Changes in Coenzyme A Levels are a Key Mechanism Regulating Metabolic Pathways

辅酶 A 水平的变化是调节代谢途径的关键机制

基本信息

批准号：
10795389
负责人：
Roberta Leonardi
金额：
$ 12.43万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2026-05-31
项目状态：
未结题

项目摘要

Project Summary Coenzyme A (CoA) is an essential cofactor and the major acyl group carrier in mammalian cells. CoA plays a central and regulatory role in energy metabolism, as its acyl-CoA derivatives are substrates for hundreds of metabolic reactions and the posttranslational modification of histones and key metabolic enzymes. CoA- dependent processes occur in multiple subcellular compartments, and major pools of CoA are found in the mitochondria, peroxisomes and cytosol. At the whole tissue level, the concentration of CoA is tightly regulated and dynamically adjusted to changes in the metabolic state. The importance of such a tight control over CoA levels is underscored by the fact that genetic manipulations that force the concentration of CoA outside of its homeostatic range result in loss of metabolic regulation and organ function. For example, the inability to increase CoA levels during a fast blunts fatty acid oxidation and gluconeogenesis in the liver, causing fasting hypoglycemia. On the other hand, an abnormally high concentration of CoA in skeletal muscle is associated with decreased muscle mass, ATP levels and exercise performance, highlighting the importance of mechanisms that prevent the accumulation of this cofactor to toxic levels. The concentration of CoA is regulated by balancing its synthesis and degradation. The process of CoA degradation is poorly characterized. Furthermore, the mechanisms that regulate the different subcellular CoA pools are incompletely understood. During the previous funding cycle, we have characterized the biochemical and regulatory properties of two CoA-degrading enzymes, NUDT7 and NUDT19, which reside in liver and kidney peroxisomes, respectively. Our published and unpublished observations support the conclusion that these enzymes regulate peroxisomal lipid metabolism. Furthermore, deletion of Nudt19 leads to the accumulation of 3-hydroxy-3-methylglutaryl-CoA in the kidneys, suggesting a connection to cholesterol synthesis. We also identified the first mammalian CoA-degrading enzyme, NUDT8, which resides in the mitochondria, and we have recently generated Nudt8-/- mice. The existence of CoA- degrading enzymes in both peroxisomes and mitochondria suggests that these enzymes contribute to the regulation of the CoA pools within these organelles. The long-term goal of our research program is to understand the mechanisms that regulate tissue CoA levels and to harness them to manipulate the metabolic network for the treatment or prevention of metabolic disorders. To move toward this goal, we propose to 1) determine the mechanisms through which NUDT19 regulates kidney lipid metabolism and kidney function and 2) determine the role played by NUDT8 in the regulation of the mitochondrial CoA pool and mitochondrial metabolism. This research program will advance our understanding of the mechanisms that regulate the peroxisomal and mitochondrial CoA pools. Furthermore, identifying the processes regulated by each CoA-degrading enzyme will aid in the development of strategies to target and correct specific CoA-dependent pathways in metabolic disorders.

项目摘要辅酶A（COA）是哺乳动物细胞中必不可少的辅因子和主要的酰基载体。 COA扮演a 由于其酰基-COA衍生物是数百种的底物，因此中心和调节作用在能量代谢中代谢反应以及组蛋白和关键代谢酶的翻译后修饰。 co 依赖过程发生在多个亚细胞室中，并且在线粒体，过氧化物酶体和细胞质。在整个组织水平上，COA的浓度受到严格调节并动态调整为代谢状态的变化。如此严格控制COA的重要性水平强调了以下事实：迫使COA集中的遗传操作在其之外稳态范围导致代谢调节和器官功能的丧失。例如，无法增加在快速钝的脂肪酸氧化和肝脏中的脂肪酸氧化和糖异生期间的COA水平，导致禁食低血糖。另一方面，骨骼肌中异常高的COA与肌肉质量，ATP水平和运动表现降低，强调了机制的重要性防止该辅助因子的积累到有毒水平。 COA的浓度通过平衡其平衡来调节合成和降解。 COA降解过程的特征很差。此外，调节不同亚细胞COA池的机制尚不完全理解。在上一个资金周期，我们已经表征了两种CoA降解酶的生化和调节特性， NUDT7和NUDT19分别存在于肝脏和肾脏过氧化物酶体中。我们出版和未出版的观察结果支持这些酶调节过氧化物酶体脂质代谢的结论。此外， NUDT19的删除导致肾脏中3-羟基-3-甲基戊二酰-COA的积累，这表明A 与胆固醇合成的连接。我们还确定了第一个哺乳动物CoA降解酶，NUDT8，它位于线粒体中，我们最近产生了NUDT8 - / - 小鼠。存在的存在过氧化物酶体和线粒体中的降解酶表明这些酶有助于该酶这些细胞器中的COA池的调节。我们研究计划的长期目标是了解调节组织COA水平并利用它们来操纵代谢网络的机制治疗或预防代谢疾病。为了朝着这个目标迈进，我们建议1）确定 NUDT19调节肾脏脂质代谢和肾功能的机制，2） NUDT8在线粒体COA池和线粒体代谢的调节中所扮演的角色。这研究计划将促进我们对调节过氧化物酶体和的机制的理解线粒体COA池。此外，确定每个CoA降解酶调节的过程将帮助制定代谢中针对和纠正特定COA依赖途径的策略疾病。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hemin and iron increase synthesis and trigger export of xanthine oxidoreductase from hepatocytes to the circulation.

DOI：
10.1016/j.redox.2023.102866
发表时间：
2023-11
期刊：
REDOX BIOLOGY
影响因子：
11.4
作者：
Devallance, Evan R.;Schmidt, Heidi M.;Seman, Madison;Lewis, Sara E.;Wood, Katherine C.;Vickers, Schuyler D.;Hahn, Scott A.;Velayutham, Murugesan;Hileman, Emily A.;Vitturi, Dario A.;Leonardi, Roberta;Straub, Adam C.;Kelley, Eric E.
通讯作者：
Kelley, Eric E.

Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes.

DOI：
10.3791/62904
发表时间：
2021-09-09
期刊：
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
影响因子：
1.2
作者：
Vickers, Schuyler D.;Saporito, Dominique C.;Leonardi, Roberta
通讯作者：
Leonardi, Roberta

Acyl-CoA thioesterase-2 facilitates β-oxidation in glycolytic skeletal muscle in a lipid supply dependent manner.

酰基辅酶 A 硫酯酶 2 以脂质供应依赖的方式促进糖酵解骨骼肌中的 β 氧化。

DOI：
10.1101/2023.06.27.546724
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Bekeova,Carmen;Han,JiIn;Xu,Heli;Kerr,Evan;Blackburne,Brittney;Lynch,ShannonC;Mesaros,Clementina;Murgia,Marta;Vadigepalli,Rajanikanth;Beld,Joris;Leonardi,Roberta;Snyder,NathanielW;Seifert,ErinL
通讯作者：
Seifert,ErinL