Palmitoylation-dependent massive endocytosis (pMEND)

棕榈酰化依赖性大量内吞作用 (pMEND)

基本信息

批准号：
9043177
负责人：
DONALD W HILGEMANN
金额：
$ 39.75万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9043177
关键词：
Acyl Coenzyme A Acylation Affect Anoxia Autophagocytosis Binding Sites Biochemical Cardiac Cardiac Myocytes Cause of Death Cell surface Cells Cessation of life Coenzyme A Coenzyme A Ligases Cytoplasm Data Defect Diet Diffusion Disease Endocytosis Endocytosis Pathway Enzymes Eukaryotic Cell Event Excision Extracellular Space Fatty Acids Health Heart Hypertension Individual Inner mitochondrial membrane Ion Channel Ischemia Lesion Link Liquid substance Mediating Membrane Membrane Potentials Membrane Proteins Metabolic Metabolic stress Metabolism Methods Mitochondria Mouse Strains Mus Muscle Cells Myocardial Ischemia Myocardium Ouabain Outcome Pathway interactions Permeability Pharmaceutical Preparations Physiological Physiology Play Process Proteins Protocols documentation Pump Regulation Reperfusion Injury Reperfusion Therapy Risk Factors Role Sarcolemma Saturated Fatty Acids Seminal Signal Pathway Signal Transduction Signaling Protein Surface Tissues Vesicle Work base biological adaptation to stress cyclophilin D drug discovery genetic regulatory protein heart cell insight long chain fatty acid mitochondrial membrane palmitoylation particle peroxiredoxin uptake

项目摘要

DESCRIPTION (provided by applicant): This project focuses on a new cardiac signaling pathway by which mitochondria regulate cytoplasmic regulatory proteins and surface membrane turnover. The pathway relies on the accumulation by mitochondria of coenzyme A (CoA) to a high concentration, such that free CoA gradients to the cytoplasm are greater than 50 to1. For this reason, transient openings of nonselective permeability transition pores (PTP's) in the inner mitochondrial membrane can generate micromolar CoA transients in the cytoplasm without significantly depleting other mitochondrial substrates. CoA transients are then converted to acyl CoA transients because acyl CoA sythetases are limited by the prevailing free cytoplasmic CoA concentration. Numerous signaling proteins will be affected. In extreme metabolic stress, as occurs upon reoxygenation of ischemic cardiac tissue, palmitoylation of surface membrane proteins via this pathway evidently leads to their clustering in liquid ordered (Lo) membrane domains followed by their internalization as massive endocytosis (pMEND). In this context pMEND is detrimental, but preliminary data indicate that the pMEND pathway contributes to constitutive sarcolemma turnover and regulates the activities of Na/K pumps in cardiac myocytes. Using multiple mice lines with deficiencies in this pathway, as well as drugs to block PTP's, we will determine what physiological and pathological roles pMEND-related endocytosis plays in cardiac myocytes. The project will provide insight into fundamental cell regulatory mechanisms that have a high impact for an understanding of the leading cause of death in the developed world.

描述（由申请人提供）：该项目着重于新的心脏信号通路，线粒体调节细胞质调节蛋白和表面膜更新。该途径依赖于辅酶A（COA）的线粒体的积累到高浓度，从而使细胞质的游离COA梯度大于50 TO1。因此，线粒体膜中非选择性通透性过渡孔（PTP）的瞬态开口可以在不显着耗尽其他线粒体底物的情况下在细胞质中产生微摩尔COA瞬变。然后将COA瞬变转换为酰基COA瞬变，因为酰基CoA sytetass酶受到现行游离细胞质COA浓度的限制。许多信号蛋白将受到影响。在极端的代谢胁迫下，正如缺血性心脏组织的重新氧化时发生的那样，通过该途径对表面膜蛋白的棕榈酰化显然导致它们在液体排序（LO）（LO）膜结构域中的聚类，然后将其内在化作为大量的内吞作用（PMEND）。在这种情况下，PMEND是有害的，但初步数据表明，PMEND途径有助于构成肌膜转换，并调节心肌细胞中Na/K泵的活性。使用该途径中缺乏缺陷的多个小鼠线以及阻断PTP的药物，我们将确定在心肌细胞中与pmend相关的内吞作用的生理和病理学作用。该项目将提供对基本细胞调节机制的洞察力，这些机制对了解发达国家的主要死亡原因产生了很大影响。