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Cocaine upregulates mitochondria-derived vesicular pathway for selective removal of oxidized cargo

可卡因上调线粒体衍生的囊泡途径，选择性去除氧化物质

基本信息

批准号：
10202546
负责人：
Natarajaseenivasan Kalimuthusamy
金额：
$ 19.81万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202546
关键词：
Astrocytes Autophagocytosis Bacteria Behavioral Bioenergetics Biological Assay Blood Brain Cardiac Cell Death Cells Charge Cocaine Cocaine Abuse Complex Coupling Cytoplasm Data Destinations Disease Electron Microscopy Excision Generations Glucose Goals Homeostasis Housekeeping Impairment In Vitro Intervention Label Lipids Lysosomes Mass Spectrum Analysis Mediating Metabolic Metabolism Microscopy Mitochondria Mitochondrial Proteins Multivesicular Body Nature Nerve Degeneration Neuraxis Neuronal Dysfunction Neurons Organelles Oxidative Phosphorylation Oxidative Stress Oxides Pathway interactions Peripheral Process Production Proteins Proteolysis Public Health Quality Control Rattus Reactive Oxygen Species Role SNAP receptor Signal Transduction Surveys Synapses Testing Time Tissues Toxic effect Transmission Electron Microscopy Vesicle base carbonyl group cocaine exposure cocaine use extracellular fatty acid oxidation high reward high risk late endosome lipophilicity neuronal survival neurotoxic neurotransmission novel novel strategies oxidative damage peroxisome prevent protein complex response syntaxin uptake vesicular release

项目摘要

Mitochondria are dynamic organelles that have a central role in cellular metabolism. Our preliminary data show that astrocytes, when exposed to cocaine, increase the OXPHOS activity leading to generation of mitochondrial reactive oxygen species (mROS). Conversely, the increased generation of mROS was not accompanied by mitochondrial depolarization, mitophagy or cell death. Based on these observations, we hypothesize that another mechanism of steady-state removal of oxidized mitochondrial protein complexes facilitated astrocytic activation, proliferation and survival and may disrupt the neuron-glia signaling, thereby contributing to synaptic impairment in the central nervous system during cocaine abuse. The current proposal will focus on identifying the mitochondrial quality control mechanism in astrocytes responsible for cocaine-induced changes. Mitochondrial quality control is an essential process required to clear the accumulation of unfolded, oxidized or otherwise damaged proteins and lipids from the organelle. As the “energy powerhouse”, mitochondria depend on several different pathways that continually survey for damage. Apart from the well-characterized pathways including constitutive mitochondrial proteolysis and mitophagy, recent studies uncovered a novel mitochondrial quality control pathway, conserved from bacteria, in which mitochondria release small, mitochondrial-derived vesicles (MDVs). In this context, we observed rapid formation of MDVs in astrocytes exposed to cocaine, suggesting MDV formation as an essential housekeeping mechanism and a first line of defense against cocaine-induced toxicity in astrocytes. Our high risk/high reward approach is (i) to observe the formation MDVs in steady state, (ii) analyze the cargo selectivity, (iii) characterize distinct MDV pools, and (iv) identify the final delivery destination (ie., transport to lysosomes or peroxisomes) in the presence of cocaine. Our long-term goal is to understand how MDVs comprise a quantitative and highly selective pathway utilized for mitochondrial quality control during cocaine use to provide a platform for future research and intervention.

线粒体是在细胞代谢中具有中心作用的动态细胞器。我们的初步数据显示，当暴露于可卡因时，星形胶质细胞增加OXPHOS活性，导致产生线粒体活性氧（mROS）。相反，mROS的产生增加并不伴随线粒体去极化、线粒体自噬或细胞死亡。根据这些观察，我们假设氧化线粒体蛋白复合物稳态去除的另一种机制促进星形胶质细胞的活化、增殖和存活，并可能破坏神经元-胶质细胞信号传导，导致可卡因滥用期间中枢神经系统的突触损伤。现时的建议将集中于确定负责可卡因诱导的变化的星形胶质细胞中的线粒体质量控制机制。线粒体的质量控制是清除线粒体内脂质积聚所必需的一个重要过程。未折叠的、氧化的或以其他方式受损的蛋白质和脂质从细胞器中分离出来。作为"能源强国"，线粒体依赖于几个不同的途径，不断调查损害。除了包括组成性线粒体蛋白水解和线粒体自噬在内的特征性途径外，发现了一种新的线粒体质量控制途径，从细菌中保存下来，其中线粒体释放小的尿道衍生囊泡（MDV）。在这种情况下，我们观察到MDV在暴露于可卡因的星形胶质细胞，表明MDV的形成是一种重要的管家机制，第一道防线对可卡因诱导的毒性星形胶质细胞。我们的高风险/高回报方法是（i）观察稳定状态下MDV的形成，（ii）分析货物选择性，（iii）表征不同的MDV 池，以及（iv）识别最终递送目的地（即，运输到溶酶体或过氧化物酶体）可卡因的存在。我们的长期目标是了解MDV是如何构成一个定量的、高度相关的在可卡因使用期间用于线粒体质量控制的选择性途径，为未来的研究提供平台。研究和干预。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MicroRNAs as Regulators of Cancer Cell Energy Metabolism.

DOI：
10.3390/jpm12081329
发表时间：
2022-08-18
期刊：
JOURNAL OF PERSONALIZED MEDICINE
影响因子：
0
作者：
Suriya Muthukumaran, Natarajaseenivasan;Velusamy, Prema;Akino Mercy, Charles Solomon;Langford, Dianne;Natarajaseenivasan, Kalimuthusamy;Shanmughapriya, Santhanam
通讯作者：
Shanmughapriya, Santhanam

Mitochondrial Magnesium is the cationic rheostat for MCU-mediated mitochondrial Ca2+ uptake.

线粒体镁是 MCU 介导的线粒体 Ca2 摄取的阳离子变阻器。

DOI：
10.21203/rs.3.rs-3088175/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Ponnusamy,Thiruvelselvan;Velusamy,Prema;Kumar,Amrendra;Morris,Daniel;Zhang,Xueqian;Ning,Gang;Klinger,Marianne;Copper,JeanE;Rajan,Sudarsan;Cheung,JosephY;Natarajaseenivasan,Kalimuthusamy;Mnatsakanyan,Nelli;Shanmughapriya,Santhana
通讯作者：
Shanmughapriya,Santhana

Cardiac Metabolism and MiRNA Interference.