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: 10418364
• 负责人: Kezhong Zhang
• 金额: $ 38.63万
• 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/10418364
• 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; Lead; Link; Liver; Lysine; Maintenance; Mechanics; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Diseases; Modification; Molecular; Mus; NAD+ kinase; NADP; Names; Nicotinamide adenine dinucleotide; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Organelles; Overnutrition; Oxidation-Reduction; Pathology; Pathway interactions; Patients; Phenocopy; Phosphotransferases; Physiology; Plasma; Play; Population; Prevention; Production; Protein Acetylation; Protein Kinase; Protein S; Reducing diet; Repression; Research; Resistance; Risk; Role; SKIL gene; 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

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紊乱的发生有内在联系，例如 非酒精性脂肪性肝炎（NASH）和2型糖尿病（T2 DM）。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）在能量代谢中起重要作用 新陈代谢.磷酸化NAD以产生NADP的NAD激酶（NADK）对 营养或压力信号。虽然胞质NADK已被表征，但关于其生成的知之甚少。 和维持NADP从线粒体，中央细胞器负责代谢过程， 能源生产，直到我们最近发现，未表征的人类基因C5 ORF 33编码长- 寻找线粒体NADK，简称MNADK。我们已经表明，MNADK，作为一种营养调节， 肝脏富集的线粒体NADK，作为唯一的从头线粒体NADP生物合成途径发挥作用。 最近，我们积累了强有力的初步证据，MNADK是维持能量稳态所必需的， 氧化还原状态与胰岛素敏感性及蛋白质S-亚硝基化修饰对MNADK活性抑制 在高脂饮食下的高脂饮食是导致肝脏脂肪变性和营养过剩引起的胰岛素抵抗的主要原因。 MNADK作为主要代谢转录调节因子乙酰化的关键调节因子发挥作用。这些 观察使我们假设MNADK是维持能量稳态和胰岛素分泌所必需的。 敏感性和MNADK活性被营养过剩抑制， NASH和T2 DM。在机械上，MNADK不仅在维持线粒体功能中起主要作用， 抗氧化保护，而且还作为主要线粒体调节因子乙酰化的关键调节因子， 在代谢挑战后形成代谢适应性的酶。 在本申请中，我们将利用分子和细胞方法， 模型，以及生物信息学，以批判性地解决功能和机制，其中唯一的 线粒体NAD激酶，MNADK，维持能量稳态并防止代谢紊乱。我们 本研究的目的有两个：目的1，确定MNADK在肝脏保存中的功能意义， 能量稳态，从而减轻代谢紊乱的风险;目标2，破译分子 MNADK维持线粒体功能和能量代谢的机制。在完成此 项目，我们将确定线粒体NAD激酶保护的功能和机制， 能量稳态，从而减轻代谢疾病的风险。我们提议的研究不仅将开放 为能量代谢的分子基础研究提供了新的范式，但也具有重要的意义。 在预防和治疗代谢性疾病方面的意义。