Mitochondrial NAD kinase: function and mechanism in metabolism

线粒体 NAD 激酶：代谢中的功能和机制

• 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
• 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

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.

项目摘要 能量代谢失调与代谢性疾病的发展本质上有关 作为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， 烟酰胺腺苷二核苷酸（NAD）及其磷酸化形式（NADP）在能量中起着重要作用 代谢。 NAD激酶（NADK）磷酸化NAD生成NADP，对 营养或应力信号。虽然胞质nadk的特征很少，但对世代知之甚少 并维护来自线粒体的NADP，负责代谢过程的中央细胞器和 能源生产，直到我们最近发现，未表征的人类基因C5orf33编码了长期 寻求线粒体nadk，称为Mnadk。我们已经表明，姆纳克（Mnadk 富含肝脏的线粒体NADK是唯一的从头线粒体NADP生物合成途径。 最近，我们积累了有力的初步证据，表明姆纳克必须维持能量稳态， 氧化还原状态和胰岛素敏感性以及蛋白质S-硝基化修饰对MNADK活性的抑制 在高脂饮食下，在很大程度上负责肝营养不良引起的肝脂肪变性和胰岛素抵抗。 MNADK是主要代谢转录调节剂的乙酰化的关键调节剂。这些 观察结果导致我们假设MNADK需要维持能量稳态和胰岛素 敏感性和通过养营对MNADK活性的抑制作用，对 纳什和T2DM。机械上，姆纳克不仅在维持线粒体功能和 抗氧化保护，但也是主要线粒体调节剂乙酰化的关键调节剂 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，遗传工程的小鼠 模型以及生物信息学，以严格解决唯一的功能和机制 线粒体NAD激酶（MNADK）保持能量稳态，并防止代谢疾病。我们的 目标将通过两个目标来实现：目标1，以确定姆纳克在保存肝的功能意义 能量稳态，从而减轻代谢疾病的风险；目标2，破译分子 MNADK维持线粒体功能和能量代谢的机制。完成此任务后 项目，我们将定义线粒体NAD激酶保留的功能和机制 能量稳态，因此减轻了代谢疾病的风险。我们拟议的研究不仅会开放 基于分子基础的基础能量代谢的新范式，但也具有重要的 对预防和治疗代谢疾病的影响。