Regulation of mitochondrial function by folate enzyme ALDH1L2 in health and disease

叶酸酶 ALDH1L2 在健康和疾病中对线粒体功能的调节

基本信息

批准号：
10372093
负责人：
SERGEY A KRUPENKO
金额：
$ 47.58万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372093
关键词：
Acids Amino Acids Anabolism Animal Model Carbon Carbon Dioxide Cell Maintenance Cells Coenzyme A Cytoplasm Dermatitis Diagnosis Diet Disease Enzymes Equilibrium Etiology Fathers Fibroblasts Folic Acid Folic Acid Deficiency Formyltetrahydrofolates Functional disorder Gene Duplication Generations Genes Glutathione Disulfide Health High Fat Diet Human Hydrolase Impairment Individual Knockout Mice Knowledge Link Lipids Maintenance Mediating Metabolic Metabolism Mitochondria Mus Mutation NADP Neurologic Outcome Oxidation-Reduction Oxidative Stress Pathway interactions Patients Phenotype Physiological Pilot Projects Play Production Reaction Regulation Role Sjogren-Larsson Syndrome Spleen Sulfhydryl Compounds Syndrome Testing Tetrahydrofolates Ulcer autism spectrum disorder base cell type clinically relevant diet-induced obesity dietary experimental study fatty acid metabolism fatty acid oxidation folic acid metabolism human disease insight knockout gene metabolic phenotype metabolomics mitochondrial dysfunction mutant oxidation rare genetic disorder response restoration

项目摘要

The physiological role of the mitochondrial folate enzyme ALDH1L2, discovered by the PI's lab in 2010, is not well understood. This enzyme catalyzes the reaction: NADP+ + 10-formyltetrahydrofolate → NADPH + CO2 + tetrahydrofolate, which can be important for the mitochondrial NADPH production from the oxidation of folate- bound one-carbon groups. In support of this function, our recent gene knockout experiments show that deletion of Aldh1l2 in mice causes increased oxidative stress. Furthermore, Aldh1l2-/- mice develop ulcerative dermatitis, and have highly enlarged (4-fold) spleen and extensively altered metabotype. The mechanistic basis underlying these phenotypes is currently unknown but has clinical relevance given the recent identification of patients with ALDH1L2 mutations who were diagnosed with a rare neurocutaneous disease or autistic spectrum disorder. Our metabolomics analysis of patient's fibroblasts identified dramatic changes in the cellular lipid repertoire, the outcome most likely caused by the impairment of mitochondrial CoA-dependent fatty acid metabolism. This leads to mitochondrial dysfunction, which is manifested as insufficient energy production and oxidative stress. In further support of this mechanism, fibroblasts from ALDH1L2-deficient patients have fragmented mitochondria and show the accumulation of lipid droplets. Importantly, the restoration of the ALDH1L2 enzyme in these fibroblasts rescues the phenotype and metabotype, making these cells similar to fibroblasts from healthy individuals. Based on these findings, we hypothesize that ALDH1L2 serves distinct metabolic function in the cell, the maintenance of redox state through the mitochondrial NADPH generation linked to the folate cycle. The loss of ALDH1L2 leads to mitochondrial dysfunction, energy disbalance and oxidative stress. Thus, deleterious mutations in the ALDH1L2 gene are underlying cause of mitochondria-related human disorders/diseases. This proposal will determine the role of ALDH1L2 in cellular metabolism and will link its mutations as causative factor of human diseases through the following aims: (1) Test the hypothesis that ALDH1L2 maintains mitochondrial redox balance and controls coenzyme A biosynthesis and fatty acid oxidation. (2) Define the role of ALDH1L2 in partitioning of one-carbon groups between energy production or mitochondria to cytoplasm shuttling. (3) Establish ALDH1L2 deficiency as the cause of rare genetic disorders in humans and explore underlying mechanisms. It is now clear that mitochondrial dysfunction is an important component in the pathophysiology of numerous diseases that had not been previously identified. The role of ALDH1L2 in maintenance of mitochondrial function, as well as in mitochondria-related diseases, is largely unexplored. This proposal will fill this knowledge gap and will provide mechanistic insight into the role of ALDH1L2 in human diseases.

线粒体叶酸酶Aldh1l2的硫代粒子作用：NADP + + 10型甲基甲基四氢叶酸盐→NADPH + CO2 +四氢叶酸盐，这对于来自氧化氧化氧化物 - 碳纤维组的线粒体NADPH生产可能很重要。小鼠的基因敲除实验会增加氧化应激罕见的神经性疾病或自动谱系的代谢组学分析。缺陷有分散的线粒体，并恢复了脂质液滴的积累。线粒体的nADPH生成叶酸周期。）假设ALDH1L2在能量产生或米奇氏菌之间的脂肪酸氧化和脂肪酸氧化之间维持了线粒体平衡的生物合成。已经被授予了ALDH1L2的作用，以及与线粒体相关的SES的作用，在很大程度上没有探索。