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）：该项目重点研究一种新的心脏信号传导途径，线粒体通过该途径调节细胞质调节蛋白和表面膜周转。该途径依赖于线粒体将辅酶 A (CoA) 积累到高浓度，使得游离 CoA 到细胞质的梯度大于 50:1。因此，线粒体内膜中非选择性通透性转换孔 (PTP) 的瞬时打开可以在细胞质中产生微摩尔 CoA 瞬变，而不会显着耗尽其他线粒体底物。然后 CoA 瞬态转化为酰基 CoA 瞬态，因为酰基 CoA 合成酶受到普遍的游离细胞质 CoA 浓度的限制。许多信号蛋白将受到影响。在极端代谢应激下，如缺血心脏组织再氧合时发生的情况，表面膜蛋白通过该途径的棕榈酰化显然导致它们聚集在液体有序（Lo）膜域中，然后以大量内吞作用（pMEND）的形式内化。在这种情况下，pMEND 是有害的，但初步数据表明 pMEND 途径有助于组成性肌膜周转并调节心肌细胞中 Na/K 泵的活动。使用该途径存在缺陷的多个小鼠系以及阻断 PTP 的药物，我们将确定 pMEND 相关内吞作用在心肌细胞中发挥的生理和病理作用。该项目将提供对基本细胞调节机制的深入了解，这些机制对于了解发达国家的主要死亡原因具有重大影响。