Mitochondrial NAD kinase: function and mechanism in metabolism

线粒体 NAD 激酶：代谢中的功能和机制

基本信息

批准号：
10595014
负责人：
Kezhong Zhang
金额：
$ 37.02万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595014
关键词：
Acetylation Address Affect Anabolism Antioxidants Bioinformatics Carnitine Development Electrons Energy Metabolism Enzymes Equilibrium Fatty Liver Generations Genes Genetic Transcription Genetically Engineered Mouse Goals Hepatic High Fat Diet Homeostasis Human Insulin Resistance Knockout Mice Knowledge Link Liver Liver Mitochondria Lysine Maintenance Mechanics Metabolic Metabolic Diseases Metabolism Mitochondria Mitochondrial Diseases Modification Molecular Mus Names Nicotinamide adenine dinucleotide Non-Insulin-Dependent Diabetes Mellitus Nutritional Organelles Overnutrition Oxidation-Reduction Pathology Pathway interactions Patients Phenocopy Phosphorylation Phosphotransferases Physiology Plasma Play Population Prevention Production Protein Acetylation Protein Kinase Protein S Reducing diet Repression Research Resistance Role Shapes Signal Transduction Sirtuins Stress Symptoms Testing United States burden of illness cofactor in vivo insulin sensitivity mitochondrial membrane new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel preservation prevent reconstitution risk mitigation

项目摘要

Project Summary Dysregulated energy metabolism is intrinsically linked to the development of metabolic disorders, such as non-alcoholic steatohepatitis (NASH) and type 2 diabetes mellitus (T2DM). As universal electron carriers, both nicotinamide adenine dinucleotide (NAD) and its phosphorylated form (NADP) play essential roles in energy metabolism. The NAD kinase (NADK), which phosphorylates NAD to generate NADP, is exquisitely sensitive to nutritional or stress signals. While the cytosolic NADK has been characterized, little is known about generation and maintenance of NADP from mitochondria, the central organelle responsible for metabolic process and energy production, until our recent discovery that the uncharacterized human gene C5ORF33 encodes the long- sought mitochondrial NADK, referred to as MNADK. We have shown that MNADK, as a nutritionally-regulated, liver-enriched mitochondrial NADK, functions as the only de novo mitochondrial NADP biosynthesis pathway. Recently, we accumulated strong preliminary evidence that MNADK is required to maintain energy homeostasis, redox state, and insulin sensitivity and that repression of MNADK activity by protein S-nitrosylation modification under the high-fat diet is largely responsible for hepatic steatosis and insulin resistance induced by overnutrition. MNADK functions as a key regulator of acetylation of major metabolic transcriptional regulators. These observations lead us to hypothesize that MNADK is required to maintain energy homeostasis and insulin sensitivity and that repression of MNADK activity by overnutrition critically contributes to the development of NASH and T2DM. Mechanically, MNADK not only plays major roles in maintaining mitochondrial function and anti-oxidative protection, but also functions as a key regulator of acetylation of major mitochondrial regulators or enzymes that shape metabolic adaptability following metabolic challenges. In this application, we will utilize molecular and cellular approaches, genetically-engineered mouse models, as well as bioinformatics to critically address the functions and mechanisms by which the sole mitochondrial NAD kinase, MNADK, maintains energy homeostasis and protects from metabolic disorders. Our goal will be achieved by two aims: Aim 1, to determine the functional significance of MNADK in preserving hepatic energy homeostasis and thus mitigating the risk of metabolic disorders; and Aim 2, to decipher the molecular mechanism by which MNADK maintains mitochondrial function and energy metabolism. Upon completion of this project, we will have defined the function and mechanism by which the mitochondria NAD kinase preserves energy homeostasis and thus mitigates the risk of metabolic disease. Our proposed research will not only open a new paradigm for the study on molecular basis underlying energy metabolism, but also have important implications in the prevention and treatment of metabolic disease.

项目概要能量代谢失调与代谢紊乱的发展有着内在的联系，例如如非酒精性脂肪性肝炎 (NASH) 和 2 型糖尿病 (T2DM)。作为通用电子载体，烟酰胺腺嘌呤二核苷酸 (NAD) 及其磷酸化形式 (NADP) 在能量方面发挥着重要作用代谢。 NAD 激酶 (NADK) 可磷酸化 NAD 生成 NADP，对营养或压力信号。虽然胞质 NADK 已被表征，但对其生成知之甚少 NADP 的维持来自线粒体，线粒体是负责代谢过程的中央细胞器，能量生产，直到我们最近发现未表征的人类基因 C5ORF33 编码长- 寻找线粒体NADK，简称MNADK。我们已经证明 MNADK 作为一种营养调节剂，肝脏富集的线粒体 NADK，作为唯一的从头线粒体 NADP 生物合成途径。最近，我们积累了强有力的初步证据，证明 MNADK 是维持能量稳态所必需的，氧化还原状态、胰岛素敏感性以及通过蛋白质 S-亚硝基化修饰抑制 MNADK 活性高脂肪饮食在很大程度上是造成肝脏脂肪变性和营养过剩诱发胰岛素抵抗的原因。 MNADK 是主要代谢转录调节因子乙酰化的关键调节因子。这些观察结果使我们推测 MNADK 是维持能量稳态和胰岛素所必需的敏感性以及营养过剩对 MNADK 活性的抑制对于发展 NASH 和 T2DM。从机械角度来看，MNADK 不仅在维持线粒体功能方面发挥着重要作用，抗氧化保护，而且还充当主要线粒体调节因子乙酰化的关键调节因子或在代谢挑战后塑造代谢适应性的酶。在此应用中，我们将利用分子和细胞方法，基因工程小鼠模型以及生物信息学，批判性地解决唯一的功能和机制线粒体 NAD 激酶 MNADK 可维持能量稳态并防止代谢紊乱。我们的该目标将通过两个目标来实现：目标 1，确定 MNADK 在保护肝脏方面的功能意义能量稳态，从而降低代谢紊乱的风险；目标 2，破译分子 MNADK 维持线粒体功能和能量代谢的机制。完成此操作后项目中，我们将定义线粒体 NAD 激酶保存的功能和机制能量稳态，从而降低代谢疾病的风险。我们提出的研究不仅将开放为研究能量代谢的分子基础提供了新的范式，同时也具有重要意义对预防和治疗代谢性疾病的影响。