.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
Protective Function of MCUb in Postischemic Remodeling Getting at the Heart of the Calcium Control Conundrum.
MCUb 在缺血后重塑中的保护功能直击钙控制难题的核心。
DOI:
10.1161/circresaha.120.317423
发表时间:
2020
期刊:
Circulation research
影响因子:
20.1
作者:
[Moyzis,AlexandraG, Gustafsson,ÅsaB]
通讯作者:
Gustafsson,ÅsaB
Autophagy: A savior in cigarette smoke-induced cardiac injury.
自噬:香烟烟雾引起的心脏损伤的救星。
DOI:
10.1016/j.yjmcc.2020.09.002
发表时间:
2020
期刊:
Journal of molecular and cellular cardiology
影响因子:
5
作者:
[Gustafsson,ÅsaB]
通讯作者:
Gustafsson,ÅsaB
Autophagy and Megamitochondria in Cardiac Aging and Heart Failure
-
批准号:10378003
-
项目类别:
-
资助金额:$48.21万
-
财政年份:2021
-
负责人:Asa B. Gustafsson
-
依托单位:
Autophagy and Megamitochondria in Cardiac Aging and Heart Failure
-
批准号:10592312
-
项目类别:
-
资助金额:$48.24万
-
财政年份:2021
-
负责人:Asa B. Gustafsson
-
依托单位:
Autophagy and Megamitochondria in Cardiac Aging and Heart Failure
-
批准号:10182464
-
项目类别:
-
资助金额:$47.67万
-
财政年份:2021
-
负责人:Asa B. Gustafsson
-
依托单位:
Secretion of mitochondria as a cellular quality control mechanism
-
批准号:10320785
-
项目类别:
-
资助金额:$56.57万
-
财政年份:2020
-
负责人:Asa B. Gustafsson
-
依托单位:
Secretion of mitochondria as a cellular quality control mechanism
-
批准号:10521290
-
项目类别:
-
资助金额:$56.57万
-
财政年份:2020
-
负责人:Asa B. Gustafsson
-
依托单位:
MCL-1 is a critical regulator of mitochondrial dynamics and function in myocytes
-
批准号:9245917
-
项目类别:
-
资助金额:$38.75万
-
财政年份:2017
-
负责人:Asa B. Gustafsson
-
依托单位:
MCL-1 is a critical regulator of mitochondrial dynamics and function in myocytes
-
批准号:9812170
-
项目类别:
-
资助金额:$7.2万
-
财政年份:2017
-
负责人:Asa B. Gustafsson
-
依托单位:
Mitochondrial Quality Control in the Aging Myocardium
-
批准号:9265769
-
项目类别:
-
资助金额:$19.38万
-
财政年份:2016
-
负责人:Asa B. Gustafsson
-
依托单位:
Regulation of Steroid Hormone Production by Inter-Organelle Substrate Exchange
-
批准号:8728843
-
项目类别:
-
资助金额:$31.98万
-
财政年份:2011
-
负责人:Asa B. Gustafsson
-
依托单位:
Mcl-1 as an essential regulator of cardiac mitochondrial function
-
批准号:8207355
-
项目类别:
-
资助金额:$1.45万
-
财政年份:2010
-
负责人:Asa B. Gustafsson
-
依托单位:
Mcl-1 as an essential regulator of cardiac mitochondrial function
-
批准号:8449693
-
项目类别:
-
资助金额:$57.18万
-
财政年份:2010
-
负责人:Asa B. Gustafsson
-
依托单位:
Mcl-1 as an essential regulator of cardiac mitochondrial function
-
批准号:8242797
-
项目类别:
-
资助金额:$62.12万
-
财政年份:2010
-
负责人:Asa B. Gustafsson
-
依托单位:
Mcl-1 as an essential regulator of cardiac mitochondrial function
-
批准号:8064733
-
项目类别:
-
资助金额:$63.09万
-
财政年份:2010
-
负责人:Asa B. Gustafsson
-
依托单位:
Mcl-1 as an essential regulator of cardiac mitochondrial function
-
批准号:7847959
-
项目类别:
-
资助金额:$58.1万
-
财政年份:2010
-
负责人:Asa B. Gustafsson
-
依托单位:
Role of Bnip3 in Myocardial Ischemia/Reperfusion
-
批准号:7837043
-
项目类别:
-
资助金额:$5.98万
-
财政年份:2009
-
负责人:Asa B. Gustafsson
-
依托单位:
Role of Bnip3 in Myocardial Ischemia/Reperfusion
-
批准号:7670800
-
项目类别:
-
资助金额:$5.77万
-
财政年份:2007
-
负责人:Asa B. Gustafsson
-
依托单位:
Regulation of Mitochondrial Autophagy by Parkin
-
批准号:8720045
-
项目类别:
-
资助金额:$37.98万
-
财政年份:2007
-
负责人:Asa B. Gustafsson
-
依托单位:
Regulation of Mitochondrial Autophagy by Parkin
-
批准号:8444859
-
项目类别:
-
资助金额:$36.89万
-
财政年份:2007
-
负责人:Asa B. Gustafsson
-
依托单位:
Regulation of Mitochondrial Autophagy by Parkin
-
批准号:8901599
-
项目类别:
-
资助金额:$4.82万
-
财政年份:2007
-
负责人:Asa B. Gustafsson
-
依托单位:
Role of Bnip3 in Myocardial Ischemia/Reperfusion
-
批准号:7887470
-
项目类别:
-
资助金额:$1.33万
-
财政年份:2007
-
负责人:Asa B. Gustafsson
-
依托单位: