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:
    10117233
  • 负责人:
  • 金额:
    $ 47.58万
  • 依托单位:
  • 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

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.
PI的实验室在2010年发现了线粒体叶酸酶ALDH1L2的生理作用,目前还没有得到很好的理解。该酶催化反应:NADP+ + 10-甲酰基四氢叶酸→NADPH + CO2 +四氢叶酸,这对于叶酸结合的一碳基团氧化产生线粒体NADPH很重要。为了支持这一功能,我们最近的基因敲除实验表明,小鼠中Aldh1l2的缺失会导致氧化应激增加。此外,Aldh1l2-/-小鼠发生溃疡性皮炎,脾脏高度扩大(4倍),代谢型广泛改变。这些表型的机制基础目前尚不清楚,但鉴于最近鉴定出患有罕见神经皮肤病或自闭症谱系障碍的ALDH1L2突变患者,其具有临床相关性。我们对患者成纤维细胞的代谢组学分析发现,细胞脂质库发生了巨大变化,其结果很可能是由线粒体辅酶a依赖性脂肪酸代谢受损引起的。这导致线粒体功能障碍,表现为能量产生不足和氧化应激。进一步支持这一机制的是,来自aldh1l2缺陷患者的成纤维细胞线粒体碎片化,并显示脂滴积聚。重要的是,这些成纤维细胞中ALDH1L2酶的恢复挽救了表型和代谢型,使这些细胞与健康个体的成纤维细胞相似。基于这些发现,我们假设ALDH1L2在细胞中具有独特的代谢功能,通过与叶酸循环相关的线粒体NADPH生成来维持氧化还原状态。ALDH1L2的缺失导致线粒体功能障碍、能量失衡和氧化应激。因此,ALDH1L2基因的有害突变是线粒体相关人类疾病的潜在原因。本提案将通过以下目的确定ALDH1L2在细胞代谢中的作用,并将其突变与人类疾病的致病因素联系起来:(1)验证ALDH1L2维持线粒体氧化还原平衡并控制辅酶A生物合成和脂肪酸氧化的假设。(2)明确ALDH1L2在能量产生或线粒体之间的单碳基团分配到细胞质穿梭中的作用。(3)确立ALDH1L2缺乏是人类罕见遗传病的病因,并探讨其机制。现在很清楚,线粒体功能障碍是许多疾病病理生理学的一个重要组成部分,以前没有发现。ALDH1L2在维持线粒体功能以及线粒体相关疾病中的作用在很大程度上尚未被探索。该建议将填补这一知识空白,并将为ALDH1L2在人类疾病中的作用提供机制见解。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

SERGEY A KRUPENKO其他文献

SERGEY A KRUPENKO的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('SERGEY A KRUPENKO', 18)}}的其他基金

Mechanistic and metabolomic underpinnings of ALDH1L1 polymorphisms in the regulation of glycine metabolism
ALDH1L1 多态性调节甘氨酸代谢的机制和代谢组学基础
  • 批准号:
    10297073
  • 财政年份:
    2021
  • 资助金额:
    $ 47.58万
  • 项目类别:
Mechanistic and metabolomic underpinnings of ALDH1L1 polymorphisms in the regulation of glycine metabolism
ALDH1L1 多态性调节甘氨酸代谢的机制和代谢组学基础
  • 批准号:
    10870688
  • 财政年份:
    2021
  • 资助金额:
    $ 47.58万
  • 项目类别:
Mechanistic and metabolomic underpinnings of ALDH1L1 polymorphisms in the regulation of glycine metabolism
ALDH1L1 多态性调节甘氨酸代谢的机制和代谢组学基础
  • 批准号:
    10663183
  • 财政年份:
    2021
  • 资助金额:
    $ 47.58万
  • 项目类别:
Mechanistic and metabolomic underpinnings of ALDH1L1 polymorphisms in the regulation of glycine metabolism
ALDH1L1 多态性调节甘氨酸代谢的机制和代谢组学基础
  • 批准号:
    10453683
  • 财政年份:
    2021
  • 资助金额:
    $ 47.58万
  • 项目类别:
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
  • 批准号:
    10597021
  • 财政年份:
    2019
  • 资助金额:
    $ 47.58万
  • 项目类别:
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
  • 批准号:
    10372093
  • 财政年份:
    2019
  • 资助金额:
    $ 47.58万
  • 项目类别:
FDH: A Novel Determinant of Tumor Suppression
FDH:肿瘤抑制的新决定因素
  • 批准号:
    8895055
  • 财政年份:
    2014
  • 资助金额:
    $ 47.58万
  • 项目类别:
Mechanism of action of a major folate enzyme
主要叶酸酶的作用机制
  • 批准号:
    8013378
  • 财政年份:
    2010
  • 资助金额:
    $ 47.58万
  • 项目类别:
FDH: A Novel Determinant of Tumor Suppression
FDH:肿瘤抑制的新决定因素
  • 批准号:
    7017706
  • 财政年份:
    2005
  • 资助金额:
    $ 47.58万
  • 项目类别:
FDH: A Novel Determinant of Tumor Suppression
FDH:肿瘤抑制的新决定因素
  • 批准号:
    7558315
  • 财政年份:
    2005
  • 资助金额:
    $ 47.58万
  • 项目类别:

相似海外基金

Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
  • 批准号:
    BB/Y006380/1
  • 财政年份:
    2024
  • 资助金额:
    $ 47.58万
  • 项目类别:
    Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
  • 批准号:
    24K17112
  • 财政年份:
    2024
  • 资助金额:
    $ 47.58万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
  • 批准号:
    2300890
  • 财政年份:
    2023
  • 资助金额:
    $ 47.58万
  • 项目类别:
    Continuing Grant
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
  • 批准号:
    23K06918
  • 财政年份:
    2023
  • 资助金额:
    $ 47.58万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
  • 批准号:
    23K05758
  • 财政年份:
    2023
  • 资助金额:
    $ 47.58万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
  • 批准号:
    23K04668
  • 财政年份:
    2023
  • 资助金额:
    $ 47.58万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
  • 批准号:
    2888395
  • 财政年份:
    2023
  • 资助金额:
    $ 47.58万
  • 项目类别:
    Studentship
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
  • 批准号:
    10761044
  • 财政年份:
    2023
  • 资助金额:
    $ 47.58万
  • 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
  • 批准号:
    10728925
  • 财政年份:
    2023
  • 资助金额:
    $ 47.58万
  • 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
  • 批准号:
    10757309
  • 财政年份:
    2023
  • 资助金额:
    $ 47.58万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了